Fibrinolysis, decreased

FMA:84050

FMA Cytokine

FMA:241981

FMA Chemokine

FMA:86578

FMA Interleukin

CL:0009002

CL inflammatory cell

CL:0000235

CL macrophage

PR:000001393

PR interleukin-6

PR:000001136

PR interleukin-1 beta

PR:000000134

PR tumor necrosis factor alpha

CHEBI:82594

CHEBI Ferritin

PR:000005897

PR C-reactive protein

CL:0000542

CL lymphocyte

GO:0051918

GO negative regulation of fibrinolysis

GO:0030195

GO negative regulation of blood coagulation

MP:0003070

MP increased vascular permeability

GO:0042311

GO vasodilation

MP:0001863

MP vascular inflammation

GO:0002534

GO cytokine production involved in inflammatory response

GO:0090195

GO chemokine secretion

GO:0006956

GO complement activation

GO:0006954

GO inflammatory response

GO:0042116

GO macrophage activation

GO:0002544

GO chronic inflammatory response

GO:0002676

GO regulation of chronic inflammatory response

GO:0032635

GO interleukin-6 production

GO:0032611

GO interleukin-1 beta production

GO:1990774

GO tumor necrosis factor secretion

HP:0012649

HP Increased inflammatory response

HP:0003281

HP Increased serum ferritin

GO:0004457

GO lactate dehydrogenase activity

HP:0011227

HP Elevated C-reactive protein level

HP:0001888

HP Lymphopenia

WIKI increased

WIKI decreased

Sars-CoV-2 Virus from the coronaviridae family related to SARS-CoV, 229E, NL63, OC43, HKU1 and MERS.

Transmitted by aerosols

2021-02-23T04:50:40

2022-09-09T05:09:36

nanoparticles

2016-12-21T09:40:06

nanomaterials

2021-04-22T09:28:39

Titanium dioxide nanoparticles

2022-08-29T08:22:45

Iron nanoparticles

2022-08-29T08:23:04

SARS-CoV

2020-03-01T10:42:46

WCS_9606

common toxicological species human

10090

NCBI mouse

10116

NCBI rats

WCS_9606

common toxicological species humans

Fibrinolysis, decreased

Hypofibrinolysis

Molecular

Background Fibrinolysis is an essential and highly regulated physiological process resulting in the enzymatic breakdown of intravascular fibrin in blood clots. The process prevents extensive fibrin deposition and  facilitates the degradation of thrombi and microthrombi in any affected organ. Fibrinolysis occurs both within the thrombi, where fibrin strands provide a surface for binding plasminogen (precursor of the primary fibrinolysin, plasmin), as well as on interaction with endothelial cell surfaces.  There are many known disorders of fibrinolysis, including congenital and acquired conditions which can result in inadequate or excessively active fibrinolytic pathways. Acquired disorders resulting in hypofibrinolysis include numerous acute and chronic conditions; malignancy, hypothyroidism, autoimmune disorders and alcoholic liver disease (<a href="https://pubmed.ncbi.nlm.nih.gov/25294122/">10.1016/j.blre.2014.09.003</a>). Hypoxia has also been demonstrated to promote hypofribrinolysis (<a href="https://www.jci.org/articles/view/307">10.1172/JCI307</a>). Conversely, disseminated intravascular coagulation (DIC) is one of the better characterized hyperfibrinolytic disorders, associated with systemic inflammation (<a href="https://pubmed.ncbi.nlm.nih.gov/25294122/">10.1016/j.blre.2014.09.003</a>). Fibrinolytic pathways act in conjunction with processes regulating coagulation and platelet activity to regulate hemostasis.  An imbalance between coagulation and the fibrinolytic pathways leads to coagulopathy and may, if unresolved, lead to bleeding diatheses, thrombosis and inflammation (thromboinflammation).   How the KE works In normal conditions fibrinolysis begins when tissue plasminogen activator (tPA, gene <a href="http://bioregistry.io/genecards:PLAT" target="_blank">PLAT</a><a href="https://bioregistry.io/genecards:PLAT">)</a>, bound to fibrin, and urokinase (uPA, gene <a href="https://bioregistry.io/genecards:PLAU" target="_blank">PLAU</a>), expressed on the endothelium, converts plasminogen to plasmin. Plasmin breaks down fibrin (which is formed during coagulation), and resolves the fibrin clot. This process results in an increase in the formation of circulating fibrin degradation products (FDP), some of which have been associated with immune activation (Chapin & Hajjar). In addition, D-Dimers, biomarkers for thrombosis, are generated when fibrin polymers get broken down. Fibrin clot formation, activation of coagulation factor XII (FXIIa, also known as the Hageman factor, gene <a href="https://bioregistry.io/genecards:F12" target="_blank">F12</a>) and increased levels of plasminogen, as well as the activation of the bradykinin system by FXIIa-stimulated increased levels of tPA/uPA. A number of endogenous molecules act to prevent excessive clot breakdown; tPA/uPA is inhibited by plasminogen activator inhibitor 1 (PAI-1, encoded by <a href="https://bioregistry.io/genecards:SERPINE1" target="_blank">SERPINE1</a>) and C1-inhibitor (C1-INH, encoded by<a href="https://bioregistry.io/genecards:SERPING1"> SERPING1</a>) inhibits plasmin (reviewed in <a href="https://doi.org/10.1007/s12016-016-8540-0">10.1007/s12016-016-8540-0</a>). Other molecules involved in plasmin inhibition include Alpha 2 antiplasmin (encoded by<a href="https://bioregistry.io/genecards:SERPINF2"> SERPINF2</a>) and alpha 2 macroglobulin (encoded by <a href="https://bioregistry.io/genecards:A2M" target="_blank">A2M</a>), each of which contribute uniquely to the precise regulation of thrombus formation and lysis. A balance must be maintained between clot formation and clot breakdown by regulating tPA and uPA.   Fibrinolysis in various diseases, including COVID-19 Fibrinolysis is reported to be dysregulated in several pathologies, including cancer, pulmonary fibrosis, kidney disease, coronary artery disease, rheumatoid arthritis, systemic sclerosis, bone destructive disease, lupus erythematosus, Alzheimer's disease, psoriasis, endometriosis and COVID-19 (reviewed in <a href="https://dx.doi.org/10.1016%2Fj.drudis.2020.06.013">10.1016/j.drudis.2020.06.013</a>). In particular, a hypofibrinolysis state has been reported in e.g. COVID-19 patients who have developed acute respiratory distress syndrome (ARDS), which is coupled to high levels of PAI-1 (<a href="https://dx.doi.org/10.1016%2Fj.drudis.2020.06.013">10.1016/j.drudis.2020.06.013</a>). In addition, reduced levels of transcripts encoding for uPA and the uPA receptor (uPAR) have been reported in the lung tissue of patients with severe COVID-19 (<a href="http://doi.org/10.7554/eLife.64330">10.7554/eLife.64330</a>). In COVID-19, the increased levels of PAI-1 have been associated with down-regulated ACE2 activity, which leads to increased angiotensin II (Ang II), which in turn promotes activation of PAI-1 (reviewed in <a href="https://doi.org/10.3390/v13010029">10.3390/v13010029</a>).  In contrast, hyperfibrinolysis has also been reported in COVID-19 patients, based on high plasmaD-dimer (DDI) levels (<a href="http://doi.org/10.3389/fphys.2020.596057">10.3389/fphys.2020.596057</a>). Thus, in some cases SARS-COV-2 promotes activation of the coagulation cascade via tissue factor, leading to high levels of fibrin and hyperactivated fibrinolysis with increased levels of plasmin. Plasmin breaks down fibrin and causes high plasma DDI levels which maintain the hyperfibrinolytic state. In acute respiratory distress syndrome (ARDS), plasminogen-plasmin activity has been found to be increased, and the fibrinolytic system is assumed to play a role due to partial inhibition of the tPA/uPA system.

In vitro systems Whole human blood model for testing the dysregulation of fibrinolysis. The same model system allows for analysis of any kind of cross talk between blood cells and plasma proteins as reflected in the cascade system (complement, contact, coagulation, fibrinolysis systems activation etc) parameters, other plasma protein alterations and cell phenotypes (flow cytometry, cyto/chemokine generation, protein release etc) (<a href="https://doi.org/10.1016/j.biomaterials.2015.01.031">10.1016/j.biomaterials.2015.01.031</a> , <a href="https://doi.org/10.1016/j.nano.2017.12.008">10.1016/j.nano.2017.12.008</a> , <a href="https://doi.org/10.1080/14686996.2019.1625721">10.1080/14686996.2019.1625721</a>).   Near-patient systems Devices for performing viscoelastic haemostatic assays (VHA) are available in most intensive care units as a near-patient method for evaluating thrombus formation under low shear stress. Outputs of such assays are primarily used in the setting of major haemorrhage to rapidly determine the need for replacement of specific blood products. Importantly, VHA can differentiate causes of coagulopathy, for example, coagulation factor deficiency vs thrombocytopenia vs excessive fibrinolysis. VHA are also able to indicate hypercoagulability; separate outputs demonstrate the contribution of fibrinogen with and without platelet activation (<a href="https://onlinelibrary.wiley.com/doi/abs/10.1111/bjh.15524">10:1111/bjh.15524</a>). In addition, transcription profiles of e.g. human bronchial alveolar lavage (BAL) samples can be measured, with targeted analyses focused on downregulation of genes transcribing for proteins involved in the fibrinolytic cascade, e.g. uPA (<a href="https://bioregistry.io/genecards:PLAU" target="_blank">PLAU</a>), uPAR (<a href="https://bioregistry.io/genecards:PLAUR" target="_blank">PLAUR</a>) (<a href="http://doi.org/10.7554/eLife.64330">10.7554/eLife.64330</a>).

High

1. D´Alonzo et al. COVID-19 and pneumonia: a role for the uPA/uPAR system. Drug Discovery Today Volume 25, Issue 8, August 2020, Pages 1528-1534 2. Ekdahl, Kristina N et al. “A human whole-blood model to study the activation of innate immunity system triggered by nanoparticles as a demonstrator for toxicity.” Science and technology of advanced materials vol. 20,1 688-698. 24 Jun. 2019, doi:10.1080/14686996.2019.1625721  3. Bernard, I.; Limonta, D.; Mahal, L.K.; Hobman, T.C. Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19. Viruses 2021, 13, 29. <a href="https://doi.org/10.3390/v13010029">https://doi.org/10.3390/v13010029</a>  4. Mast AE, Wolberg AS, Gailani D, Garvin MR, Alvarez C, Miller JI, Aronow B, Jacobson D. SARS-CoV-2 Suppresses Anticoagulant and Fibrinolytic Gene Expression in the Lung. eLife 2021;10:e64330 DOI: 10.7554/eLife.64330 5. Curry N.S, Davenport R, Pavord S, Mallett S.V, Kitchen D, Klein A.A, Maybury H, Collins P.W, Laffan M. The use of viscoelastic haemostatic assays in the management of major bleeding - A British Society for Haematology Guideline. British Journal of Haematology. 2018. doi: 10.1111/bjh.15524  6. Chapin JC & Hajjar KA. Fibrinolysis and the control of blood coagulation. Blood Rev. 2015;29(1):17-24 7. Pinsky DJ, Liao H, Lawson CA, Yan SF, Chen J, Carmeliet P et al. Coordinated Induction of Plasminogen Activator Inhibitor-1 (PAI-1) and Inhibition of Plasminogen Activator Gene Expression by Hypoxia Promotes Pulmonary Vascular Fibrin Deposition. J Clin Invest. 1998;102(5):919-928 8. Hofman, Z., de Maat, S., Hack, C.E. et al. Bradykinin: Inflammatory Product of the Coagulation System. Clinic Rev Allerg Immunol 51, 152–161 (2016). <a href="https://doi.org/10.1007/s12016-016-8540-0">https://doi.org/10.1007/s12016-016-8540-0</a> 9. Jacob et al. COVID-19-Associated Hyper-Fibrinolysis: Mechanism and Implementations. Front. Physiol., 16 December 2020 | <a href="https://doi.org/10.3389/fphys.2020.596057">https://doi.org/10.3389/fphys.2020.596057</a>  10. Lisa E. Gralinski, Armand Bankhead III, Sophia Jeng, Vineet D. Menachery, Sean Proll, Sarah E. Belisle, Melissa Matzke, Bobbie-Jo M. Webb-Robertson, Maria L. Luna, Anil K. Shukla, Martin T. Ferris, Meagan Bolles, Jean Chang, Lauri Aicher, Katrina M. Waters, Richard D. Smith, Thomas O. Metz, G. Lynn Law, Michael G. Katze, Shannon McWeeney, Ralph S. Baric. Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury. mBio Aug 2013, 4 (4) e00271-13; DOI: 10.1128/mBio.00271-13 AOPWiki 2021-04-20T02:41:30

2021-10-19T11:33:19

Bradykinin system, hyperactivated

Bradykinin, activated

Molecular

Background Bradykinin (BK) plays an important role in the kinin-kallikrein system (<a href="https://bioregistry.io/wikipathways:WP5089">KKS</a>) as a regulator of blood pressure and can induce vasodilation, increase blood flow, as well as hypotension. BK is also an important part of the inflammatory process after injury, inducing pain stimulation, and increased vascular permeability. Hyperactivation of the BK system is associated with vasodilation and vascular leakage allowing for infiltration of inflammatory cells.   How the KE works BK is formed by the proteolytic activity of kallikrein on kininogens. Kininogens are expressed by alveolar cells (alveolar type 1.1, 1/2, 2.2., 2.3, and 2.4 cells). Plasma kallikrein (produced by the pancreas) processes high-molecular weight kininogen (<a href="https://bioregistry.io/genecards:KNG1">HMWK</a> produced by the liver) into BK, and tissue kallikrein processes low-molecular weight kininogen (LMWK produced by the liver) into Lys-BK. BK and Lys-BK are ligands for the bradykinin receptor <a href="https://bioregistry.io/genecards:BDKRB2">B2R</a> on endothelial cells, e.g. in the alveolar capillaries. Carboxypeptidases further process BK and Lys-BK into des-Arg9-BK and Lys-des-Arg9-BK respectively, which are ligands for <a href="https://bioregistry.io/genecards:BDKRB1">B1R</a> on endothelial cells, and which are up-regulated under proinflammatory conditions. Another factor of the BK-system is the <a href="https://bioregistry.io/genecards:SERPING1" target="_blank">SERPING1</a> gene which encodes for the  C1-inhibitor. BK can only be produced when the C1-inhibitor is not in effect, allowing the plasma kallikrein to process HMWK into BK.  <a href="https://bioregistry.io/genecards:ACE" target="_blank">ACE</a> and <a href="https://bioregistry.io/genecards:ACE2" target="_blank">ACE2</a>, e.g. present on type II pneumocytes in the alveoli, also play direct roles in the inactivation of the bradykinin system. <a href="https://bioregistry.io/genecards:ACE" target="_blank">ACE </a>catalyzes conversion of BK into inactive peptides, while <a href="https://bioregistry.io/genecards:ACE2" target="_blank">ACE2</a> inactivates des-Arg9-BK (DABK) and Lys-des-Arg9-BK. Thus, down-regulation of the enzymes leads to activation of the bradykinin system. Furthermore, BK receptor signaling (B1R and B2R) is augmented by the Renin-Angiotensin System (RAS), and increased levels of angiotensin II (AngII) and angiotensin 1-9 (Ang1-9) may indicate activation of the BK system (potentially through resensitization of B2R). Finally, the coagulation factor XII (<a href="https://bioregistry.io/genecards:F12" target="_blank">F12</a>) is a direct activator of kallikrein, through cleavage of prekallikrein into plasma kallikrein.   Evidence for the KEs perturbation In COVID-19 In response to SARS-COV-2 infection, BK production increases due to the SERPING1 gene that encodes for the C1-inhibitor being strongly downregulated as a result of infection (<a href="https://doi.org/10.7554/eLife.59177">10.7554/eLife.59177</a>). Downregulation of ACE2 and upregulation of ACE causes RAS to produce the BK-augmenting peptide Ang1-9 (<a href="https://doi.org/10.3390/v13010029">10.3390/v13010029</a>). The shift of the system towards increased production of BK, increased DABK, and increased B1R/B2R signaling leads to a hyperactive BK system or “storm,” potentially responsible for many COVID-19 symptoms. The BK storm is maintained by several points of inhibition, including suppressed NFkappaB, Vitamin D and its receptor, and the previously mentioned decreased expression of SERPING1. BK overproduction causes blood vessels to burst, leading to the leakage of fluid into the lungs, and hyaluronic acid overproduction causing the lungs to be unable to take in oxygen and expel CO2. This ultimately leads to the severe breathing symptoms of COVID-19 (<a href="https://doi.org/10.7554/eLife.57555">10.7554/eLife.57555</a>). The BK storm is also known to affect other major organs like the kidneys, cardiac tissue, muscles, and the brain. In addition, the ACE2 receptor is known to be co-expressed with elements of the kallikrein-kinin (bradykinin) system (<a href="https://doi.org/10.1038/s41598-020-76488-2">10.1038/s41598-020-76488-2</a>).

Near-patient systems In human samples (e.g. BAL) the activation of the bradykinin system could potentially be measured on transcriptional level, with focus on activation of <a href="https://bioregistry.io/genecards:KLKB1" target="_blank">KLKB1</a>, <a href="https://bioregistry.io/genecards:KNG1" target="_blank">KNG1</a>, <a href="https://bioregistry.io/genecards:KLK1" target="_blank">KLK1</a> (-15), <a href="https://bioregistry.io/genecards:CPN1" target="_blank">CPN1</a>, and the BK receptors <a href="https://bioregistry.io/genecards:BDKRB1" target="_blank">BDKRB1</a> and <a href="https://bioregistry.io/genecards:BDKRB2" target="_blank">BDKRB2</a>, as well as potential down-regulation of <a href="https://bioregistry.io/genecards:SERPING1" target="_blank">SERPING1</a>. Activation of the <a href="https://bioregistry.io/wikipathways:WP4969">RAAS </a>system should also be monitored, specifically on <a href="https://bioregistry.io/genecards:AGT" target="_blank">AGT</a>, <a href="https://bioregistry.io/genecards:AGTR1" target="_blank">AGTR1</a>, and <a href="https://bioregistry.io/genecards:AGTR2" target="_blank">AGTR2</a>. Additional indications may be obtained from transcriptional up-regulation of <a href="https://bioregistry.io/genecards:ACE2" target="_blank">ACE2 </a>(potential result as a compensatory mechanism due to the “high-jacking” by the virus) and down-regulation of <a href="https://bioregistry.io/genecards:ACE" target="_blank">ACE</a> (<a href="https://doi.org/10.7554/eLife.59177">10.7554/eLife.59177</a>).    In vitro systems Whole human blood model for testing the activation of the kallikrein system (<a href="https://doi.org/10.1016/j.biomaterials.2015.01.031">10.1016/j.biomaterials.2015.01.031</a> , <a href="https://doi.org/10.1016/j.nano.2017.12.008">10.1016/j.nano.2017.12.008</a> , <a href="https://doi.org/10.1080/14686996.2019.1625721">10.1080/14686996.2019.1625721</a> ). The system has initially been applied only to nanomaterials.

Not Specified Male Not Specified Female High

1. Garvin et al. A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. eLife 2020;9:e59177 DOI: 10.7554/eLife.59177 2. Sidarta-Oliveira, D., Jara, C.P., Ferruzzi, A.J. et al. SARS-CoV-2 receptor is co-expressed with elements of the kinin–kallikrein, renin–angiotensin and coagulation systems in alveolar cells. Sci Rep 10, 19522 (2020). <a href="https://doi.org/10.1038/s41598-020-76488-2">https://doi.org/10.1038/s41598-020-76488-2</a> 3. Bernard et al. Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19. Viruses 2021, 13(1), 29; <a href="https://doi.org/10.3390/v13010029">https://doi.org/10.3390/v13010029</a>  4. Veerdonk et al. Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome. eLife 2020;9:e57555 DOI: 10.7554/eLife.57555  5. Carvalho 2021 doi: 10.1016/j.peptides.2020.170428 6. Ekdahl 2019 doi: 10.1080/14686996.2019.1625721 7. Long 2015 doi:10.3109/17435390.2015.1088589 8. Atzatzi-Aguilar 2015 10.1186/s12989-015-0094-4 AOPWiki 2021-04-20T02:42:07

2022-01-24T11:39:26

Increased, secretion of proinflammatory mediators

Increased proinflammatory mediators

Cellular

Pro-inflammatory mediators are the chemical and biological molecules that initiate and regulate inflammatory reactions. Pro-inflammatory mediators are secreted following exposure to an inflammogen in a gender/sex or developmental stage independent manner. They are secreted during inflammation in all species. Different types of pro-inflammatory mediators are secreted during innate or adaptive immune responses across various species (Mestas and Hughes, 2004). Cell-derived pro-inflammatory mediators include cytokines, chemokines, and growth factors. Blood derived pro-inflammatory mediators include vasoactive amines, complement activation products and others. These modulators can be grouped based on the cell type that secrete them, their cellular localisation and also based on the type of immune response they trigger. For example, members of the interleukin (IL) family including <a href="https://bioregistry.io/genecards:IL2">IL-2</a>, <a href="https://bioregistry.io/genecards:IL4">IL-4</a>, <a href="https://bioregistry.io/genecards:IL7">IL-7</a>, <a href="https://bioregistry.io/genecards:IL9">IL-9</a>, <a href="https://bioregistry.io/genecards:IL15">IL-15</a>, <a href="https://bioregistry.io/genecards:IL21">IL-21</a>, <a href="https://bioregistry.io/genecards:IL3">IL-3</a>, <a href="https://bioregistry.io/genecards:IL5">IL-5</a> and Granulocyte-macrophage colony stimulating factor (<a href="https://bioregistry.io/genecards:CSF2">GM-CSF</a>) are involved in the adaptive immune responses. The pro-inflammatory cytokines include IL-1 family (<a href="https://bioregistry.io/genecards:IL1a">IL-1</a>α , <a href="https://bioregistry.io/genecards:IL1b">IL-1</a>β, <a href="https://bioregistry.io/genecards:IL1ra">IL-1r</a>α, <a href="https://bioregistry.io/genecards:IL18">IL-18</a>, <a href="https://bioregistry.io/genecards:IL36a">IL-36</a>α, <a href="https://bioregistry.io/genecards:IL36b">IL-36</a>β, <a href="https://bioregistry.io/genecards:IL36g">IL-36</a>γ, <a href="https://bioregistry.io/genecards:IL36Ra">IL-36R</a>α, <a href="https://bioregistry.io/genecards:IL37">IL-37</a>), <a href="https://bioregistry.io/genecards:IL6">IL-6 </a>family, Tumor necrosis factor (<a href="https://bioregistry.io/genecards:TNF">TNF</a>) family, <a href="https://bioregistry.io/genecards:IL17">IL-17</a>, and Interferon gamma (<a href="https://bioregistry.io/genecards:IFNg">IFN</a>-γ) (Turner et al., 2014). While <a href="https://bioregistry.io/genecards:IL4">IL-4</a> and <a href="https://bioregistry.io/genecards:IL5">IL-5</a> are considered T helper (Th) cell type 2 response, <a href="https://bioregistry.io/genecards:IFNg">IFN</a>-γ is suggested to be Th1 type response. Different types of pro-inflammatory mediators are secreted during innate or adaptive immune responses across various species (Mestas and Hughes, 2004). However, <a href="https://bioregistry.io/genecards:IL1">IL-1</a> family cytokines, <a href="https://bioregistry.io/genecards:IL4">IL-4</a>, <a href="https://bioregistry.io/genecards:IL5">IL-5</a>, <a href="https://bioregistry.io/genecards:IL6">IL-6</a>, <a href="https://bioregistry.io/genecards:TNFa">TNF</a>-α, IFN-γ are the commonly measured mediators in experimental animals and in humans. Similar gene expression patterns involving inflammation and matrix remodelling are observed in human patients of pulmonary fibrosis and mouse lungs exposed to bleomycin (Kaminski, 2002). Literature evidence for its perturbation: Several studies show increased proinflammatory mediators in rodent lungs and bronchoalveolar lavage fluid, and in cell culture supernatants following exposure to a variety of carbon nanotube (CNT) types and other materials. Poland et al., 2008 showed that long and thin CNTs (>5 µm) can elicit asbestos-like pathogenicity through the continual release of pro-inflammatory cytokines and reactive oxygen species. Exposure to crystalline silica induces release of inflammatory cytokines (TNF-α, IL-1, IL-6), transcription factors (Nuclear factor kappa B [NF-κB], Activator protein-1 [AP-1]) and kinase signalling pathways in mice that contain NF-κB luciferase reporter (Hubbard et al., 2002). Boyles et al., 2015 found that lung responses to long multi-walled carbon nanotubes (MWCNTs) included high expression levels of pro-inflammatory mediators Monocyte chemoattractant protein 1 (MCP-1), Transforming growth factor beta 1 (TGF-β1), and TNF-α (Boyles et al., 2015). Bleomycin administration in rodents induces lung inflammation and increased expression of pro-inflammatory mediators (Park et al., 2019). Inflammation induced by bleomycin, paraquat and CNTs is characterised by the altered expression of pro-inflammatory mediators. A large number of nanomaterials induce expression of cytokines and chemokines in lungs of rodents exposed via inhalation (Halappanavar et al., 2011; Husain et al., 2015a). Similarities are observed in gene programs involving pro-inflammatory event is observed in both humans and experimental mice (Zuo et al., 2002).

The selection of pro-inflammatory mediators for investigation varies based on the expertise of the lab, cell types studied and the availability of the specific antibodies. Real-time reverse transcription-polymerase chain reaction (qRT-PCR) – will measure the abundance of cytokine mRNA in a given sample. The method involves three steps: conversion of RNA into cDNA by reverse transcription method, amplification of cDNA using the PCR, and the real-time detection and quantification of amplified products (amplicons) (Nolan et al., 2006). Amplicons are detected using fluorescence, increase in which is directly proportional to the amplified PCR product. The number of cycles required per sample to reach a certain threshold of fluorescence (set by the user – usually set in the linear phase of the amplification, and the observed difference in samples to cross the set threshold reflects the initial amount available for amplification) is used to quantify the relative amount in the samples. The amplified products are detected by the DNA intercalating minor groove-binding fluorophore SYBR green, which produces a signal when incorporated into double-stranded amplicons. Since the cDNA is single stranded, the dye does not bind enhancing the specificity of the results. There are other methods such as nested fluorescent probes for detection, but SYBR green is widely used. RT-PCR primers specific to several pro-inflammatory mediators in several species including mouse, rat and humans, are readily available commercially. Enzyme-linked immunosorbent assays (ELISA) – permit quantitative measurement of antigens in biological samples. The method is the same as described for the MIE. Both ELISA and qRT-PCR assays are used in vivo and are readily applicable to in vitro cell culture models, where cell culture supernatants or whole cell homogenates are used for ELISA or mRNA assays. Both assays are straight forward, quantitative and require relatively a small amount of input sample. Apart from assaying single protein or gene at a time, cytokine bead arrays or cytokine PCR arrays can also be used to detect a whole panel of inflammatory mediators in a multiplex method (Husain et al., 2015b). This method is quantitative and especially advantageous when the sample amount available for testing is scarce. Lastly, immunohistochemistry can also be used to detect specific immune cell types producing the pro-inflammatory mediators and its downstream effectors in any given tissue (Costa et al., 2017). Immunohistochemistry results can be used as weight of evidence; however, the technique is not quantitative and depending on the specific antibodies used, the assay sensitivity may also become an issue (Amsen and De Visser, 2009). Cell models - of varying complexity have been used to assess the expression of pro-inflammatory mediators. Two dimensional submerged monocultures of the main fibrotic effector cells – lung epithelial cells, macrophages, and fibroblasts – have routinely been used in vitro due to the large literature base, and ease of use, but do not adequately mimic the in vivo condition (Sharma et al., 2016; Sundarakrishnan et al., 2018). Recently, the EpiAlveolar in vitro lung model (containing epithelial cells, endothelial cells, and fibroblasts) was used to predict the fibrotic potential of MWCNTs, and researchers noted increases in the pro-inflammatory molecules TNF-α, IL-1β, and the pro-fibrotic TGF-β using ELISA (Barasova et al., 2020). A similar, but less complicated co-culture model of immortalized human alveolar epithelial cells and idiopathic pulmonary fibrosis patient derived fibroblasts was used to assess pro-fibrotic signalling, and noted enhanced secretion of Platelet derived growth factor (PDGF) and Basic fibroblast growth factor (bFGF), as well as evidence for epithelial to mesenchymal transition of epithelial cells in this system (Prasad et al., 2014). Models such as these better capitulate the in vivo pulmonary alveolar capillary, but have lower reproducibility as compared to traditional submerged mono-culture experiments.

Human, mouse, rat Cytokines are the common pro-inflammatory mediators secreted following inflammogenic stimuli. Cytokines can be defined as a diverse group of signaling protein molecules. They are secreted by different cell types in different tissues and in all mammalian species, irrespective of gender, age or sex. A lot of literature is available to support cross species, gender and developmental stage application for this KE. The challenge is the specificity; most cytokines exhibit redundant functions and many are pleotropic.

CL:0000255

CL eukaryotic cell

High Male High Female

High

Adults

High High High

1. Amsen D, de Visser KE, Town T. Approaches to determine expression of inflammatory cytokines. Methods Mol Biol. 2009;511:107-42. doi: 10.1007/978-1-59745-447-6_5.  2. Barosova H, Maione AG, Septiadi D, Sharma M, Haeni L, Balog S, O'Connell O, Jackson GR, Brown D, Clippinger AJ, Hayden P, Petri-Fink A, Stone V, Rothen-Rutishauser B. Use of EpiAlveolar Lung Model to Predict Fibrotic Potential of Multiwalled Carbon Nanotubes. ACS Nano. 2020 Apr 28;14(4):3941-3956. doi: 10.1021/acsnano.9b06860.  3. Boyles MS, Young L, Brown DM, MacCalman L, Cowie H, Moisala A, Smail F, Smith PJ, Proudfoot L, Windle AH, Stone V. Multi-walled carbon nanotube induced frustrated phagocytosis, cytotoxicity and pro-inflammatory conditions in macrophages are length dependent and greater than that of asbestos. Toxicol In Vitro. 2015 Oct;29(7):1513-28. doi: 10.1016/j.tiv.2015.06.012.  4. Costa PM, Gosens I, Williams A, Farcal L, Pantano D, Brown DM, Stone V, Cassee FR, Halappanavar S, Fadeel B. Transcriptional profiling reveals gene expression changes associated with inflammation and cell proliferation following short-term inhalation exposure to copper oxide nanoparticles. J Appl Toxicol. 2018 Mar;38(3):385-397. doi: 10.1002/jat.3548. 5. Halappanavar S, Jackson P, Williams A, Jensen KA, Hougaard KS, Vogel U, Yauk CL, Wallin H. Pulmonary response to surface-coated nanotitanium dioxide particles includes induction of acute phase response genes, inflammatory cascades, and changes in microRNAs: a toxicogenomic study. Environ Mol Mutagen. 2011 Jul;52(6):425-39. doi: 10.1002/em.20639.  6. Hubbard AK, Timblin CR, Shukla A, Rincón M, Mossman BT. Activation of NF-kappaB-dependent gene expression by silica in lungs of luciferase reporter mice. Am J Physiol Lung Cell Mol Physiol. 2002 May;282(5):L968-75. doi: 10.1152/ajplung.00327.2001. 7. Husain M, Kyjovska ZO, Bourdon-Lacombe J, Saber AT, Jensen KA, Jacobsen NR, Williams A, Wallin H, Halappanavar S, Vogel U, Yauk CL. Carbon black nanoparticles induce biphasic gene expression changes associated with inflammatory responses in the lungs of C57BL/6 mice following a single intratracheal instillation. Toxicol Appl Pharmacol. 2015a Dec 15;289(3):573-88. doi: 10.1016/j.taap.2015.11.003. 8. Husain M, Wu D, Saber AT, Decan N, Jacobsen NR, Williams A, Yauk CL, Wallin H, Vogel U, Halappanavar S. Intratracheally instilled titanium dioxide nanoparticles translocate to heart and liver and activate complement cascade in the heart of C57BL/6 mice. Nanotoxicology. 2015b;9(8):1013-22. doi: 10.3109/17435390.2014.996192. 9. Kaminski N. Microarray analysis of idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol. 2003 Sep;29(3 Suppl):S32-6. 10. Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol. 2004 Mar 1;172(5):2731-8. doi: 10.4049/jimmunol.172.5.2731. 11. Nolan T, Hands RE, Bustin SA. Quantification of mRNA using real-time RT-PCR. Nat Protoc. 2006;1(3):1559-82. doi: 10.1038/nprot.2006.236. 12. Park SJ, Im DS. Deficiency of Sphingosine-1-Phosphate Receptor 2 (S1P2) Attenuates Bleomycin-Induced Pulmonary Fibrosis. Biomol Ther (Seoul). 2019 May 1;27(3):318-326. doi: 10.4062/biomolther.2018.131. 13. Poland CA, Duffin R, Kinloch I, Maynard A, Wallace WA, Seaton A, Stone V, Brown S, Macnee W, Donaldson K. Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. Nat Nanotechnol. 2008 Jul;3(7):423-8. doi: 10.1038/nnano.2008.111. 14. Prasad S, Hogaboam CM, Jarai G. Deficient repair response of IPF fibroblasts in a co-culture model of epithelial injury and repair. Fibrogenesis Tissue Repair. 2014 Apr 29;7:7. doi: 10.1186/1755-1536-7-7.  15. Sharma M, Nikota J, Halappanavar S, Castranova V, Rothen-Rutishauser B, Clippinger AJ. Predicting pulmonary fibrosis in humans after exposure to multi-walled carbon nanotubes (MWCNTs). Arch Toxicol. 2016 Jul;90(7):1605-22. doi: 10.1007/s00204-016-1742-7.  16. Sundarakrishnan A, Chen Y, Black LD, Aldridge BB, Kaplan DL. Engineered cell and tissue models of pulmonary fibrosis. Adv Drug Deliv Rev. 2018 Apr;129:78-94. doi: 10.1016/j.addr.2017.12.013. 17. Turner MD, Nedjai B, Hurst T, Pennington DJ. Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta. 2014 Nov;1843(11):2563-2582. doi: 10.1016/j.bbamcr.2014.05.014.  18. Zuo F, Kaminski N, Eugui E, Allard J, Yakhini Z, Ben-Dor A, Lollini L, Morris D, Kim Y, DeLustro B, Sheppard D, Pardo A, Selman M, Heller RA. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6292-7. doi: 10.1073/pnas.092134099. AOPWiki 2018-01-02T13:12:11

2023-05-17T15:18:03

Increased, recruitment of inflammatory cells

Recruitment of inflammatory cells

Tissue

Pro-inflammatory cells originate in bone marrow and are recruited to the site of infection or injury via circulation following specific pro-inflammatory mediator (cytokine and chemokine) signalling. Pro-inflammatory cells are recruited to lungs to clear the invading pathogen or the toxic substance. Monocytes (dendritic cells, macrophages, and neutrophils) are subsets of circulating white blood cells that are involved in the immune responses to pathogen or toxicant stimuli (Kolaczkowska and Kubes, 2013; Kopf et al., 2015). They are derived from the bone marrow. They can differentiate into different macrophage types and dendritic cells. They can be categorised based on their size, the type of cell surface receptors and their ability to differentiate following external or internal stimulus such as increased expression of cytokines. Monocytes participate in tissue healing, clearance of toxic substance or pathogens, and in the initiation of adaptive immunity. Recruited monocytes can also influence pathogenesis (Ingersoll et al., 2011). Sensing or recognition of pathogens and harmful substances results in the recruitment of monocytes to lungs (Shi and Pamer, 2011). Activated immune cells secrete a variety of pro-inflammatory mediators, the purpose of which is to propagate the immune signalling and response, which when not controlled, leads to chronic inflammation, cell death and tissue injury. Thus, Event 1496 and Event 1497 act in a positive feedback loop mechanism and propagate the proinflammatory environment. Literature evidence for its perturbation: Macrophages accumulate in bronchoalveolar fluid (BALF) post-exposure to bleomycin (Phan et al., 1980; Smith et al., 1995). Nanomaterial (NM)-induced inflammation is predominantly neutrophilic (Poulsen et al., 2015; Rahman L et al., 2017a; Rahman et al., 2017b; Shvedova et al., 2005). An increased number of neutrophils (Reynolds et al., 1977) is observed in the BALF of patients with idiopathic pulmonary fibrosis. Eosinophils are a type of white blood cells and a type of granulocytes (contain granules and enzymes) that are recruited following exposure to allergens, during allergic reactions such as asthma or during fibrosis (Reynolds et al., 1977). Multi-walled carbon nanotubes (MWCNTs) induce increased eosinophil count in lungs (Købler C et al., 2015). MWCNTs act as allergens and induce lung infiltration of eosinophils and cause airway hypersensitivity (Beamer et al., 2013). It is important to note that the stressor-induced Event 1495, Event 1496, and Event 1497 are part of the functional changes that we collectively consider as inflammation, and together, they mark the initiation of acute inflammatory phase. Event 1495 and Event 1496 occur at the cellular level. Event 1497 occurs at the tissue level.

In vivo, recruitment of pro-inflammatory cells is measured using BALF cellularity assay. The fluid lining the lung epithelium is lavaged (BALF) and its composition is assessed as marker of lung immune response to the toxic substances or pathogens. BALF is assessed quantitatively for types of infiltrating cells, levels and types of cytokines and chemokines. Thus, BALF assessment can aid in developing dose-response of a substance, to rank a substances’ potency and to set up no effect level of exposure for the regulatory decision making. For NMs, in vivo BALF assessment is recommended as a mandatory test (discussed in ENV/JM/MONO(2012)40 and also in OECD inhalation test guideline for NMs). Temporal changes in the BALF composition can be prognostic of initiation and progression of lung immune disease (Cho et al., 2010). In vitro, it is difficult to assess the recruitment of pro-inflammatory cells. Thus, a suit of pro-inflammatory mediators specific to cell types are assessed using the same techniques mentioned above (real-time reverse transcription-polymerase chain reaction [qRT-PCR], enzyme-linked immunosorbent assays [ELISA], immunohistochemistry) in cell culture models, as indicative of recruitment of cells into the lungs. Alternatively, the use of precision cut lung slices can allow for limited assessment of recruitment of tissue resident inflammatory cells, based on the repertoire of cells remaining in the specific slice following harvesting. This method was used to show that there is a histological increase in inflammatory foci following treatment with bleomycin and MWCNTs (Rahman et al., 2020). Finally, more complicated microfluidic lung-on-a-chip devices can be used to assess the migration of select immune cells and fibroblasts toward a simulated epithelium following treatment with a pro-fibrotic compound (He et al., 2017). However, this method is limited to two cell types, and it lacks the reservoirs of immune cells present in the body in vivo.

Human, mouse, rat

High Mixed

High

All life stages

High High High

1. Beamer CA, Girtsman TA, Seaver BP, Finsaas KJ, Migliaccio CT, Perry VK, Rottman JB, Smith DE, Holian A. IL-33 mediates multi-walled carbon nanotube (MWCNT)-induced airway hyper-reactivity via the mobilization of innate helper cells in the lung. Nanotoxicology. 2013 Sep;7(6):1070-81. doi: 10.3109/17435390.2012.702230. 2. Cho WS, Duffin R, Poland CA, Howie SE, MacNee W, Bradley M, Megson IL, Donaldson K. Metal oxide nanoparticles induce unique inflammatory footprints in the lung: important implications for nanoparticle testing. Environ Health Perspect. 2010 Dec;118(12):1699-706. doi: 10.1289/ehp.1002201.  3. He J, Chen W, Deng S, Xie L, Feng J, Geng J, et al. Modeling alveolar injury using microfluidic co-cultures for monitoring bleomycin-induced epithelial/fibroblastic cross-talk disorder. RSC Advances. 2017 7(68):42738-49. doi: 10.1039/C7RA06752F. 4. Ingersoll MA, Platt AM, Potteaux S, Randolph GJ. Monocyte trafficking in acute and chronic inflammation. Trends Immunol. 2011 Oct;32(10):470-7. doi: 10.1016/j.it.2011.05.001. 5. Købler C, Poulsen SS, Saber AT, Jacobsen NR, Wallin H, Yauk CL, Halappanavar S, Vogel U, Qvortrup K, Mølhave K. Time-dependent subcellular distribution and effects of carbon nanotubes in lungs of mice. PLoS One. 2015 Jan 23;10(1):e0116481. doi: 10.1371/journal.pone.0116481.  6. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013 Mar;13(3):159-75. doi: 10.1038/nri3399.  7. Kopf M, Schneider C, Nobs SP. The development and function of lung-resident macrophages and dendritic cells. Nat Immunol. 2015 Jan;16(1):36-44. doi: 10.1038/ni.3052. 8. Phan SH, Thrall RS, Ward PA. Bleomycin-induced pulmonary fibrosis in rats: biochemical demonstration of increased rate of collagen synthesis. Am Rev Respir Dis. 1980 Mar;121(3):501-6. doi: 10.1164/arrd.1980.121.3.501.  9. Poulsen SS, Saber AT, Williams A, Andersen O, Købler C, Atluri R, Pozzebon ME, Mucelli SP, Simion M, Rickerby D, Mortensen A, Jackson P, Kyjovska ZO, Mølhave K, Jacobsen NR, Jensen KA, Yauk CL, Wallin H, Halappanavar S, Vogel U. MWCNTs of different physicochemical properties cause similar inflammatory responses, but differences in transcriptional and histological markers of fibrosis in mouse lungs. Toxicol Appl Pharmacol. 2015 Apr 1;284(1):16-32. doi: 10.1016/j.taap.2014.12.011.  10. Rahman L, Wu D, Johnston M, William A, Halappanavar S. Toxicogenomics analysis of mouse lung responses following exposure to titanium dioxide nanomaterials reveal their disease potential at high doses. Mutagenesis. 2017a Jan;32(1):59-76. doi: 10.1093/mutage/gew048.  11. Rahman L, Jacobsen NR, Aziz SA, Wu D, Williams A, Yauk CL, White P, Wallin H, Vogel U, Halappanavar S. Multi-walled carbon nanotube-induced genotoxic, inflammatory and pro-fibrotic responses in mice: Investigating the mechanisms of pulmonary carcinogenesis. Mutat Res Genet Toxicol Environ Mutagen. 2017b Nov;823:28-44. doi: 10.1016/j.mrgentox.2017.08.005.  12. Rahman L, Williams A, Gelda K, Nikota J, Wu D, Vogel U, Halappanavar S. 21st Century Tools for Nanotoxicology: Transcriptomic Biomarker Panel and Precision-Cut Lung Slice Organ Mimic System for the Assessment of Nanomaterial-Induced Lung Fibrosis. Small. 2020 Sep;16(36):e2000272. doi: 10.1002/smll.202000272.  13. Reynolds HY, Fulmer JD, Kazmierowski JA, Roberts WC, Frank MM, Crystal RG. Analysis of cellular and protein content of broncho-alveolar lavage fluid from patients with idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis. J Clin Invest. 1977 Jan;59(1):165-75. doi: 10.1172/JCI108615. 14. Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol. 2011 Oct 10;11(11):762-74. doi: 10.1038/nri3070.  15. Shvedova AA, Kisin ER, Mercer R, Murray AR, Johnson VJ, Potapovich AI, Tyurina YY, Gorelik O, Arepalli S, Schwegler-Berry D, Hubbs AF, Antonini J, Evans DE, Ku BK, Ramsey D, Maynard A, Kagan VE, Castranova V, Baron P. Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice. Am J Physiol Lung Cell Mol Physiol. 2005 Nov;289(5):L698-708. doi: 10.1152/ajplung.00084.2005.   16. Smith RE, Strieter RM, Zhang K, Phan SH, Standiford TJ, Lukacs NW, Kunkel SL. A role for C-C chemokines in fibrotic lung disease. J Leukoc Biol. 1995 May;57(5):782-7. doi: 10.1002/jlb.57.5.782.  AOPWiki 2018-01-03T09:31:07

2023-05-12T17:03:00

Hyperinflammation

Tissue

Hyperinflammation can be defined as an uncontrolled and self-perpetuating inflammatory process that results in tissue damage. The state of hyperinflammation is also observed in cytokine storm syndrome, cytokine release syndrome, haemophagocytic lymphohistiocytosis, macrophage activation syndrome and in conditions of sepsis; however, it is not a frequent observation. For example, in COVID-19 infection, hyperinflammation plays a critical role in driving the disease severity. Although high viral titre initiates the cascade, the disease severity itself is dependent on the severity of the inflammatory state. Clinically, the hallmarks of hyperinflammation state include excessive serum levels of pro-inflammatory mediator C-reactive protein (<a href="http://bioregistry.io/genecards:CRP">CRP</a>), reduced or absence of lymphocytes (lymphopenia), high levels of ferritin and D-dimer, and increased lactate dehydrogenase. Higher neutrophil to lymphocyte ratio is another clinical marker. Some research studies have also associated high serum levels of<a href="https://bioregistry.io/genecards:IL6"> IL6</a> protein and accumulation of neutrophils to be causal and indicative of hyperinflammation. Other molecular markers associated with hyperinflammation include <a href="http://bioregistry.io/genecards:IL1B">IL1ꞵ</a> and <a href="http://bioregistry.io/genecards:TNFA">TNFɑ</a> and have together with IL6 and a multitude of other cytokines, chemokines and other proinflammatory factors been identified as potential therapeutic targets (<a href="https://doi.org/10.1371/journal.pone.0254374">Desvaux et al. 2021</a>). While the total serum levels of these markers is important, more critically, how fast the levels increase in serum is taken into consideration in judging the severity (<a href="http://doi.org/10.1101/2021.01.11.20248765">Bergamaschi et al. 2021</a>). The number of studies that have reported on the various markers of hyperinflammation is listed in Table-1.   Although the initiation and promotion of inflammation involves several cell types including epithelial cells, alveolar macrophages, type I and II pneumocytes and dendritic cells, the cell types that play role on inducing hyperinflammatory state may include macrophages, dendritic cells and neutrophils. Lack of neutrophil plays an important role in slowing the viral clearance and thus perpetuating the condition. Hyperferritinaemia is associated with high macrophage activation. Weight of evidence KE Hyperinflammation <table border="1" bordercolor="#ccc" cellpadding="5" cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse"> <tbody> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:56px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:110px"> References </td> <td colspan="6" style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:396px"> Markers </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:127px"> Comments </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:56px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:110px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Research </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:60px"> Clinical </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:94px"> Clinical </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:57px"> Clinical </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:69px"> Clinical </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:59px"> Research </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:127px">   </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:56px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:110px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> IL6, TNFa </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:60px"> CRP </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:94px"> Lymphopenia </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:57px"> Ferritin </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:69px"> Lactate dehydrogenase </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:59px"> Impaired IFN 1 type response </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:127px">   </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Human </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:110px"> Lazear H.M et al., Immunity. 2019;50:907–923.  </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Increased protein levels, NFkB pathway activation </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:60px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:94px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:57px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:69px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:59px"> Reduced IFN stimulated genes </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:127px">   </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Human </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:110px"> Zhang B, Zhou X, Qiu Y, et al. Clinical characteristics of 82 death cases with COVID‐19. medRxiv. 2020. </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Increased </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:60px"> Increased </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:94px"> Present, also thrombocytopenia </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:57px"> IncreasedIncreased D-dimer </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:69px"> Increased </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:59px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:127px">   </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Human </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:110px"> J Clin.  Invest. 2020;<a href="http://www.jci.org/130/5" style="color:blue; text-decoration:underline">130(5)</a>:2620-2629. <a href="https://doi.org/10.1172/JCI137244" style="color:blue; text-decoration:underline">https://doi.org/10.1172/JCI137244</a> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Increased </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:60px"> Increased </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:94px"> Present </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:57px"> Increased D-dimer </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:69px"> Increased </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:59px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:127px">   </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Human </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:110px"> Hadjadj et al., Science doi: <a href="http://dx.doi.org/10.1126/science.abc6027" style="color:blue; text-decoration:underline" target="_blank">10.1126/science.abc6027</a> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Increasedprotein </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:60px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:94px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:57px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:69px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:59px"> Impaired </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:127px">   </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Human </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:110px"> Del Valle DM et al., Medrxiv : the Preprint Server for Health Sciences. 2020 May.  </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Increased protein </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:60px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:94px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:57px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:69px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:59px"> Impaired </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:127px">   </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Human </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:110px"> Chen G ei al., J Clin Invest. 2020;130(5):2620-2629 </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Increased IL-6 </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:60px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:94px"> Present </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:57px"> Increased ferritin and D-dimer </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:69px"> Increased </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:59px"> Marginal reduction </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:127px">   </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Human </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:110px"> Cheng L et al., Journal of Clinical Laboratory Analysis <a href="https://onlinelibrary.wiley.com/toc/10982825/2020/34/10" style="color:blue; text-decoration:underline" title="View Volume 34, Issue 10">Volume34, Issue10</a> October 2020 e23618 <a href="https://doi.org/10.1002/jcla.23618" style="color:blue; text-decoration:underline">https://doi.org/10.1002/jcla.23618</a>   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> IL-6 increased </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:60px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:94px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:57px"> Increased ferritin levels </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:69px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:59px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:127px"> Review – meta analysis of 52 studies that have data for ferritin levels. Showing severity can be predicted by ferritin levels. Connections with inflammation state. </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Human </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:110px"> Manson JJ et al., <a href="https://www.sciencedirect.com/science/journal/26659913" style="color:blue; text-decoration:underline" title="Go to The Lancet Rheumatology on ScienceDirect">The Lancet Rheumatology</a> <a href="https://www.sciencedirect.com/science/journal/26659913/2/10" style="color:blue; text-decoration:underline" title="Go to table of contents for this volume/issue">Volume 2, Issue 10</a>, October 2020, Pages e594-e602   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:56px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:60px"> Increased </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:94px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:57px"> Increased Ferritin levels </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:69px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:59px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:127px"> Logitudinal cohort study showing association of hyperinflammation with prognosis. Only CRP and Ferritin levels considered. </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Human </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:110px"> Caricchio R, et al.,  Ann Rheum Dis doi:10.1136/ annrheumdis-2020-218323 </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Increased </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:60px"> Increased </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:94px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:57px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:69px"> Increased </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:59px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:127px"> Recommended criteria for assessing hyperinflammation </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Human </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:110px"> Mojtabavi, H., et al., Eur Cytokine Netw 31, 44–49 (2020). https://doi.org/10.1684/ecn.2020.0448 </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Increased </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:60px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:94px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:57px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:69px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:59px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:127px"> Review- meta-analysis of available data. 11 studies included. </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Human </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:110px"> Henry B et al.,  Acta Biomed. 2020;91(3):e2020008. doi:10.23750/abm.v91i3.10217 </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:56px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:60px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:94px"> Lymphopenia and neutrophilia </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:57px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:69px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:59px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:127px"> Meta-analysis study – 22 studies included. Correlation between lymphopenia and neutrophilia at admission with severity of disease. </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Human </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:110px"> Jin J-M et al., Front. Public Health, 29 April 2020 | <a href="https://doi.org/10.3389/fpubh.2020.00152" style="color:blue; text-decoration:underline">https://doi.org/10.3389/fpubh.2020.00152</a> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:56px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:60px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:94px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:57px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:69px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:59px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:127px"> Gender differences </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Ex vivo, human lung tissue </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:110px"> Chu H, et al., Clin Infect Dis. 2020;71(6):1400-1409. </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Increased IL-6 </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:60px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:94px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:57px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:69px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:59px"> Impaired IFN I, II, III signalling </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:127px">   </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:56px"> Mouse </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:110px"> Channappanavar et al.,  Cell Host Microbe 19 (2) (2016) 181–193, </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:56px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:60px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:94px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:57px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:69px">   </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:59px"> Reduced IFN I response </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:127px"> SARS-COV </td> </tr> </tbody> </table>

Hyperinflammation is observed in all age groups with high rates of infection and mortality observed in aged population. In children, although the rate of infection is low, hyperinflammatory syndrome is observed leading to long term disabilities. However, mortality rate in young children and adults below 40 years of age is less pronounced. Data in other developmental stages is lacking. Prevalence of hyperinflammation is same in men and women; however, studies have found that men develop more severe symptoms than women.

Not Specified Mixed High Moderate

1. Caricchio R, et al.,  Ann Rheum Dis doi:10.1136/ annrheumdis-2020-218323 2. Channappanavar et al.,  Cell Host Microbe 19 (2) (2016) 181–193, 3. Chen G ei al., J Clin Invest. 2020;130(5):2620-2629 4. Cheng L et al.,Journal of Clinical Laboratory Analysis<a href="https://onlinelibrary.wiley.com/toc/10982825/2020/34/10"> Volume34, Issue10</a>, October 2020 e23618, <a href="https://doi.org/10.1002/jcla.23618">https://doi.org/10.1002/jcla.23618</a> 5. Chu H, et al., Clin Infect Dis. 2020;71(6):1400-1409. 6. Del Valle DM et al., Medrxiv : the Preprint Server for Health Sciences. 2020 May. 7. J Clin.  Invest. 2020;<a href="http://www.jci.org/130/5">130(5)</a>:2620-2629. <a href="https://doi.org/10.1172/JCI137244">https://doi.org/10.1172/JCI137244</a> 8. Jin J-M et al., Front. Public Health, 29 April 2020 | <a href="https://doi.org/10.3389/fpubh.2020.00152">https://doi.org/10.3389/fpubh.2020.00152</a> 9. Hadjadj et al., Science doi: <a href="http://dx.doi.org/10.1126/science.abc6027">10.1126/science.abc6027</a> 10. Henry B et al.,  Acta Biomed. 2020;91(3):e2020008. doi:10.23750/abm.v91i3.10217 11. Lazear H.M et al., Immunity. 2019;50:907–923. 12. Manson JJ et al.,<a href="https://www.sciencedirect.com/science/journal/26659913"> The Lancet Rheumatology</a> <a href="https://www.sciencedirect.com/science/journal/26659913/2/10">Volume 2, Issue 10</a>, October 2020, Pages e594-e602 13. Mojtabavi, H., et al., Eur Cytokine Netw 31, 44–49 (2020). https://doi.org/10.1684/ecn.2020.0448 14. Zhang B, Zhou X, Qiu Y, et al. Clinical characteristics of 82 death cases with COVID‐19. medRxiv. 2020. AOPWiki 2021-04-20T02:44:25

2021-12-29T02:29:24

<upstream-id>f622d23d-c4bf-4b85-aab9-60f0c46b52e8</upstream-id> <downstream-id>67309182-5a36-4bde-a6f9-fc5a040748ac</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b43113a3bd8> AOPWiki 2021-04-20T02:45:45

2021-04-20T02:45:45

<upstream-id>f622d23d-c4bf-4b85-aab9-60f0c46b52e8</upstream-id> <downstream-id>033aeb9c-2e6d-41e8-ae6c-f313bb3ee990</downstream-id> Hypofibrinolysis is the process of a decreased fibrinolytic response, or decreasing the breakdown of fibrin in blood clots.  Hallmarks of a hypofibrinolysis state include elevated levels of TAFI and PAI-1 inhibitors, a dysregulated uPA/uPAR system, increased fibrinogen, and high levels of CRP (Bachler et al, 2021). These markers were found as a result of perturbation from SARS-COV-2 infection, although nanomaterial stressors can result in hypofibrinolysis as well. The results of hypofibrinolysis include an increase in coagulation levels and thrombosis(Hofman et al, 2016).   Hypofibrinolysis increases proinflammatory mediator levels through increase in PAI-1, a dysregulated uPA/uPAR system, and high levels of CRP. These markers of hypofibrinolysis increase proinflammatory mediators through endothelial cell dysfunction and activate pathways that lead to an increase in proinflammatory cytokines such as IL-2, TNF, and IL-6.

The biological plausibility is high as there is a relationship that understands that the evidence that indicates hypofibrinolysis, such as PAI-1, increased proinflammatory mediators levels when tested as a stressor. The increase of proinflammatory mediators through hypofibrinolysis is what leads to hypercogulation.   The result of hypofibrinolysis is increased levels of PAI-1 inhibitor, dysregulated uPA/uPAR system, high levels of C-reactive protein (CRP), and increased fibrinogen ( Bachler et al, 2016.) Increased expression of proinflammatory mediators such as IL6, TNF-Alpha, and MCP-1 followed exposure of PAI-1 inhibitor in mice, where macrophage were activated through NFKB and TLR4 (Gupta et al, 2016). This same data was discovered in human small cell lung cancer patients as well (Zhu et al, 2017). In a postmortem study of COVID-19 patients, expression of proinflammatory mediators was found in blood vessels parallel to PAI-1 localization (D’Agnillio et al, 2014). CRP, a proinflammatory mediator, also has a significant correlation with hypofibrinolysis, as studied in sepsis patients (Boudjeltia et al, 2004). A dysregulated uPA/uPAR system can also cause the increase of proinflammatory mediators, as uPA activation of co-receptors vascular endothelial growth factor(VEGF) VEGF-A and VEGF-2 causes signaling leading to downstream activation of proinflammatory pathways like NFKB and STAT3. (Sproston et al, 2018,  D’Alonzo et al, 2020)).

The empirical evidence is moderate, as an established relationship between hypofibrinolysis and increased proinflammatory mediators is evident, however due to the uncertain and ongoing nature of the COVID-19 pandemic, it's hard to establish any kind of dose response relationship as a result of the SARS-COV-2 stressor.     <table> <tbody> <tr> <td> stressor </td> <td> species </td> <td> study type </td> <td> dose </td> <td> KE upstream (fibrinolysis decrease) </td> <td> KE down stream (proinflammatory mediator increase) </td> <td> description </td> <td> reference </td> </tr> <tr> <td> SARS-COV-2 </td> <td> human </td> <td> in vivo </td> <td> Plasma from 118 severe COVID-19 patients and 30 control </td> <td> Elevations in both PAI-1 and tPA levels were found with strong correlation (r= 0.52, p<0.0001). PAI-1 levels experience higher elevation compared to tPA, leading to hypofibrinolysis </td> <td>A strong correlation between PAI-1 levels and neutrophil counts and markers of neutrophil activation</td> <td> Observed plasma from 118 COVID-19 patients and measured PAI-1 and tPA levels. Elevations in both PAI-1 and tPA levels were found with strong correlation (r= 0.52, p<0.0001). PAI-1 levels experience higher elevation compared to tPA, leading to hypofibrinolysis.   Molecule -> Molecule: SARS-COV-2 -> PAI-1/tPA </td> <td> Zuo, Y., Warnock, M., Harbaugh, A. et al. Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients. Sci Rep 11, 1580 (2021). https://doi.org/10.1038/s41598-020-80010-z </td> </tr> <tr> <td> Lipopolysaccharide (LPS from E. coli) </td> <td> Male wild-type (WT), PAI-1 deficient (PAI-1/), and TLR4 deficient (TLR4/) mice </td> <td> in vitro </td> <td> The pumps released their content at a steady rate of 1 mL/h over a period of three days </td> <td> Comparing PAI-1 deficient and wild type mice allows us to compare hypofibrinolysis induced mice with regular fibrinolysis effects.  </td> <td> macrophage levels in lungs increased in WT mice vs PAI-1 deficient mice (20% vs 12% 24 hrs later)   plasma levels of TNF-a (175 pg/ml with PAI-1 vs 100 pg/ml PAI-1 deficient.)   MIP-2 (750 pg/ml with PAI-1 vs 500 pg/ml PAI-1 deficient)  </td> <td> PAI-1 activates macrophages through TLR4 binding, leading to NFKB activation, which activates macrophages and increases proinflammatory mediators </td> <td> Gupta KK, Xu Z, Castellino FJ, Ploplis VA. Plasminogen activator inhibitor-1 stimulates macrophage activation through Toll-like Receptor-4. Biochem Biophys Res Commun. 2016 Aug 26;477(3):503-8. doi: 10.1016/j.bbrc.2016.06.065. Epub 2016 Jun 15. PMID: 27317488. </td> </tr> <tr> <td> SARS-COV-2 </td> <td> humans </td> <td> in vivo </td> <td> 20 critically ill COVID-19 patients vs 60 control </td> <td> decreased fibrinolysis in COVID-19 patients vs control (longer fibrinolytic response, lower lysis levels, increased clotting levels, higher fibrinogen and CRP levels)  </td> <td>Increased levels of proinflammatory mediators such as CRP were discovered. CRP has strong association with other proinflammatory mediators such as TNF and IL6.</td> <td> <h5 dir="ltr">A study of 20 ill COVID-19 patients using ClotPro assays and a measuring of lysis time that informs us the symptoms of those suffering from hypofibrinolysis due to covid-19 infection, which include higher fibrinogen levels, higher thrombocyte count, higher C-reactive protein levels, and increase lysis counts</h5>   SARS-COV-2 -> hypofibrinolysis -> Fibrinogen/thrombocytes/CRP/lysis </td> <td> <h5 dir="ltr">Bachler, <a href="https://doi.org/10.1016/j.bja.2020.12.010">https://doi.org/10.1016/j.bja.2020.12.010</a></h5> </td> </tr> <tr> <td> </td> <td> humans </td> <td> in vivo </td> <td> 11 ICU patients with sepsis vs 21 non sepsis patients </td> <td> High Fibrinogen levels in sepsis patients (657+-123) indicate hypofibrinolysis </td> <td> Increase of proinflammatory mediator CRP (24.2 in sepsis compared to 7.6 in non-sepsis). CRP has high association with TNF-alpha and IL6 proinflammatory mediators as well. </td> <td> <h5 dir="ltr">A study of 32 ICU patients with sepsis or other non-sepsis diagnosis. The Euglobulin Clot Lysis Time (ECLT) measured fibrinolytic levels by balancing tPA and PAI-1 activity. Results found a significant correlation between increased CRP levels and hypofibrinolysis infection</h5>   Fibrinogen/leukocytes/platelet ->  tPA/PAI-1 -> CRP </td> <td> <h5 dir="ltr">Boudjeltia, https://doi.org/10.1186/1477-9560-2-7</h5> </td> </tr> <tr> <td> SARS-COV-2 </td> <td> Postmortem lung autopsy samples of COVID-19 patients </td> <td> in vivo </td> <td> 18 lung samples of COVID-19 victims </td> <td> Expression of genes encoding key inhibitors of fibrinolysis, including SERPINE1 [SERPINF1 (A2AP), THBS1 (thrombospondin 1), and HRG (histidine-rich glycoprotein) were elevated  </td> <td> High expression of inflammatory cytokines TNF, IL6, IL8, MCP-1 in plasma.    Endothelial and inflammatory cell expression of IL6 and TGF-1 in pulmonary blood vessels and alveolar septal capillaries also paralleled the local- ization of PAI-1 </td> <td>Lung autopsy samples find that inhibitor of fibrinolysis genes such as SERPINE1 is highly upregulated, along side proinflammatory mediators such as IL6 and TGF-1.</td> <td> <h5 dir="ltr">D’Agnillo et al, 2014. doi: https://doi.org/10.1126/scitranslmed.abj7790</h5> </td> </tr> <tr> <td> PAI-1 </td> <td> Human monocyte cell lines U937 and THP-1 from non-small cell lung cancer patients </td> <td> in vivo </td> <td> 5, 15, 25, 35, 45 nM of PAI-1 </td> <td>With a PAI-1 dose of higher and higher levels, higher PAI-1 levels have a stronger correlation to hypofibrinolysis.</td> <td> low concentrations (5 and 15 nM) of PAI-1 significantly increased proinflammatory cytokines CCL-17, CCL-22, and IL-6 .    Higher concentrations (25, 35 and 45 nM) of PAI-1 increased CCL-17, CCL-22 and IL-6 expression dose dependently   Secretion of TGF-beta increased significantly 72 hours after PAI-1 treatment. </td> <td> <h5 dir="ltr">PAI-1 promotes increase in proinflammatory mediators due to TLR4 binding, leading to NFKB and STAT3 activation, causing macrophage and proinflammatory mediator increase</h5> </td> <td> <h5 dir="ltr">Zhu et al, 2017. DOI: 10.1159/0004860</h5> </td> </tr> </tbody> </table>

<table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>MF Specification</th> <th>Effect(s) on the KER</th> <th>Reference(s)</th> </tr> </thead> <tbody> <tr> <td> Chemicals (weak evidence) </td> <td>PFAS (PFOS) </td> <td>PFOS activates NF-κB and significantly induces the production of TNF-α and IL-6 in Kupffer cells [1], in HAPI cells [2] and in microglial cells [3], as well as in the liver of zebrafish [4].</td> <td> 1) doi: <a href="https://doi.org/10.1016/j.chemosphere.2018.02.137" rel="noreferrer noopener" target="_blank" title="Persistent link using digital object identifier">10.1016/j.chemosphere.2018.02.137</a> 2) doi: <a href="https://doi.org/10.1016/j.intimp.2015.05.019" rel="noreferrer noopener" target="_blank" title="Persistent link using digital object identifier">0.1016/j.intimp.2015.05.019</a> 3) doi: <a href="https://doi.org/10.1002/jat.3119">10.1002/jat.3119</a> 4) doi: <a href="https://doi.org/10.1016/j.fsi.2019.05.018" rel="noreferrer noopener" target="_blank" title="Persistent link using digital object identifier">10.1016/j.fsi.2019.05.018</a> </td> </tr> <tr> <td>Age</td> <td>Young/old people</td> <td>During the aging process, alterations of coagulation and fibrinolysis have been evidenced. Hypercoagulability with higher plasma concentrations of fibrinogen and factor VIII seems to be the basis of the increased thrombotic tendency occurring with age [1]. Hemostatic changes during aging have been described associated to plasma concentrations of some coagulation factors, such as fibrinogen, factor V, factor VII, factor VIII, factor IX, high molecular weight kininogen and prekallikrein increase in healthy humans in parallel with the physiological processes of aging. Fibrinogen levels increase in response to IL-6, which itself is strongly correlated with aging. Regarding anticoagulant proteins being modulated during aging, heparin co-factor II levels showed an age-related decrease, independently of sex [2]. The fibrinolytic system is also affected in aging and has previously been described as a systemic state of ‘‘thrombotic preparedness’’ with an acquired thrombophilia, characterized by heightened inflammation and impaired fibrinolytic capability [3]. To date, the implication of PAI-1 has been demonstrated in the process of cellular senescence. A null mutation in the PAI-1 gene was reported to increase aging in humans [4]. Increased PAI-1 production contributes to the multi-morbidity of aging. Both chronological and stress-induced accelerated aging are associated with cellular senescence and accompanied by marked increases in PAI-1 expression in tissues [5]. Furthermore, PAI-1 governs cellular senescence by regulating the extracellular proteolysis of the senescence-associated secretory phenotype (SASP). It has also been demonstrated that miR-146a negatively modulates PAI-1 in senescent cells, preventing an excessive increase in the production of inflammatory mediators and limiting some of the potentially deleterious effects of the SASP [6]. For this reason, PAI-1 is not only a key mediator of cellular senescence and aging but also of aging-related pathologies [5].</td> <td> 1) 10.1016/j.exger.2007.06.014 2) 10.1016/j.critrevonc.2006.06.004 3) 10.1007/s11239-009-0433-0 4) 10.1097/HS9.0000000000000570 5) 10.1161/ATVBAHA.117.309451 6) 10.1167/iovs.09-4874 </td> </tr> <tr> <td>Lipids</td> <td>Atherogenic dyslipidemia</td> <td> Lipoproteins play an integral role in hemostasis and thrombosis. Apolipoprotein A1 (ApoA1), a component of HDL, is ubiquitously antithrombotic [1]. In COVID-19. Morelli et al. observed significantly increased odds for venous thrombosis with lower ApoA1 and ApoB levels in a large case-control study [2]. ApoA1 prevented thrombosis in mice by upregulating nitric oxide availability [3], while in vitro studies have demonstrated its potential at fostering the anticoagulant protein C pathway [4]. In correlation with other biomarkers, observational studies have shown that low levels of ApoA1 and low levels in ApoB/ApoA1 in COVID-19 patients would potentially be associated with an “anti-fibrinolytic state” [5], as ApoA1 negatively correlated with PAI-1 while ApoB/ApoA1 were positively associated with plasminogen, resulting in reduced fibrinolytic capacity. Thus, the low HDL precondition associated with atherogenic dyslipidemia observed in severe COVID-19 may contribute to coagulopathy via the loss of the antithrombotic effect provided by these lipoproteins. </td> <td> 1) doi: 10.1001/jama.2009.1619 2) doi:  10.1007/s10654-017-0251-1 3) doi: 10.1161/ATVBAHA.112.252130 4) doi:  <a href="https://doi.org/10.1016/j.dsx.2021.04.011" style="color:blue; text-decoration:underline" target="_blank" title="Persistent link using digital object identifier">10.1016/j.dsx.2021.04.011</a> 5) doi:  <a href="https://doi.org/10.1016/j.dsx.2021.04.011" style="color:blue; text-decoration:underline" target="_blank" title="Persistent link using digital object identifier">10.1016/j.dsx.2021.04.011</a></td> </tr> <tr> <td>Vitamin D (moderate evidence)</td> <td>Vitamin D deficiency</td> <td> Low vitamin D status increases the risk of endothelial dysfunction with increased intracellular oxidative stress [1]. In endothelial cells, vitamin D regulates the synthesis of the vasodilator nitric oxide (NO) by mediating the activity of the endothelial NO synthase. High production of reactive oxygen species (ROS) increases NO degradation and impairs NO synthesis: impaired NO bioavailability is an early event toward the development of vascular damage. In this process, vitamin D acts as a protective agent against oxidative stress, by counteracting ROS production and enhancing the activity of anti-oxidative enzymes such as superoxide dismutase [1]. The antiphospholipid syndrome, a human autoimmune disease with thrombotic manifestations associated with low vitamin D serum levels, provides supportive evidence of the prothrombotic effect of vitamin D deficiency [2]. </td> <td> [1] doi: 10.3390/nu12020575 [2] doi: 10.1177/0961203318801520 </td> </tr> <tr> <td>genetic factors</td> <td> </td> <td> The blood group influences thrombogenesis. Factor-VIII vonWillebrand factor is lower in people with group 0 and higher blood levels of Factor VIII are associated with higher thrombotic risk [1]. Emerging evidence indicates that COVID-19 patients are at a high risk of developing coagulopathy and thrombosis, conditions that elevate levels of D-dimer [2]. It is believed that homocysteine, an amino acid that plays a crucial role in coagulation, may also contribute to these conditions. At present, multiple genes are implicated in the development of these disorders. For example, SNPs in FGG, FGA, and F5 mediate increases in D-dimer and SNPs in ABO, CBS, CPS1 and MTHFR mediate differences in homocysteine levels, and SNPs in TDAG8 associate with heparininduced thrombocytopenia. The gene–gene interaction network revealed three clusters that each contained hallmark genes for D-dimer/fibrinogen levels, homocysteine levels, and arterial/venous thromboembolism with F2 and F5 acting as connecting nodes [3]. </td> <td> [1] doi: 10.1046/j.1365-3148.2001.00315.x [2] doi: 10.1016/j.hrtlng.2021.01.011 [3] doi: 10.3389/fphar.2020.587451 </td> </tr> <tr> <td>Therapeutic intervention against COVID-19.</td> <td>Heparin</td> <td> Enhances the anticoagulant property of anti-thrombin, prevents fibrin formation and inhibits thrombin-induced activation of platelets and other coagulation factors [1,2].</td> <td> 1) 10.3389/fmed.2021.615333 2) 10.1161/hq0701.093686 </td> </tr> <tr> <td>Diet (weak)</td> <td>Plant-based diets may improve fibrinolysis markers</td> <td> <ul> <li>A few studies in human populations found indications that plant-focused or plant-based diets improve fibrinolysis markers, including shorter ELT (euglobulin lysis test, an indicator of higher fibrinolytic activity), increased fibrinolytic activity, increased EFA (euglobulin fibrinolytic activity), and decreased PAI-1 [290,291]. </li> <li>Other studies found associations between high meat intake and PAI-1 and PAI-1ag levels, indicating lower fibrinolytic activity [292,293]. </li> <li>Some studies found no association between dietary patterns or dietary components and fibrinolytic activity [294]. </li> </ul> </td> <td> <ul> <li>290: <a href="http://doi.org/10.1016/S0049-3848(99)00014-6">http://doi.org/10.1016/S0049-3848(99)00014-6</a></li> <li>291: <a href="http://doi.org/10.1093/ajcn/59.4.935">http://doi.org/10.1093/ajcn/59.4.935</a></li> <li>292: <a href="http://doi.org/10.3390/nu9040336">http://doi.org/10.3390/nu9040336</a></li> <li>293: <a href="http://doi.org/10.2337/dc08-1325">http://doi.org/10.2337/dc08-1325</a></li> <li>294: <a href="http://doi.org/10.20452/pamw.16123">http://doi.org/10.20452/pamw.16123</a></li> </ul>   </td> </tr> </tbody> </table>

Due to the uncertain and ongoing nature of the COVID-19 pandemic, it is difficult to understand a dose response relationship as a result of the SARS-COV-2 stressor, however individuals hit harder by the virus (hospitalizations) find themselves with higher proinflammatory mediator levels as a result of hypofibrinolysis.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42fc5566c0> AOPWiki 2021-04-20T02:47:10

2023-02-07T23:43:40

<upstream-id>67309182-5a36-4bde-a6f9-fc5a040748ac</upstream-id> <downstream-id>f622d23d-c4bf-4b85-aab9-60f0c46b52e8</downstream-id> Bradykinin (BK) plays an important role in the <a href="https://bioregistry.io/wikipathways:WP5089">kinin-kallikrein system</a> (KKS) as a regulator of blood pressure and can induce vasodilation, increase blood flow, as well as hypotension. BK is also an important part of the inflammatory process after injury, inducing pain stimulation. Activation of the BK system is associated with vasodilation and vascular leakage, allowing for infiltration of proinflammatory cells such as <a href="https://bioregistry.io/genecards:IL6">IL6</a> ((Hofman et al, 2016). During SARS-CoV-2 infection, increased activity of kallikrein activates the bradykinin system. Bradykinin is known to stimulate tissue plasminogen activator (<a href="http://bioregistry.io/genecards:PLAT">tPA</a>), a protein that increases fibrinolysis. However, <a href="https://bioregistry.io/genecards:ACE2">ACE2</a> downregulation from SARS-COV-2 infection increases Angiotensin 1 and II (ANG 1 and ANGII), which increases Plasminogen activator inhibitor (<a href="https://bioregistry.io/genecards:SERPINE1">PAI-1</a>) levels and decreases tPA levels (Mogielnicki et al, 2014). PAI-1 inhibits the protective effects of tPA/uPA in fibrinolysis, decreasing fibrinolysis. Data shows that both Bradykinin, and subsequently tPA levels and PAI-1 levels increase in COVID-19 patients, but PAI-1 increases at a higher rate than tPA, leading to hypofibrinolysis(Zuo et al, 2021). Bradykinin, as a result of its role as a vasodilator, <a href="https://bioregistry.io/GO:0043117">increases vascular permeability</a>, which increases levels of proinflammatory mediators such as IL6 (Sprague et al, 2009). These proinflammatory mediators have been found to increase PAI-1 levels, which ultimately leads to hypofibrinolysis(Kang et al, 2020. Rega et al, 2020).

The biological plausability of this KER is high, as there is a clear relationship between bradykinin activation and fibrinolysis decrease. Bradykinin system activation increases bradykinin levels. Normally, increased bradykinin levels will cause increased stimulation of bradykinin receptor 2 (<a href="https://bioregistry.io/genecards:BDKRB2">BDKRB2</a>), leading to an increase of tissue plasminogen activator (<a href="http://bioregistry.io/genecards:PLAT">tPA</a>) and urokinase plasminogen activator (<a href="http://bioregistry.io/genecards:PLAU">uPA</a>) (Garvin et al, 2020). However, in COVID-19 patients, SARS-COV-2 causes <a href="https://bioregistry.io/genecards:ACE2">ACE2</a> downregulation and angiotensin 2(ANG II) increase. ANG II is notable because it increase Plasminogen activator inhibitor-1 (<a href="https://bioregistry.io/genecards:SERPINE1">PAI-1</a>) and decreases tPA, discovered in a dose study of rats (Mogielnicki et al, 2014) Interestingly, in COVID-19 patients, there is still an increase in tPA and uPA observed, meaning that while ANG II does decrease tPA levels, because bradykinin activation still occurs at a higher rate than ANGII decreases tPA, that means the net effect is higher tPA levels. In COVID-19 patients, we see higher PAI-1 inhibitor levels compared to tPA/uPA levels, and that increased ratio ultimately leads to hypofibrinolysis in COVID-19 patients (Zuo et al, 2021).  Bradykinin also increase vascular permeability, causing increased levels of proinflammatory cytokines such as <a href="https://bioregistry.io/genecards:TNF">TNF-&prop;</a>, C-reactive protein (CRP), and IL6. These cytokines have been found to increase PAI-1 levels, thus leading to hypofibrinolysis (Kang et al, 2020. Rega et al, 2005.).

The empirical evidence of this KER is moderate, as there is evidence, i.e COVID-19 patients, that bradykinin activation and fibrinolysis decrease occurs. Evidence however more shows these events happening conccurently rather than happening at a later time, where one event leads to the other event.     <table> <tbody> <tr> <td> stressor </td> <td> species </td> <td> study type </td> <td> dose </td> <td> KE upstream (bradykininactivation) </td> <td> KE down stream (fibrinolysis decrease) </td> <td> description </td> <td> reference </td> </tr> <tr> <td> SARS-COV-2 </td> <td> human </td> <td> in vivo </td> <td> Plasma from 118 severe COVID-19 patients and 30 control </td> <td> </td> <td> Elevations in both PAI-1 and tPA levels were found with strong correlation (r= 0.52, p<0.0001). PAI-1 levels experience higher elevation compared to tPA, leading to hypofibrinolysis. </td> <td> Observed plasma from 118 COVID-19 patients and measured PAI-1 and tPA levels. Elevations in both PAI-1 and tPA levels were found with strong correlation (r= 0.52, p<0.0001). PAI-1 levels experience higher elevation compared to tPA, leading to hypofibrinolysis.   Molecule -> Molecule: SARS-COV-2 -> PAI-1/tPA </td> <td> Zuo, Y., Warnock, M., Harbaugh, A. et al. Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients. Sci Rep 11, 1580 (2021). https://doi.org/10.1038/s41598-020-80010-z </td> </tr> <tr> <td> SARS-COV-2 </td> <td> human </td> <td> in vivo </td> <td> 9 BAL samples of critically ill COVID-19 patients and 40 control  </td> <td> Bradykinin(BK) receptors BDKRB1 and BDKRB2 are highly upregulated in COVID-19 patients vs non-existent in control. BK precursor kininogen and all kallikreins are undetected in controls but expressed in COVID-19 BAL.   High downregulation of SERPING1 gene, causing an increase in BK. </td> <td> </td> <td> The observation of 9 BAL samples of COVID-19 patients finds upregulation of bradykinin receptors 1 and 2, leading to an increase in bradykinin levels and an increase in tPA/uPA levels   Molecule -> Molecule:    SARS-COV-2 -> BDKRB1/BDKRB2 -> BK ->tPA/uPA </td> <td> Garvin, M.R.; Alvarez, C.; Miller, J.I.; Prates, E.T.; Walker, A.M.; Amos, B.K.; Mast, A.E.; Justice, A.; Aronow, B.; Jacobson, D. A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. eLife 2020, 9. </td> </tr> <tr> <td> Angiotensin (1-9) </td> <td> Male Wistar rats (180–200 g) </td> <td> In vivo </td> <td> Ang-(1–9) in doses of 200 (n = 10),400 (n = 13),800 (n = 12) and 1600 pmol/kg/min (n = 13) </td> <td> </td> <td> Increased PAI-1 levels while decreasing tPA levels  </td> <td> Dose of ANG1-9 in rats find increased PAI-1 levels and decreased tPA levels, leading to hypofibrinolysis </td> <td> Mogielnicki A, Kramkowski K, Hermanowicz JM, Leszczynska A, Przyborowski K, Buczko W. Angiotensin-(1-9) enhances stasis-induced venous thrombosis in the rat because of the impairment of fibrinolysis. J Renin Angiotensin Aldosterone Syst. 2014 Mar;15(1):13-21. doi: 10.1177/1470320313498631. Epub 2013 Jul 24. PMID: 23884911. </td> </tr> <tr> <td> SARS-COV-2 </td> <td> human </td> <td> </td> <td> Review article </td> <td> ACE2 downregulation leads to bradykinin receptor binding, causing activation of bradykinin system </td> <td> ACE2 downregulation by SARS-COV-2 causes increased ANG1-9 which upregulates PAI-1 inhibitor, leading to hypofibrinolysis </td> <td> Discusses ACE2 downregulation as a result of SARS-COV-2, leading to increased Ang II and ANG1-9. Angiotensin II upregulates PAI-1 and breaks down tPA. </td> <td> Bernard I, Limonta D, Mahal LK, Hobman TC. Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19. Viruses. 2021; 13(1):29. https://doi.org/10.3390/v13010029 </td> </tr> <tr> <td> SiL6R </td> <td> Human endothelial cells </td> <td> In vivo </td> <td> 20 ng/mL of IL6 and 50/100 ng/mL of SIL6R </td> <td> Bradykinin activation induces proinflammatory mediator level increase thru vasodilation </td> <td> SIL6R and ILl6 treatment together (IL6 trans signaling) causes increase of PAI-1    In COVID-19 patients, blockade of IL6 with tocilizumab caused PAI-1 levels to decrease. </td> <td> Bradykinin is pre-established as a vasodilator that increases proinflammatory cytokine levels. Patients of all stressors had significantly higher proinflammatory cytokine levels than the controls.    Study into endothelial cells finds that proinflammatory cytokine levels increase significantly when treated with IL6 and soluble IL6R (IL6 trans signaling), also increased include PAI-1 levels </td> <td> Kang S, Tanaka T, Inoue H, Ono C, Hashimoto S, Kioi Y, Matsumoto H, Matsuura H, Matsubara T, Shimizu K, Ogura H, Matsuura Y, Kishimoto T. IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome. Proc Natl Acad Sci U S A. 2020 Sep 8;117(36):22351-22356. doi: 10.1073/pnas.2010229117. Epub 2020 Aug 21. PMID: 32826331; PMCID: PMC7486751. </td> </tr> <tr> <td> Adipose tissue </td> <td> IL6 </td> <td> In vivo </td> <td> 100 ng/mL </td> <td> </td> <td> IL6 levels, increased when bradykinin activation occurs. n subcutaneous and visceral adipose tissue, IL6 increased PAI-1 levels up to 3.5 fold. Dose dependent response found with lower dose (0.1, 1) that visceral adipose tissue had higher PAI-1 levels than subcutaneous. Higher dose (10,100) had relatively equal PAI-1 levels.  </td> <td> </td> <td> Rega, G et al. (2005, April 19). Inflammatory cytokines interleukin-6 and oncostatin m induce plasminogen activator inhibitor-1 in human adipose tissue. Circulation. Retrieved January 19, 2022, from https://www.ahajournals.org/doi/full/10.1161/01.CIR.0000161823.55935.BE </td> </tr> </tbody> </table>

While the evidence connecting bradykinin activation and fibrinolysis decrease is evident, a direct relationship where bradykinin activation leads to fibrinolysis decrease is harder to establish. One of the outcomes of bradykinin runs opposite to fibrinolysis decrease, as bradykinin increases tPA levels where hypofibrinolysis decreases tPA levels as a result of PAI-1 increase. Without a stressor that affects PAI-1 levels more drastically than bradykinin affects tPA levels, such as SARS-COV-2, this relationship would not be possible.

SARS-COV-2 is shown to be a modulating factor as Bradykinin activation normally causes increased tPA/uPA, which would cause fibrinolysis, not hypofibrinolysis.

Understanding quantitative linkage is difficult as the global pandemic caused by SARS-COV-2 is still a major factor in the world, however it is clear that individuals more severely affected by SARS-COV-2 (hospitalizations) result in higher change of fibrinolysis decrease as a result of bradykinin activation. Perturbation of the RAAS system where ANGII levels are greater than ANGI levels cause this relationship. What specifically causes more severe SARS-COV-2 reactions is yet to be understood.

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b43131878c0> AOPWiki 2021-04-20T02:46:53

2022-01-24T11:49:00

<upstream-id>67309182-5a36-4bde-a6f9-fc5a040748ac</upstream-id> <downstream-id>033aeb9c-2e6d-41e8-ae6c-f313bb3ee990</downstream-id> Bradykinin (BK) plays an important role in the kinin-kallikrein system (<a href="https://bioregistry.io/wikipathways:WP5089">KKS</a>) as a regulator of blood pressure and can induce vasodilation, increase blood flow, as well as hypotension. BK is also an important part of the inflammatory process after injury, induces pain stimulation, and increases vascular permeability (Maas, <a href="https://link.springer.com/article/10.1007/s12016-016-8540-0">10.1007/s12016-016-8540-0</a>). The bradykinin system gets activated through various methods, including nanoparticles and SARS-COV-2 via the contact activation system (Maas, <a href="https://link.springer.com/article/10.1007/s12016-016-8540-0">10.1007/s12016-016-8540-0</a>, Ekdahl doi: 10.1080/14686996.2019.1625721). Activation of the bradykinin system leads to increase of proinflammatory mediators due to increased production of proinflammatory mediator bradykinin(<a href="https://doi.org/10.1161/01.CIR.95.5.1115">https://doi.org/10.1161/01.CIR.95.5.1115</a>)  as well as upregulating bradykinin receptor 1 (<a href="https://bioregistry.io/genecards:BDKRB1">BDKRB1</a>) and 2(<a href="https://bioregistry.io/genecards:BDKRB2">BDKRB2</a>), leading to induction of proinflammatory mediators such as <a href="https://bioregistry.io/genecards:IL2">IL-2</a>, <a href="https://bioregistry.io/genecards:IL6">IL-6</a> and <a href="https://bioregistry.io/genecards:IL8">IL-8</a> (<a href="https://doi.org/10.1165/rcmb.2002-0040OC">https://doi.org/10.1165/rcmb.2002-0040OC</a>) and the activation of the <a href="https://bioregistry.io/wikipathways:WP4562">NFKb pathway</a> leading to production of proinflammatory mediators <a href="https://bioregistry.io/genecards:TNF">TNF</a> and <a href="https://bioregistry.io/genecards:IL1">IL1</a>(<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC507648/">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC507648/</a>).

Bradykinin (BK) system activation causes increased production of bradykinin. Bradykinin has been established as a potent proinflammatory mediator due to bradykinin’s role in inflammation. BK acts as a vasodilator, increases vascular permeability, and stimulates prostaglandin synthesis(https://www.ncbi.nlm.nih.gov/books/NBK537187/).  Bradykinin can also induce proinflammatory cytokine production such as <a href="https://bioregistry.io/genecards:TNF">TNF</a>, <a href="https://bioregistry.io/genecards:IL2">IL2</a>, <a href="https://bioregistry.io/genecards:IL6">IL6</a>, and<a href="https://bioregistry.io/genecards:IL8"> IL8</a> through stimulation of ERK1/2 and <a href="https://bioregistry.io/wikipathways:WP400">p38 MAPK</a> pathways, causing inflammation and leading to an increase in proinflammatory mediators (<a href="https://www.frontiersin.org/articles/10.3389/fphar.2020.01278/full">https://www.frontiersin.org/articles/10.3389/fphar.2020.01278/full</a>).

<table> <tbody> <tr> <td> stressor </td> <td> species </td> <td> study type </td> <td> dose </td> <td> KE upstream (bradykinin activation) </td> <td> KE down stream (proinflammatory mediator increase) </td> <td> description </td> <td> reference </td> </tr> <tr> <td> bradykinin </td> <td> airway smooth muscle cells </td> <td> in vivo </td> <td> 1 micro-meter BK for 0 to 24 h </td> <td> </td> <td> Bradykinin significantly increased IL-6, greater dose of BK, greater IL6 levels . BK-induced IL-6 expression may be regulated by p38 MAPK and ERK1/2 pathways. </td> <td> Study of airway smooth muscle cells that shows how Bradykinin induces IL6 production. bradykinin -> IL6 </td> <td> Huang et al, 2002. doi: <a href="https://doi.org/10.1165/rcmb.2002-0040OC">https://doi.org/10.1165/rcmb.2002-0040OC</a>  </td> </tr> <tr> <td> bradykinin </td> <td> human lung tissue </td> <td> in vivo </td> <td> 0, 0.1, 1, 10, 100, and 1000 nM of Bradykinin </td> <td> </td> <td> IL6 and IL8 production increased as BK dose increased.   Use of bradykinin receptor antagonists caused IL6 and IL8 levels to decrease.   Phosphorylation of p38 MAPK and ERK1/2 were rapidly induced as a result of BK stimulation. </td> <td> <h5 dir="ltr">Study indicating how Bradykinin stimulates IL-6 and IL-8 production by human lung fibroblasts through ERK- and p38 MAPK-dependent mechanisms.</h5> Bradykinin -> ERK/p38 MAPK -> IL-6/IL-8 </td> <td> Hayashi et al. 2000. doi: 10.1034/j.1399-3003.2000.016003452.x. </td> </tr> <tr> <td> bradykinin </td> <td> human lung fibroblast cell line WI-38 </td> <td> in vivo </td> <td> 1, 10, 100, 1000 nM of Bradykinin </td> <td> </td> <td> Bradykinin sharply increases production of proinflammatory cytokine IL1-B and activates transcription factor NFK-B. </td> <td> <h5 dir="ltr">Stimulation of human lung fibroblast cell line WI-38 with Bradykinin led to increased levels of proinflammatory cytokines interleukin 1-beta and activation of NFKB. </h5> Bradykinin -> IL-1B/NFKB </td> <td> Pan et al, 1996. doi: <a href="https://dx.doi.org/10.1172%2FJCI119009">10.1172/JCI119009</a> </td> </tr> <tr> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> <h5 dir="ltr">A review of studies establishes how bradykinin plays a prominent role in inflammation as a potent proinflammatory agent. Bradykinin is a vasodilator which widens blood vessels, which allows fluid to leak from the vessel into tissues, increasing inflammation.</h5> Bradykinin -> proinflammatory mediator </td> <td> Hornig et al. 1997. doi: <a href="https://doi.org/10.1161/01.CIR.95.5.1115">https://doi.org/10.1161/01.CIR.95.5.1115</a> </td> </tr> <tr> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> <h5 dir="ltr">A review article establishing bradykinin as a proinflammatory mediator because bradykinin causes increased vasodilation and vascular permeability, leading to the induction of inflammation and inflammatory cytokines</h5> Bradykinin -> proinflammatory mediator -> cytokines </td> <td> Goilas et al. 2007. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2658795 </td> </tr> <tr> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> <h5 dir="ltr">Bradykinin-induced B2R signals generate IL-6 and the activation of B1R or B2R can result in Substance P(SP) production with both IL-6 and SP participating in the recruitment of neutrophils and the activation of JAK2 cell signals. </h5> Bradykinin -> B2R signalling -> IL-6 -> B1R/B2R -> SP -> neutrophils/JAK2 </td> <td> Curran et al, 2020. <a href="https://doi.org/10.3389/fphar.2020.01278">https://doi.org/10.3389/fphar.2020.01278</a>  </td> </tr> <tr> <td> SARS-COV-2 </td> <td> human </td> <td> in vivo </td> <td> 9 BAL samples of critically ill COVID-19 patients and 40 control  </td> <td> Expression of  kininogen and kallikreins expressed in COVID-19 BAL, but not control samples. Bradykinin receptors BKB2R and BKB1R are expressed 207 and 2945 fold higher in COVID-19 samples than the control samples </td> <td> proinflammatory cytokine IL2 highly upregulated in COVID-19 BAL samples compared to control, IL2 is induced by BK in the lung, causing vascular leakage </td> <td> <h5 dir="ltr">Proinflammatory cytokine IL2 was found highly upregulated in symptomatic but not asymptomatic COVID-19 patients and is upregulated (21 fold) in the BAL samples compared to controls. This cytokine is induced by BK in the lung, and causes vascular leakage syndrome (VLS), which appears to be mediated through CD44. </h5> Bradykinin -> IL-2 -> CD44 -> vascular leakage syndrome </td> <td> Garvin et al, 2020. doi: <a href="https://dx.doi.org/10.7554%2FeLife.59177">10.7554/eLife.59177</a> </td> </tr> <tr> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> https://pubmed.ncbi.nlm.nih.gov/23361105/ </td> </tr> </tbody> </table>

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b431336ccd0> AOPWiki 2021-04-20T02:45:56

2022-01-14T15:02:21

<upstream-id>67309182-5a36-4bde-a6f9-fc5a040748ac</upstream-id> <downstream-id>4d904cb5-2bd3-4580-bc7e-01e01a2c2160</downstream-id> Bradykinin (BK) plays an important role in the kinin-kallikrein system (<a href="https://bioregistry.io/wikipathways:WP5089">KKS</a>) as a regulator of blood pressure and can induce vasodilation, increase blood flow, as well as hypotension. BK is also an important part of the inflammatory process after injury, inducing pain stimulation, and increased vascular permeability (Maas, <a href="https://link.springer.com/article/10.1007/s12016-016-8540-0">10.1007/s12016-016-8540-0</a>). The bradykinin system gets activated through various methods, including nanoparticles and SARS-COV-2 via the contact activation system (Maas, <a href="https://link.springer.com/article/10.1007/s12016-016-8540-0">10.1007/s12016-016-8540-0</a>). Activation of the bradykinin system increases production of bradykinin. Bradykinin increases vascular permeability and activates endothelial cells(Garvin 2020 doi: 10.7554/eLife.59177). Vascular permeability is present in covid-19 patients with severe vascular damage and neutrophil infiltration (Carvalho 2021 doi: 10.1038/s41577-021-00522-1). Endothelial cell activation by bradykinin causes loss of anti-inflammatory properties and recruitment of  proinflammatory mediators such as an increase in <a href="https://bioregistry.io/genecards:IL6">IL6</a>, <a href="https://bioregistry.io/genecards:CXCL10">CXCL10</a>, <a href="https://bioregistry.io/genecards:TNF">TNF</a> as well as hyperactivation of <a href="https://bioregistry.io/genecards:CD4">CD4</a>+ and <a href="https://bioregistry.io/genecards:CD8">CD8</a>+, and increased numbers of monocytes, including plasmablast-like neutrophils and eosinophils, all hallmarks of a hyperinflammatory state (Bernard 2020 doi: 10.3390/v13010029). <a href="https://bioregistry.io/genecards:IL6">IL-6</a>, activated by bradykinin’s activation of the endothelium, also exacerbates hyperinflammation.

Activation of the bradykinin system increases production of bradykinin. Bradykinin increases vascular permeability by DABK binding to <a href="https://bioregistry.io/genecards:BDKRB1">B1</a> receptor, leading to leaky blood vessels (Garvin 2020 doi: 10.7554/eLife.59177), activated <a href="https://bioregistry.io/wikipathways:WP4969">RAS</a> and BK which leads to increased permeability of endothelium, (Bernard 2020 doi: 10.3390/v13010029) and bradykinin binding to bradykinin receptor 2 leading to endothelium dysfunction (Zwaveling 2020 doi: 10.1016/j.jaci.2020.08.038).  Patients suffering from severe COVID-19 have had evidence of vascular damage, neutrophil infiltration and neutrophil extracellular traps inside micro-vessels (Carvalho 2021 doi: 10.1038/s41577-021-00522-1).  RAAS dysfunction and bradykinin system activation causes Endothelial dysfunction, leading to immunothrombosis and induction of a pro-thrombotic state, causing hyperinflammation and increased platelets (Bernard 2020 doi: 10.3390/v13010029). The endothelial dysfunction also causes loss of anti-inflammatory properties and recruitment of  proinflammatory mediators such as an increase in <a href="https://bioregistry.io/genecards:IL6">IL6</a>, <a href="https://bioregistry.io/genecards:CXCL10">CXCL10</a>, <a href="https://bioregistry.io/genecards:TNF">TNF</a>, hyperactivation of <a href="https://bioregistry.io/genecards:CD4">CD4</a>+ and <a href="https://bioregistry.io/genecards:CD8">CD8</a>+, and increased numbers of monocytes, including plasmablast-like neutrophils and eosinophils, all hallmarks of a hyperinflammatory state (Ekdahl 2019 doi: 10.1080/14686996.2019.1625721). Bradykinin also activates pathways to proinflammatory cytokine production for cytokines such as <a href="https://bioregistry.io/genecards:IL6">IL6</a>, and IL6 exacerbates hyperinflammation (Bernard 2020 doi: 10.3390/v13010029). Finally, bradykinin activation is activated by nanomaterials and specifically coagulation factor XII (<a href="https://bioregistry.io/genecards:F12">F12</a>), and due to the bradykinin system being activated via the contact system, the coagulation cascade is activated as well, leading to increased production of fibrinogen and fibrin, leading to more production of D-dimers, a biomarker for hyperinflammation (Maas, <a href="https://link.springer.com/article/10.1007/s12016-016-8540-0">10.1007/s12016-016-8540-0</a>).

<table> <tbody> <tr> <td> description </td> <td> reference </td> </tr> <tr> <td> Review study that details the vascular complications the Bradykinin storm has in covid-19 and discusses bradykinin’s role in inflammation and how bradykinin leads to Vasodilation and increased vascular permeability </td> <td> McCarthy et al, 2021. <a href="https://doi.org/10.1016/j.vph.2020.106826">https://doi.org/10.1016/j.vph.2020.106826</a> </td> </tr> <tr> <td> Review study that discusses how bradykinin causes vascular permeability through BDKRB1 receptor by BK1-8, which also causes neutrophil recruitment, leakage of fluid into the lungs and increased inflammatory cells  </td> <td> Garvin 2020 doi: 10.7554/eLife.59177 </td> </tr> <tr> <td> A review study that discusses endothelium cell infection by SARS-COV-2. Activated RAAS system and bradykinin system activation leads to endothelial cell dysfunction from increased bradykinin. That endothelial cell dysfunction causes immunothrombosis and induces a pro-thrombotic state, leading to hyperinflammation. </td> <td> Bernard 2020 doi: 10.3390/v13010029 </td> </tr> <tr> <td> A review study discussing how pulmonary edema can be caused by bradykinin in SARS-COV-2 and how increase in endothelial cell permeability is caused by bradykinin binding to the Bradykinin 2 receptor </td> <td> Zwaveling 2020 doi: 10.1016/j.jaci.2020.08.038 </td> </tr> <tr> <td> A review study of immunological insights of COVID-19 patients. Patients suffering from severe COVID-19 have had evidence of vascular damage, neutrophil infiltration and neutrophil extracellular traps inside micro-vessels </td> <td> Carvalho 2021 doi: 10.1038/s41577-021-00522-1 </td> </tr> <tr> <td> A review study of the innate immunity study in humans that discusses how endothelial cell dysfunction causes loss of anti-inflammatory properties and recruitment of  proinflammatory mediators,markers of hyperinflammation </td> <td> Ekdahl 2019 doi: 10.1080/14686996.2019.1625721 </td> </tr> <tr> <td> A review study of vascular permeability, how it gets caused by bradykinin, and how it can lead to hyperinflammation </td> <td> Welsh 2015  doi: <a href="https://dx.doi.org/10.3109%2F03009734.2015.1064501">10.3109/03009734.2015.1064501</a> </td> </tr> <tr> <td> A review study that discusses bradykinin induced vascular complications due to COVID-19 and how bradykinin leads to vascular permeability and vasodilation  </td> <td> McCarthy, <a href="https://doi.org/10.1016/j.vph.2020.106826">https://doi.org/10.1016/j.vph.2020.106826</a>) </td> </tr> </tbody> </table>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b43133df078> AOPWiki 2021-04-20T02:47:21

2021-10-19T16:19:18

<upstream-id>033aeb9c-2e6d-41e8-ae6c-f313bb3ee990</upstream-id> <downstream-id>d415f369-d29d-4dda-9857-b847673b8085</downstream-id> Pro-inflammatory mediators are the chemical and biological molecules that initiate and regulate inflammatory reactions. They are secreted following inflammation or exposure to an inflammogen. Commonly measured pro-inflammatory mediators include Interleukin (IL)-1 family cytokines, <a href="https://bioregistry.io/genecards:IL4">IL-4</a>,<a href="https://bioregistry.io/genecards:IL5"> IL-5</a>, <a href="https://bioregistry.io/genecards:IL6">IL-6</a>, Tumor necrosis factor alpha (<a href="https://bioregistry.io/genecards:TNFa">TNF</a>-α), Interferon gamma (<a href="https://bioregistry.io/genecards:IFNg">IFN</a>-γ) (<a href="https://aopwiki.org/events/1496">KE1496</a>) Proinflammatory mediator increase is caused when there’s increased inflammation. This can be found in many ways, including bradykinin system activation or hypofibrinolysis (Hofman et al., 2016). With more proinflammatory mediators, this causes increased signaling from proinflammatory cytokines, which promotes leukocyte recruitment, which will differentiate into proinflammatory cells (Villeneuve et al., 2018). Increased proinflammatory mediators means this process happens more, which means increase recruitment of inflammatory cells.

The biological plausibility of this KER is high. There are very well established functional relationships between the secreted signalling molecules and the chemotactic effects on pro-inflammatory cells (Harris, 1954; Petri and Sanz 2018). Increased proinflammatory mediators means more pro-inflammatory cytokines, chemokines, vasoactive amines, and lipid mediators (Villeneuve et al., 2018). Increased signaling from these Cytokines and Chemokines promote leukocyte recruitment to areas of infection, including monocytes and neutrophils (Khatri et al., 2017; Leick et al., 2014; Marchini et al., 2016). The leukocytes will differentiate into mature pro-inflammatory cells, in response to mediators they encounter in the local tissue microenvironment (Villeneuve et al., 2018). With higher levels of leukocytes from increased pro-inflammatory mediators, it causes an increase in pro-inflammatory cells (Libby, 2015).

The empirical support for this KER is moderate. There are many studies which show temporal and dose-dependent recruitment of immune cells following increases in pro-inflammatory mediators. However, these mediators exhibit pleiotropy, and knockdown or knockout of a single pathway or mediator can result in compensation and recruitment of immune cells at a later time, as is seen in Nikota et al.,. 2017. (Chen et al., 2016; Nikota et al., 2017; Schremmer et al., 2016) (Additional studies available in <a href="https://aopwiki.org/system/dragonfly/production/2023/05/15/352dxc9mru_KE1_KE2_Table_1.pdf">Table 1</a>). Dose-Response Evidence: Many studies provide dose-response evidence of this KER. For example, in vitro and in vivo studies testing stressors at different doses/concentrations have demonstrated a dose-response relationship; at the higher dose of the stressor, the pro-inflammatory mediators increased, leading to an increase of pro-inflammatory cell recruitment.  Ma et al. (2016) studied inflammatory responses in male BALB/c mice exposed to multi-walled carbon nanotubes (MWCNTs) administered intravenously at different doses (0.5-4 mg/kg) for 2 days. A dose-dependent relationship was found between the levels of the inflammatory mediators IL-6 and TNF-α and the MWCNT dose. At the highest dose, 4 mg/Kg, white blood cells, lymphocytes, and neutrophils levels increased. Porter et al. (2020) have demonstrated that MWCNTs caused dose-dependent and time-dependent pulmonary inflammation in male C57BL/6J mice. Animals received a single dose of 2.5, 10, or 40 µg/mouse. At 40 µg/mouse, IL-1β and IL-18 increased at one day post-exposure. Moreover, polymorphonuclear leukocytes increased on day 1, and after 7 days the number of inflammatory cells was higher. Zinc oxide (ZnO) nanoparticles (NPs) can induce metal fume fever and acute inflammation. Female C57BL/6J mice were intratracheally instilled once at 11, 33, and 100 µg/kg with coated ZnO NPs. Inflammatory responses were evaluated after 1, 3, and 28 days of exposure. An increase in Serum Amyloid A3 (Saa3) mRNA in lung tissue was observed at 33 and 100 µg/kg. Neutrophils accumulated in bronchoalveolar lavage fluid (BALF) after 28 days of exposure in a dose-dependent manner (Hadrup et al., 2019). Polyhexamethylene guanidine phosphate (PHMG-P) is used as a disinfectant. PHMG-P at 0.3, 0.9, and 1.5 mg/kg was instilled into the lungs of mice. At 7- and 14-days post-exposure an increase in the levels of pro-inflammatory markers (IL-1β, IL-6, and C-X-C motif chemokine ligand [CXCL]1) and an increase in mRNA levels of Monocyte chemoattractant protein (MCP)1, Matrix metalloproteinase (MMP)2, and MMP12 was seen. Moreover, on day 7, neutrophils were recruited to the inflamed site. These changes were observed in a dose-response manner (Song et al., 2014). Bourdon et al. 2012 evaluated the toxicity of carbon black nanoparticles (CBNPs) in mouse lung and liver. C57BL/6 mice were exposed to Printex 90 CBNPs with 0.018, 0.054, or 0.162 mg, and after 1, 3, and 28 days of the single instillation, BALF was analyzed. Polymorphonuclear cell counts in BALF increased in a dose-dependent manner with the strongest recruitment 1- and 3-days post-exposure and remained elevated at day 28. CBNPs also increased the expression of Saa3 mRNA levels in lung tissue on days 1, 3, and 28 in a dose-dependent manner. Although this response decreased over time, the expression of Saa3 mRNA increased at all time points, which indicates a persistent acute phase response. A study evaluated the mechanisms of toxicity after exposure to particulate matter (PM2.5) in a tri-culture system: A549 cells (alveolar epithelial cells) and THP-1 differentiated macrophages in the apical chamber; meanwhile, EA.hy926 endothelial cells were cultured in the basolateral chamber. The system was exposed to PM2.5 at three different concentrations 20, 60, and 180 µg/ml for 24 h. An increase in the pro-inflammatory mediators IL-6, IL-8, and TNF-α was observed, as well an increase in mRNA expression of MMP9, Intercellular adhesion molecule 1 (ICAM-1), and caveolin 1 (CAV-1). These genes are involved in the movement and recruitment of leukocytes in sites of inflammation. Changes were observed in a concentration-dependent manner (Wang et al., 2019). In another study, female C57BL/6 mice were exposed to 18, 54, or 162 µg of MWCNT/mouse via single intratracheal instillation. An increased gene expression of Cxcl1, IL-6, Metallothionein-2 (Mt2), Saa1, and Saa2 was observed in a dose-dependent manner at 24 h post-exposure. Moreover, an increase in the recruitment of pro-inflammatory cells was observed in a dose-dependent manner (Poulsen et al., 2013). Temporal Evidence: There is significant evidence of the temporal relationship between the two KES.  In vitro and in vivo studies have demonstrated that pro-inflammatory mediators (Event 1496) increased prior to the recruitment of pro-inflammatory cells (Event 1497). Female C57BL/6J mice were exposed to carbon NPs at 20 µg/mouse via intratracheal instillation. An increase in the levels of cytokines CXCL1, CXCL2, and CXCL5 at 3 h post-exposure was observed, with peaks after 12 and 18 h post-exposure. These pro-inflammatory mediators preceded neutrophil recruitment (12 and 24 h post-exposure) (Chen et al., 2016). Alveolar macrophages (AM) were isolated from lungs 3 to 12 h after instillation, but they did not show a pro-inflammatory response. The authors suggest that AM are not involved in the initiation of the inflammatory response. Meanwhile, alveolar epithelial type II cells induced the highest CXCL levels and acute neutrophilic inflammation. Nickel oxide (NiO) NPs intratracheally instilled at one single dose 200 cm2/rat into female Wistar rats induced an increase of pro-inflammatory cytokines in BALF, at 24 and 74 h for Cytokine-Induced neutrophil chemoattractant 3 (CINC-3) and eotaxin, respectively. At 24 h and 48 h, neutrophils were observed, and after 72 h, the levels of neutrophils, eosinophils, and macrophages increased (Lee et al., 2016). Porter et al. (2002) have shown pulmonary inflammation in rats exposed to crystalline silica aerosol at a concentration of 15 mg/m3 (6h/day, 5 days/week) for 116 days.  Lung disease was linked to TNF-α and IL-10 production in a timely response (10-116 days). The number of polymorphonuclear cells in the BALF increased progressively from day 41 - 116. One study has demonstrated a dose-response and temporal relationship for these two KEs (Patowary et al., 2020). Female Wistar rats were exposed to oleoresin capsicum sprays at 2, 6, and 10%, and after 1, 3, and 24 h post-exposure, blood cell and BALF cytokines were evaluated. The pro-inflammatory cytokine TNF-α increased in a dose-dependent manner, and polymorphonuclear cells increased in a time-dependent manner. Schremmer et al. (2016) have reported the time course of chemotaxis in vitro in response to the challenge of biopersistent particles and their relation to inflammatory mediators.  NR8383 rat alveolar macrophages were challenged with different types of particles for 1, 4, and 16 h. The cell supernatants obtained from different time points were used to evaluate the chemotaxis of unexposed NR8383 macrophages. They found that nanosized silica at 16 µg/cm2 induced an elevated transcription of C-C motif chemokine ligand (CCL)4, CXCL1, CXCL3, and TNF-α in a time-dependent manner. The pro-inflammatory cytokines present in the supernatants induced chemotaxis of unexposed macrophages at 4 and 16 h post-exposure. Husain et al. (2015) found increased expression of genes related to chemotactic recruitment of pro-inflammatory cells at 3 h and 1 day after exposure to 162 µg/mouse CBNPs in female C57BL/6 mice. They observed an increase in the gene expression of pro-inflammatory mediators at day 1 (CXCL2, Ccl2), day 3 (IL-17, IL-33), day 14 (Cd2), and day 42 (Cxcl) post-exposure. The KE2 (Event 1497) increased over time with the maximum levels of neutrophils, macrophages, eosinophils, and lymphocytes at 4- and 5-days post-exposure. This response suggests chronic inflammation occurs because of an incomplete resolution of acute inflammation. Rahman et al. (2017) evaluated whether different titanium dioxide (TiO2) NPs induce lung inflammation. C57BL/6 mice were exposed to 18, 54, 162, or 486 µg/mouse of TiO2 NPs via single intratracheal instillation. At 1-day post-exposure, gene expression analysis showed more changes in genes associated with inflammation and fibrosis. Moreover, after 1- and 28 days post-exposure, an increase in cell counts in BALF was observed in a dose-dependent manner. Ho et al. (2013) evaluated the inflammatory response in mice exposed to coated quantum dots, cadmium-based NPs, (QD705-poly(ethylene glycol[PEG], QD705-COOH) at 12 or 60 µg/mouse. At 2-, 17- and 90-days post-exposure, an increase in the level of TNF-α, IL-1b, IL-6, CXCL1, CCL2, CCL1, CCL17, and CXCL13 mRNA levels in lungs was observed and the amount of polymorphonuclear cells in BALF increased in a dose-dependent manner at day 7 post-exposure. The inflammatory response increased on days 2 and 17, but on day 90 decreased. QD705-COOH induced granulomas persistently presented from 2 to 90 days. Morimoto et al. (2010) examined the different kinds of cytokines related to lung inflammation by NiO exposure. Rats were intratracheally exposed to 0.33 mg/Kg and 0.66 mg/kg NiO NPs and were sacrificed at day 3, after 1 week, 1, 3, and 6 months post-exposure. Infiltration of alveolar macrophages in lung tissue and BALF was observed from day 3 to 3 months post-exposure, with higher levels after 1 and 3 months. Before the recruitment of inflammatory cells, an increase in the level of pro-inflammatory cells such as MCP-1 and IL-1β in BALF was observed. NiO NPs induced a persistent inflammatory effect. Kamata et al. (2011) studied the impact of CBNPs on susceptible subjects with predisposing lung disease and the effects of nanoparticles on inflammation and fibrotic changes. To achieve this goal, female C57BL/6J mice were intratracheally administered with bleomycin 20 µg/mouse and CBNPs 10 µg/mouse. Evaluations were performed post-exposure at different time points. An increase of IL-6 and CCL2 in BALF was observed at days 2 and 7. After 7- and 14 days, a recruitment of pro-inflammatory cells was observed. Oxidant injury (evaluated as nitrotyrosine expression) was observed after 7 days and 14 days. The levels of Transforming growth factor beta (TGF-β) increased over time with the highest level at day 14. Finally, they observed an increase in lung collagen deposition and a decrease in lung compliance at day 21.

Attenuation or complete abrogation of KE1 (<a href="https://aopwiki.org/events/1496">KE1496</a>) and KE2 (<a href="https://aopwiki.org/events/1497">KE1497</a>) following inflammogenic stimuli is observed in rodents lacking functional Interleukin 1 receptor type 1 (IL-1R1) or other cell surface receptors that engage innate immune response upon stimulation (Gasse et al., 2007; Halappanavar et al., 2013). However, following exposure to MWCNTs, it has been shown that absence of IL-1R1 signalling is compensated for eventually and neutrophil influx is observed at a later post-exposure time point (Nikota et al., 2017). In another study, acute neutrophilic inflammation induced by MWCNTs was suppressed at 24 h in mice deficient in IL-1R1 signalling; however, these mice showed exacerbated neutrophilic influx and fibrotic response at 28 days post-exposure (Girtsman et al., 2014). The early defence mechanisms involving damage-associated molecular patterns is fundamental for survival, which may necessitate activation of compensatory signalling pathways. As a result, inhibition of a single biological pathway mediated by an individual cell surface receptor may not be sufficient to completely abrogate the lung inflammatory response. Forced suppression of pro-inflammatory and immune responses early after exposure to substances that cannot be effectively cleared from lungs, may enhance the injury and initiate other pathways leading to exacerbated response. Most of the studies evaluate one dose at different time points or one-time point at different concentrations. Moreover, some studies have demonstrated that a stressor can lead to the recruitment of pro-inflammatory cells, but the presence of pro-inflammatory mediators was not determined (Westphal et al., 2015). Recruitment of pro-inflammatory cells is a key event that is complicated to replicate in vitro conditions as cell migration is induced by cooperative chemotactic mediators (Gouwy et al., 2015) which are produced and released from different cells. Therefore, more kinetics studies in co-culture techniques are needed to fill this gap.

<table border="1" bordercolor="#ccc" cellpadding="5" cellspacing="0" class="table table-bordered table-fullwidth" style="border-collapse:collapse"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>MF Specification</th> <th>Effect(s) on the KER</th> <th>Reference(s)</th> </tr> <tr> <th> </th> <th> </th> <th> </th> <th> </th> </tr> <tr> <th> Air pollution </th> <th> </th> <th> Air pollution primes immunity; increases the levels of circulating IL-1β, IL-6 and TNF-α; impairs the normal functions of macrophages and alveolar cells. Exposure to particulate air pollution, such as PM2.5, is associated with pulmonary inflammation [1,2]. Both short term and chronic exposures to fine particulate matter (PM) have been shown to increase levels of circulating IL-1β, IL-6 and TNF-α [3-5]. Air pollution works as a priming factor that exacerbates the inflammatory phenotype of COVID-19 and further dysregulates immune cell activity. Dysregulation of the immune cell functions, on the other hand, plays a role in tissue damage and the ability of the immune system to fight pathogens, which increases the susceptibility to concomitant bacterial superinfection, for instance [6-9]. </th> <th style="text-align:justify"> [1] Zhao et al., 2013 [2] Jia et al., 2021 [3] Tsai et al., 2012 [4] Ljungman et al., 2009 [5] Kido et al., 2011 [6] Knoll et al., 2021 [7] Glencross et al., 2020 [8] Yamasaki and Eeden, 2018 9) Signorini et al., 2018 </th> </tr> </thead> <tbody> <tr> <td> Chemicals (weak evidence) </td> <td> Per- and polyfluoroalkyl substances (PFAS) (Perfluorooctane sulfonate [PFOS], perfluorooctanoic acid [PFOA], perfluorobutane sulfonic acid [PFBS], perfluorooctane sulfonamide [PFOSA], and perfluorodecanoic acid [PFDA]) </td> <td> Several in vitro studies in human-derived cells have shown that PFAS can modify the secretion of pro-inflammatory mediators in a dose-dependent manner [1].  PFOS exposure significantly induced IL-1 IL-4, IL-6, and IL-8 in human lymphocytes and reduced chemokines CXCL8 and CXCL10 secretion in human bronchial epithelial cells while increasing of IL-1α release [2]; both PFOS and PFOA enhanced IL-1β release in response to Poly I:C [3]; PFOS, PFOA, PFBS, PFOSA, and PFDA exposure decreased PHA-induced release of IL-4, IL-10, and IL-6 and PFOS, PFOSA, and PFDA decreased IFN-γ release in human leukocytes with PFOS as a more potent inhibitor of cytokine production than other PFAS, and leukocytes obtained from female donors appeared to be more sensitive to the in vitro immunomodulating effects of PFAS, compared to leukocytes from male donors [4]. In a rat study exposed to PFOS, increased serum levels of TNF-α and IL-6 were observed. Kupffer cells exposed to PFOS showed cell activation, which was mostly inhibited by anti-TNF-α or anti-IL-6 treatment. Moreover, NF-κB inhibitor and JNK inhibitor significantly inhibited the production of IL-6 [5,6]. </td> <td> [1] Tian et al., 2021 [2] Li et al., 2020 [3] Sørli et al., 2020 [4] Corsini et al., 2012 [5] Han et al., 2018 [6] EFSA CONTAM Panel, 2020 </td> <td> </td> </tr> <tr> <td colspan="1" rowspan="2">Sex</td> <td>Female sex (XX chromosomes)</td> <td> Females produce higher amounts of the antiviral infection cytokine IFN-α than men [1].  Estrogens are critical regulators of gene expression and functions in innate immune cells, including monocytes, macrophages, and dendritic cells, as well as lymphocytes such as T helper 1/2 (TH1/2) cells, regulatory T-cells (Treg cells), and B cells. One of the major forms of estrogen, estradiol, has been shown to dampen the production of excessive innate inflammatory cytokines by monocytes and macrophages [2]. In the presence of progesterone, CD4+ Th cells skew from Th-1 to Th-2 in the production of anti-inflammatory cytokines, specifically IL-4 and IL-10 [3]. The cellular types involved in male and female immune responses to SARS-CoV-2 are distinct and immune response in females is enriched with activated T-cells [1]. In lactating women, higher SARS-CoV-2 reactive memory B-cells and antibody titers have been associated with the hormone prolactin [4]. Poor T-cell response to SARS-CoV-2 correlates with worse disease progression in female patients. </td> <td> [1] Takahashi et al., 2020 [2] Scully et al., 2020 [3] Mauvais-Jarvis et al., 2020 [4] Gonçalves et al., 2021 </td> </tr> <tr> <td>Male sex (XY chromosomes)</td> <td> Males display a higher innate immune response to SARS-CoV-2 than females, which conditions their cytokine profile. Men have higher levels of the innate immune cytokines IL-8 and IL-18 in circulation  [1]. Moreover, elderly men in particular display autoantibodies against IFN-α more frequently [5]. The cellular types involved in male and female immune responses to SARS-CoV-2 are distinct. Men display higher circulating levels of non-classical monocytes [1]. Higher innate immune activation in men leads to higher plasma levels of the inflammatory cytokines IFN-α [6], IL-8 and IL-18 [1], driving hyperinflammation and more pronounced lymphopenia in males. </td> <td> [5] Bastard et al., 2020 [6] Agrawal et al., 2021 </td> </tr> <tr> <td> Age </td> <td>Old people</td> <td>During aging, a subclinical chronic inflammatory response develops leading to an immune senescent state, where pathogen protective immune responses are impaired, but the production of inflammatory cytokines, such as <a href="http://bioregistry.io/genecards:IL6">IL-6</a>, is increased. This process is called inflammaging. The persistent <a href="http://bioregistry.io/genecards:IL6">IL-6</a> elevation can induce lung tissue inflammation and mortality. The rate of inflammaging is higher in men and accelerated inflammaging is believed to worsen COVID-19 outcomes [1]. The chronic inflammatory status is associated with a dramatic depletion of B lymphocyte-driven acquired immunity. Aging also attenuates the upregulation of co-stimulatory molecules critical for T-cell priming and reduces antiviral IFN production by alveolar macrophages and dendritic cells in response to infection with the influenza virus [2].</td> <td> [1] Bonafè et al., 2020 [2] Kovacs et al., 2017</td> </tr> <tr> <td rowspan="2">Lipids</td> <td> Atherogenic dyslipidemia </td> <td> Lipids impact innate and adaptive immune responses [1,2]. In COVID-19. The atherogenic dyslipidemia associated with COVID-19 severity (high tryglycerides and low total, low density lipoprotein and high density lipoprotein cholesterol) was inversely correlated with inflammatory biomarkers such as increased levels of serum C-reactive protein (CRP), <a href="http://bioregistry.io/genecards:IL6">IL-6</a>, IL-8, and IL-10 [3,4]. </td> <td rowspan="2"> [1] Hubler and Kennedy, 2016 [2] Bernardi et al., 2018 [3] Henry et al., 2021 [4] Caterino et al., 2021 [5] Hubler and Kennedy, 2016 [6] Winer et al., 2009 [7] Im et al., 2011 [8] Muscogiuri et al., 2020 </td> </tr> <tr> <td> Obesity </td> <td> In obesity, immune cells interact with various classes of lipids, which can control the plasticity of macrophages and T lymphocytes. In COVID-19. Altered lipid homeostasis is associated with severe COVID-19 outcomes and, at the same time, with chronic inflammation and inflammatory polarization of macrophages and T lymphocytes [5]. Th1 lymphocytes are more prevalent in adipose tissue of obese patients [6]. In the same way, Th1 lymphocytes are elevated in visceral fat [6]. Both macrophages and T lymphocytes interact with lipids that influence their proliferation, differentiation, polarization [7] and transcriptional regulation, which is tightly controlled by Sterol regulatory element-binding protein (SREBP) and Liver X receptors (LXRs), expressed in macrophages and known regulators of cytokine release. Adipose tissue produces many pro-inflammatory adipokines and cytokines, which lead to low-grade inflammation and the recruitment of immune cells which may clarify the connection between obesity and COVID-19 severity [8]. </td> </tr> <tr> <td>Gut microbiota</td> <td>Gut dysbiosis (alteration of gut microbiota)</td> <td> The gut microbiota is increasingly acknowledged to play a central role in human health and disease, notably by shaping the immune response. Notably some bacteria living in the gut produce short-chain fatty acids (SCFA), recognized as mediators of the intestinal inflammatory response [1]. SCFAs modulate inflammation by regulating immune cell cytokine production such as TNF-α, IL-12, IL-6 [2]. For example, butyrate decreased the lipopolysaccharide (LPS)-induced TNF-α expression in monocytes [4] and activated Treg cells, blocking an excessive inflammatory response [1,3]. In COVID-19. In a COVID-19 cohort, the depletion of several bacterial species (B. adolescentis, E. rectale and F. prausnitzii, known to play immunomodulatory roles in the human gastrointestinal system) was linked to increased plasma concentrations of TNF-α, CXCL10, CCL2 and IL-10 [4]. Conversely, two species enriched in the COVID-19 cohort, B. dorei and Akkermansia muciniphila, were positively correlated with IL-1β, IL-6 and CXCL8. Using a machine learning model [5], it was reported that the disruption of gut microbiota significantly correlated with pro-inflammatory cytokines and may predispose normal individuals to severe COVID-19. Decreases in the abundance of butyrate-producing bacteria and a decline in SCFA were observed in severe COVID-19 [4,6,7,8]. Reduced relative proportion of bacteria producing SCFA was observed in Syrian hamsters infected with SARS-CoV-2, compared to non-infected controls, with a transient decrease in systemic SCFA amounts [9]. However, SCFA supplementation in hamsters during infection had no effect on inflammatory parameters. Targeted analysis of fecal metabolites showed significantly lower fecal concentrations of SCFAs in COVID-19 patients, which correlated with disease severity and increased plasma concentrations of CXCL-10 and CRP [10]. </td> <td> [1] Yoo et al., 2020 [2] Vinolo et al., 2011 [3] Atarashi et al., 2013 [4] Yeo et al., 2021 [5] Gou et al., 2021 [6] Zuo et al., 2020 [7] Gu et al., 2020 [8] Grenga et al., 2022 [9] Sencio et al., 2022 [10] Zhang et al., 2022 </td> </tr> <tr> <td>Vitamin D (low evidence)</td> <td>Vitamin D deficiency</td> <td> There is a complex interplay between vitamin D and the immune response to viral infections. Low vitamin D status is proposed to induce upregulation of the TNF-α and downstream of Nuclear Factor Kappa B Subunit 1 (NF–κB1) signaling pathway, which regulates inflammatory reactions toward viral infection in macrophages [1,2]. Vitamin D was shown as a potent suppressor of IFN-γ mediated macrophages response, preventing the release of inflammatory cytokines and chemokines [3]. Thus, release of pro-inflammatory cytokines might be exacerbated in COVID-19 patients with vitamin D deficiency [4]. </td> <td> [1] Hassan et al., 2022 [2] Książek et al., 2021 [3] Helming et al., 2005 [4] Munshi et al., 2021 </td> </tr> <tr> <td> Genetic factors </td> <td> </td> <td> The inflammatory response manifested by increased cytokine levels results in inhibition of heme oxygenase (HO-1), with a subsequent loss of cytoprotection. In the 50-non-coding regions of the HO-1 gene, there are two polymorphic sites, namely the (GT)n dinucleotide and T (-413) A sites, which regulate the transcriptional activity of HO-1. These polymorphisms have been shown to be associated with the occurrence and progression of numerous diseases, including COVID-19 [1]. The timing of the IFN response to SARS-CoV-2 infection can vary with viral load and genetic differences in host response. When the viral load is low, IFN responses are engaged and contribute to viral clearance, resulting in mild infection. When viral load is high and/or genetic factors slow antiviral responses, virus replication can delay the IFN response and cytokine storm can occur before adaptive responses clear the virus, resulting in severe disease including multisystem inflammatory syndrome in Children (MIS-C) [2]. </td> <td> [1] Singh et al., 2020 [2] Rowley, 2020 </td> </tr> <tr> <td colspan="1" rowspan="3"> Therapeutic intervention against COVID-19 </td> <td> Tocilizumab and Sarilumab </td> <td> Are anti-IL-6 receptor monoclonal antibodies, which reduce inflammation [1] by attaching to the IL-6 receptor (as IL-6 receptor inhibitors) [2]. Tocilizumab, a biological drug approved for rheumatoid arthritis, is currently being evaluated for its efficacy against the effects of systemic IL-6 elevation (ClinicalTrial.gov accessed on March 2022, NCT04317092, NCT04320615, NCT04306705) [3]. </td> <td> [1] WHO, 2021. [2] European Medicines Agency, 2021 [3] Bonafè et al., 2020 </td> </tr> <tr> <td> Baricitinib </td> <td> Is an immunosuppressant that blocks the action of enzymes known as Janus kinases (JK), which play an important role in inflammatory processes (JAK inhibitor) [1–4]. </td> <td> [1] Jorgensen et al., 2020 [2] Bekerman et al., 2017 [3] Neveu et al., 2015 [4] Richardson et al., 2020 </td> </tr> <tr> <td> Low molecular weight heparins (LMWHs) </td> <td> Have anti-inflammatory effects by blocking pro-inflammatory mediators (TNF-α, IL-6 and Leukotriene [LTB4]) [1]. </td> <td> [1] Buijsers et al., 2020 </td> </tr> <tr> <td colspan="1"> Pre-existing heart failure </td> <td> </td> <td> Dysregulation of renin angiotensin system due to pre-existing heart failure can have detrimental inflammatory effects both locally (in the heart) and systematically. The Angiotensin converting enzyme 2 (ACE2)/Angiotensin (Ang) (1-7) pathway is associated with the attenuation of a wide range of pro-inflammatory cytokines and chemokines, such as IL-1, IL-5, IL-6, IL-12, CCL2, TNF-α and MCP-1 [1]. </td> <td> [1] Rodrigues Prestes et al., 2017.                      </td> </tr> <tr> <td colspan="1"> Diet </td> <td> Dietary elements linked to pro-inflammatorymediators </td> <td> High-fat diets have been linked—in multiple studies—to promote an “inflammatory status” in the gut and subsequently other organs [1]. Compounds found in many plant foods may affect COVID-19 prognosis by blocking inflammatory mediators and pathways. Bousquet et al. [2,3] identified bioactive compounds contained in spices and fermented vegetables, including capsaicin, cinnamaldehyde, curcumin, genistein, gingerol, mustard oil, piperine, wasabi, and sulforaphane, that upregulate the signaling of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a potent endogenous antioxidant which blocks oxidative stress from the Angiotensin type I receptor (AT1R) axis, inhibits overproduction of proinflammatory cytokines and chemokines (including IL-6), and limits the activation of NF-κB. There is some in vitro evidence that Lactobacillus, found in many fermented foods, works through the same mechanism [4]. Finally, naringin, a compound found in citrus fruits, reduced LPS-induced IL-6 expression levels in vitro [5]. </td> <td> [1] Duan et al., 2018 [2] Bousquet et al., 2021a [3] Bousquet et al., 2020 [4] Bousquet et al., 2021b [5] Liu et al., 2022 </td> </tr> </tbody> </table>

A majority of the in vivo studies are conducted with only one dose and thus, it is difficult to derive quantitative dose-response relationships based on the existing data. However, it is clear from the studies referenced above that greater concentrations or doses of pro-fibrotic substances results in higher release of alarmins, and consequently, higher pro-inflammatory signalling. The above studies also demonstrate strong temporal relationships between the individual KEs.

Activated pro-inflammatory cells secrete pro-inflammatory mediators, and those mediators' goal is to cause signalling and response, which can lead to chronic inflammation (<a href="https://aopwiki.org/events/1497">KE1497</a>). Chronic inflammation means proinflammatory mediators increase and increased recruitment of inflammatory cells acts in a positive feedback loop, which continues a pro-inflammatory environment.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4313496ed0> AOPWiki 2018-01-05T13:18:46

2023-05-18T12:46:20

<upstream-id>d415f369-d29d-4dda-9857-b847673b8085</upstream-id> <downstream-id>4d904cb5-2bd3-4580-bc7e-01e01a2c2160</downstream-id> The recruitment of proinflammatory cells occurs as a result of proinflammatory mediator signaling, recruiting the cells, such as monocytes which can differentiate into different macrophage types, to clear out invading toxic pathogens. However, when invading toxic pathogens are not properly cleared out and pro-inflammatory mediators are not controlled, the proinflammatory cells persist, causing a positive feedback loop leading to a dysregulated para-inflammation, which is responsible for chronic inflammation conditions (Medzhitov et al). This persistence causes over-activated proinflammatory macrophages, recruitment of neutrophils, and mass levels of proinflammatory cytokines (Medzhitov et al). Hyperinflammation properties include higher levels of inflammatory markers in blood (CRP, ferritin, and D- dimers), increased neutrophil to lymphocyte ratio, and increased proinflammatory cytokines.    In COVID-19 patients, monocytes are derived into pro-inflammatory macrophages as a result of SARS-COV-2 infection (Merad et al).  Pro-inflammatory macrophages along with neutrophils and T-cells are recruited into the lung epithelium and exacerbate inflammation by establishing the proinflammatory feedback loop that persists and causes the hyperinflammatory state (Gustine et al).  Hyperinflammation in COVID-19 is also triggered by pyroptosis and tissue damage (reviewed in Tan et al. 2021 <a href="https://doi.org/10.3389/fimmu.2021.742941">https://doi.org/10.3389/fimmu.2021.742941</a>). SARS-COV-2 activates Gasdermin D (GSDMD), a key trigger of pyroptosis in pro-inflammatory macrophages. When pyroptosis causes cell death in these macrophages, it releases mass amounts of pro-inflammatory cytokines, ROS, and LDH, leading to hyperinflammation (Zhang et al). A number of so called alarmins have been associated with the evolution towards hyperinflammation. Alarmins are a family of immunomodulatory proteins that act as damage-associated molecular patterns (DAMPs) and recruit and activate various immune cells such as monocytes, macrophages, lymphoid cells and myeloid dendritic cells. Multiple proteins from this family, including especially IL33 and S100 family proteins (S100A4, S100A7, S100A9, S100A12, S100B, and S100P) have been identified to be associated with the later stages of inflammation culminating in hyperinflammation in the lungs (Desvaux et al. 2021 <a href="https://doi.org/10.1371/journal.pone.0254374">https://doi.org/10.1371/journal.pone.0254374</a>). IL33 and the S100 family proteins can stimulate production of IL1B, IL6 and TNFA, some of the hallmark molecules associated with hyperinflammation (reviewed in Desvaux et al. 2021).

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>MF Specification</th> <th>Effect(s) on the KER</th> <th>Reference(s)</th> </tr> </thead> <tbody> <tr> <td colspan="1" rowspan="2">SEX</td> <td> <table class="table table-bordered table-fullwidth"> <tbody> <tr> <td colspan="1" rowspan="2"> </td> <td>female sex (XX chromosomes)</td> </tr> </tbody> </table> </td> <td>Females produce higher amounts of the antiviral infection cytokine IFN- a than men [1].  Estrogens are critical regulators of gene expression and functions in innate immune cells, including monocytes, macrophages, and dendritic cells, as well as lymphocytes such as T-helper 1/2 (TH1/2) cells, regulatory T-cells (Tregs), and B cells. One of the major forms of estrogen, estradiol, has been shown to dampen the production of excessive innate inflammatory cytokines by monocytes and macrophages [2]. In the presence of progesterone, CD4+ T-helper cells skew from Th-1 to Th-2 in the production of anti-inflammatory cytokines, specifically IL-4 and IL-10 [3]. The cellular types involved in male and female immune responses to SARS-CoV-2 are distinct and immune response in females is enriched with activated T-cells [1]. In lactating women, higher SARS-CoV-2 reactive memory B-cells and antibody titers have been associated with the hormone prolactin [4]. Poor T-cell response to SARS-CoV-2 correlates with worse disease progression in female patients.</td> <td> 1.) DOI: 10.1038/s41586-020-2700-3 2.) DOI: 10.1038/s41577-020-0348-8 3.) DOI: 10.1016/S0140-6736(20)31561-0 4.) DOI: 10.1016/j.xcrm.2021.100468 </td> </tr> <tr> <td>male sex (XY chromosomes)</td> <td> Males display a higher innate immune response to SARS-CoV-2 than females,which conditions their cytokine profile. Men have higher levels of the innate immune cytokines IL-8 and IL-18 in circulation  [1]. Moreover, elderly men in particular display autoantibodies against IFN-a more frequently [5]. The cellular types involved in male and female immune responses to SARS-CoV-2 are distinct. Men display higher circulating levels of non-classical monocytes [1]. Higher innate immune activation in men leads to higher plasma levels of the inflammatory cytokines IFN-a [6], IL-8 and IL-18 [1], driving hyperinflammation and more pronounced lymphopenia in males. </td> <td> 5.) DOI: 10.1126/science.abd4585 6.) DOI: 10.3389/fimmu.2021.739757 </td> </tr> <tr> <td colspan="1">Age</td> <td>Young/old people</td> <td>During aging, a subclinical chronic inflammatory response develops leading to an immune senescent state, where pathogen protective immune responses are impaired, but the production of inflammatory cytokines, such as IL-6, is increased. This process is called inflammaging. The persistent IL-6 elevation can induce lung tissue inflammation and mortality. The rate of inflammaging is higher in men and accelerated inflammaging is believed to worsen COVID-19 outcomes [1]. The chronic inflammatory status is associated with a dramatic depletion of B lymphocyte-driven acquired immunity. Aging also attenuates the upregulation of co-stimulatory molecules critical for T-cell priming and reduces antiviral IFN production by alveolar macrophages and dendritic cells (DCs) in response to infection with the influenza virus [2].</td> <td> 1) 10.1016/j.cytogfr.2020.04.005 2) 10.1016/j.cger.2017.06.002 </td> </tr> <tr> <td colspan="1">Vitamin D (low evidence)</td> <td>Vitamin D deficiency </td> <td> Vitamin D deficiency was shown to promote intestinal mucosal barrier dysfunction with higher permeability in infection-induced or TNF-treated cells and in in vivo colitis models [1,2]. An association between increased markers of intestinal permeability and vitamin D deficiency has been observed in critically ill subjects from ICU [3]. </td> <td> [1] doi: 10.1093/infdis/jiu235 [2] doi: 10.1097/MIB.0000000000000526 [3] doi: 10.1136/jim-2019-001132 </td> </tr> <tr> <td colspan="1">Genetic factors</td> <td> </td> <td>The inflammatory response manifested by increased cytokine levels results in inhibition of heme oxygenase (HO-1), with a subsequent loss of cytoprotection. In the 50-non-coding regions of the HO-1 gene, there are two polymorphic sites, namely the (GT)n dinucleotide and T (-413) A sites, which regulate the transcriptional activity of HO-1. These polymorphisms have been shown to be associated with the occurrence and progression of numerous diseases, including COVID-19 [1]. The timing of the IFN response to SARS-CoV-2 infection can vary with viral load and genetic differences in host response. When the viral load is low, IFN responses are engaged and contribute to viral clearance, resulting in mild infection. When viral load is high and/or genetic factors slow antiviral responses, virus replication can delay the IFN response and cytokine storm can occur before adaptive responses clear the virus, resulting in severe disease including MIS-C [2].</td> <td> [1] doi: 10.1016/j.freeradbiomed.2020.10.016 [2] doi: 10.1038/s41577-020-0367-5 </td> </tr> <tr> <td colspan="1">Air pollution</td> <td>Air pollution, particularly PM2.5</td> <td> Air pollution and PM2.5 induce detrimental recruitment of cytotoxic effectors that contribute to tissue damage and sustained hyperinflammation. Pulmonary macrophages have been shown to be hyper-activated in the lungs of COVID-19 patients. This, in turn, can result in detrimental recruitment of cytotoxic effectors that affect tissue damage and hyperinflmmation [1]. Furthermore, air pollution induces imbalanced activation of cytotoxic and protective immune effectors [2]. </td> <td> [1] https://doi.org/10.3389/fimmu.2021.720109 [2] https://doi.org/10.3389/fncel.2021.647643 </td> </tr> <tr> <td colspan="1">Pre-existing heart failure</td> <td> </td> <td> Hyperinflammation is one of the hallmarks of HF and counteracting the inflammatory response has been for years a target for various experimental therapies [1]. Crucial pro-inflammatory mediators such as TNF-α, IL-1 and IL-6 have been shown to affect endothelial inflammation, leading to the recruitment of monocytes, themselves secreting cytokines, thus contributing to the cytokine storm [2]. ACE2 downregulation leads to a shift towards the Ang II/AT1R pathway, and a proinflammatory response leading to the recruitment of inflammatory cells, such as monocytes and macrophages in the heart [3,4]. In addition, ADAM17 is implicated in a wide range of cardiovascular pathologies [5] and its expression is increased in HF [6,7]. ADAM17 is known as a sheddase of ACE2, but also as the TNF-α converting enzyme (TACE) [8]. According to Palacios et al. [382], increased levels of ADAM17 are correlated not only with mortality, but also with increased circulation of soluble forms of TNF-α and its corresponding receptors (soluble TNFR1/2)—key mediators of the COVID-19-associated cytokine storm [383,384] and the activation of inflammatory cells like macrophages and neutrophils [385]. Thus, pre-existing HF and associated enhanced ADAM17 expression might predispose an organism to enhanced pro-inflammatory cell activation. </td> <td> 1: https://www.nature.com/articles/nrcardio.2014.28 2: https://doi.org/10.1016/j.jacc.2020.01.014 3: https://doi.org/10.1016/j.stemcr.2021.07.012 4: https://doi.org/10.1161/CIRCRESAHA.121.319060 5: https://link.springer.com/article/10.1007/s00018-021-03779-w 6: https://doi.org/10.1016/j.ejheart.2004.02.007 7: https://doi.org/10.1161/01.CIR.99.25.3260 8: https://doi.org/10.3390/ijms22168423 9: https://doi.org/10.1016/j.hsr.2021.100011 10: https://doi.org/10.3389/fimmu.2020.01446 11: https://doi.org/10.1016/j.cell.2020.11.025 </td> </tr> <tr> <td colspan="1">Diet</td> <td>Compounds found in foods may be able to affect hyperinflammation via inflammatory mediators </td> <td> <ul> <li>Piperine (found in black pepper), inhibits the production of IFN- and IL-2 in human peripheral blood mononuclear cells [399] and neutralizes free radicals and ROS [400]. </li> <li>Linoin, a compound found in lemon, has been found to inhibit CD4+ T-cell proliferation by inhibition of NF-�B translocation in human cells [401]. The isoflavone Biochanin-A similarly prevents cell proliferation and LPS-induced inflammatory mediator release in vitro [402]. </li> <li>Increased fiber intake in humans is shown to reduce Creactive protein [403]. </li> <li>Parthenolide, a potent phenolic compound, inhibited inflammatory mediators in vitro in microglia, monocytes, macrophages, and neutrophils, including IL-6, NF–kB, and TNF- [404,405]. </li> <li>Arachidonic acid, a fatty acid found in numerous foods, enhances the function of -amino butyric acid (GABA) receptors, which attenuates severe inflammatory illness in coronavirus-infected mice. This contrasts with other dietary fatty acids, which induce systemic inflammation [406].</li> </ul> </td> <td> <ul> <li>399: <a href="http://doi.org/10.4238/2012.March.14.5">http://doi.org/10.4238/2012.March.14.5</a></li> <li>400: <a href="http://doi.org/10.1358/mf.2000.22.5.796644">http://doi.org/10.1358/mf.2000.22.5.796644</a></li> <li>401: <a href="http://doi.org/10.1016/j.ejphar.2011.08.035">http://doi.org/10.1016/j.ejphar.2011.08.035</a></li> <li>402: <a href="http://doi.org/10.1016/j.ejphar.2010.11.026">http://doi.org/10.1016/j.ejphar.2010.11.026</a></li> <li>403: <a href="http://doi.org/10.1038/ejcn.2009.8">http://doi.org/10.1038/ejcn.2009.8</a></li> <li>404: <a href="http://doi.org/10.1002/ptr.3732">http://doi.org/10.1002/ptr.3732</a></li> <li>405: <a href="http://doi.org/10.1002/ptr.6776">http://doi.org/10.1002/ptr.6776</a></li> <li>406: <a href="http://doi.org/10.1186/s40246-020-00297-x">http://doi.org/10.1186/s40246-020-00297-x</a></li> </ul> </td> </tr> </tbody> </table> </div>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b43134ede10> AOPWiki 2021-04-20T02:46:22

2023-02-08T09:25:40

Decreased fibrinolysis and activated bradykinin system leading to hyperinflammation

Dysregulated fibrinolysis/bradykinin leading to hyperinflammation

Cataia Ives

Penny Nymark, Institute of Environmental Medicine, Karolinska Institute, Sweden Marvin Martens, Maastricht University, Netherlands Merlin Mei, Environmental Protection Agency, US Holly Mortensen, Environmental Protection Agency, US Dan Jacobson, Oak Ridge National Laboratory, US Jenny Waspe, Sheffield Hospital, UK Sabina Halappanavar, Health Canada, Canada CIAO members (https://www.ciao-covid.net/)

BY-SA

Under Development

1.96

2.0

This AOP describes a sequence of molecular, cellular and tissue events associated with immune response, and leading to an uncontrolled, self-perpetuating inflammatory response referred to as hyperinflammation. The AOP is developed with the intent to clarify the complex inflammatory processes associated with the ongoing COVID-19 pandemic caused by the coronavirus SARS-CoV-2. In the broader context, this AOP is applicable to other fields of research including toxicology, with a specific focus on the toxicity and inflammatory elements of nanomaterials. AOP 392 is referred to as a “hub” AOP since it is hypothesized to describe and connect the process of hyperinflammation to other related AOPs, including organ, individual, population, or community-focused AOPs. Such AOPs can include the COVID-19 associated AOPs currently in development (e.g. AOPs 319 and 320) or previously established AOPs (e.g. AOP 173 and 302). In addition, the AOP may be used as a basis for development of new AOPs fit for specific purposes, including e.g. connection to MIEs relevant for SARS-CoV-2 such as the<a href="https://bioregistry.io/genecards:ACE2"> ACE2</a> binding KE, which leads to the imbalanced fibrinolysis/bradykinin activation MIEs (AOP392). Fibrinolysis (MIE) is the breakdown of fibrin in blood clots which prevents blood clots from growing too large, and hypo-fibrinolysis occurs when the fibrinolysis process becomes impaired. High levels of the <a href="https://bioregistry.io/genecards:SERPINE1">SERPINE1</a> inhibitor and dysregulation of the uPA/uPAR system found in COVID-19 patients are the main weights of evidence found in support of <a href="https://bioregistry.io/go:0051918">hypo-fibrinolysis</a>(KE1866). <a href="https://bioregistry.io/hmdb:HMDB0004246">Bradykinin</a> is a peptide that plays an important role in blood pressure regulation and inflammation. Activation of the bradykinin system, causing a bradykinin upregulation, is seen in BAL samples of COVID-19 patients, as well as evidence of <a href="https://bioregistry.io/genecards:BDKRB1">B1</a> and <a href="https://bioregistry.io/genecards:BDKRB2">B2</a> receptor binding in COVID-19 patients(KE1867). Decrease of fibrinolysis and bradykinin upregulation causes inflammation, which evolves into hyperinflammation, an uncontrolled and self-perpetuating inflammatory process that results in tissue damage. Further exploration of how inflammation becomes uncontrolled and evolves into hyperinflammation is needed. There are high serum levels of pro-inflammatory cytokines such as <a href="https://bioregistry.io/genecards:IL6">IL-6</a>, <a href="https://bioregistry.io/genecards:CXCL8">CXCL8</a>, and <a href="https://bioregistry.io/genecards:TNF">TNF</a>, indicating inflammation (KE1496 and 1497) as well as evidence of high D-dimer, <a href="https://bioregistry.io/genecards:CRP">CRP</a>, neutrophil, and a lack of lymphocytes, all evidence of hyperinflammation(AO 1868). The WoE involving <a href="http://purl.bioontology.org/ontology/npo#NPO_199">nanomaterials</a>, the other stressor associated with the AOP, is that certain nanomaterials directly interact with coagulation factor XII (<a href="https://bioregistry.io/genecards:F12">FXII</a>). Several proteins of the <a href="https://bioregistry.io/wikipathways:WP558">coagulation system</a>, including fibrinogen and kallikrein, bind to <a href="https://bioregistry.io/ctd.chemical:C009495">TiO2 </a>and α-<a href="https://bioregistry.io/ctd.chemical:C00499">Fe2O3</a> nanoparticles (NPs), and induce clot formation triggered by FXII. This leads to fibrinolysis decrease (KE1866). Nanomaterial activation of FXII also activates the bradykinin system and generates increased bradykinin (KE1867). When proteins of the coagulation system bind to <a href="https://bioregistry.io/ctd.chemical:C009495">TiO2 </a>and α-<a href="https://bioregistry.io/ctd.chemical:C00499">Fe2O3</a> NPs, it causes the release of proinflammatory cytokines, leading to inflammation (KE1496 and 1497), and eventually leading to hyperinflammation (AO1868). COVID-19 has been a global pandemic that the world has faced for over a year, making this AOP relevant to the understanding of the disease. The other applicability of the AOP is through nanomaterials, including examples such as TiO2, which can promote activation of this AOP in the same mechanism. Nanoparticles such as TiO2 are included in many essential items of day to day life, including food and drug treatments, making this AOP applicable to the future of human health. AOP 392 is developed as a part of the <a href="https://www.ciao-covid.net/">CIAO project</a>, Modelling the Pathogenesis of COVID-19 Using the Adverse Outcome Pathway (AOP). The overall goal was to organize, consolidate, and understand the vast amount of data that is constantly evolving as a result of the COVID-19 pandemic and identify knowledge gaps that may be missing using the AOP framework. Many AOPs were developed as a part of the CIAO project, each AOP focusing on a specific element of the SARS-COV-2 virus responses in humans. AOP392 focuses on the inflammatory responses. AOP 392 covers a set of events that act in concert towards perturbing inflammation. Hypo-fibrinolysis represents the first event (KE1866), in which interaction with SARS-COV-2 or nanomaterials causes decreased fibrinolytic response. The activation of the bradykinin system(KE1867) (MIE2), also instigated by SARS-COV-2 or nanomaterial stressors, can overactivate the bradykinin system and increases bradykinin production. As a result of hypo-fibrinolysis (KE1866), and bradykinin activation (KE1867), there is an increase in pro-inflammatory mediators secretion (KE1496), which signals the recruitment of pro-inflammatory cells into the lungs (KE1497). This KE process represents the changes occurring in inflammation. The increase in pro-inflammatory cells levels lead to a higher neutrophil to lymphocyte ratio, increased CRP, and high D-dimer and ferritin levels, all hallmarks of a hyperinflammatory state (KE1868). Hyperinflammation plays a critical role in driving the severity of the COVID-19 disease. Further exploration of the inflammation to hyperinflammation process is needed.

SARS-COV <a href="https://bioregistry.io/genecards:SERPINE1" target="_blank">SERPINE1 </a>is inactivated causing an imbalance between fibrinolysis and coagulation (urokinase pathway). Also genes associated with the induction of a procoagulant state (thrombin, <a href="https://bioregistry.io/genecards:F7" target="_blank">F7</a>a, <a href="https://bioregistry.io/genecards:F11" target="_blank">F11</a>a, <a href="https://bioregistry.io/genecards:F12" target="_blank">F12</a>a, <a href="https://bioregistry.io/genecards:PLAU" target="_blank">PLAU</a>, <a href="https://bioregistry.io/genecards:PLAUR" target="_blank">PLAUR</a>, tissue factor <a href="https://bioregistry.io/genecards:F2R" target="_blank">F2R</a>) and other <a href="https://bioregistry.io/wikipathways:WP1802">fibrinolysin pathway</a> components were altered by infection nanoparticles Several proteins of the coagulation system, including fibrinogen, HMWK, kallikrein, <a href="https://bioregistry.io/genecards:F12" target="_blank">F12</a>, <a href="https://bioregistry.io/genecards:F11" target="_blank">F11</a>, and C1-INH bind to <a href="https://bioregistry.io/chebi:134441">TiO2 </a>NPs, and induce <a href="https://bioregistry.io/wikipathways:WP558">clot formation</a> triggered specifically by <a href="https://bioregistry.io/genecards:F12" target="_blank">F12</a>, as well as release of pro-inflammatory cytokines and chemokines (IL-8 [<a href="https://bioregistry.io/genecards:CXCL8" target="_blank">CXCL8</a>], MIP-1α [<a href="https://bioregistry.io/genecards:CCL3" target="_blank">CCL3</a>], MIP-1β [<a href="https://bioregistry.io/genecards:CCL4" target="_blank">CCL4</a>] and MCP-1 [<a href="https://bioregistry.io/genecards:CCL2" target="_blank">CCL2</a>]). SARS-COV-2 <a href="https://bioregistry.io/genecards:SERPING1" target="_blank">SERPING1 </a>is downregulated in severe COVID-19 BAL samples lifting the suppression of <a href="https://bioregistry.io/genecards:F12" target="_blank">F12</a>

SARS-CoV-2 Directly, the BK precursor kininogen as well as several kallikreins are up-regulated in COVID-19 patient bronchial alveolar lavage (BAL) samples. Indirectly, SARS-COV-2 affects the Renin-angiotensin system by downregulating ACE2. With ACE2 unable to  inactivates DABK and Lys-des-Arg9-BK enzymes, an activation of the bradykinin system would be triggered. SARS-COV-2 also highly downregulates the <a href="https://bioregistry.io/genecards:SERPING1" target="_blank">SERPING1 </a>gene, which encodes for the C1-inhibitor, leading to increased bradykinin production.   Nanomaterials <a href="http://purl.bioontology.org/ontology/npo#NPO_1892">Ag</a>, <a href="https://bioregistry.io/chebi:134441">TiO2</a>, and <a href="http://purl.bioontology.org/ontology/npo#NPO_729">Fe2O3 </a>nanoparticles directly interact with <a href="https://bioregistry.io/genecards:F12" target="_blank">F12 </a>and activate the bradykinin system.

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AOPWiki 2021-04-20T02:35:18

2023-09-25T16:27:06