Frustrated phagocytosis

CL:0000235

CL macrophage

FMA:84050

FMA Cytokine

CL:0009002

CL inflammatory cell

CHEBI:26523

CHEBI reactive oxygen species

GO:0090734

GO site of DNA damage

GO:0005694

GO chromosome

GO:1990391

GO DNA repair complex

CL:0000066

CL epithelial cell

CL:0000077

CL mesothelial cell

UBERON:0002048

UBERON lung

GO:0006909

GO phagocytosis

GO:0050663

GO cytokine secretion

GO:0006954

GO inflammatory response

GO:0042116

GO macrophage activation

GO:1903409

GO reactive oxygen species biosynthetic process

GO:0042769

GO DNA damage response, detection of DNA damage

D009154

MESH mutation

GO:0031052

GO chromosome breakage

MP:0008866

MP chromosomal instability

MP:0008058

MP abnormal DNA repair

GO:0008283

GO cell proliferation

HP:0100526

HP Neoplasm of the lung

MP:0008014

MP increased lung tumor incidence

WIKI decreased

WIKI increased

High aspect ratio material

2019-08-13T04:38:40

Reactive oxygen species

2017-06-16T08:32:10

2017-08-15T10:43:27

Ionizing Radiation Ionizing radiation can vary in energy, dose, charge, and in the spatial distributions of energy transferred to other matter (linear energy transfer per unit length or LET) (ICRU 1970). At the same dose, low and high LET both generate energy deposition events, including many higher energy events (Goodhead and Nikjoo 1989). However, they differ in the spatial distribution and upper range of intensity of energy deposited. Lower LET such as gamma rays sparsely deposit many individual excitations or small clusters of excitations of low energy (Goodhead 1988). In contrast, high LET such as alpha particles have fewer tracks but readily transfer their energy to matter and therefore deposit their energy over a much smaller area (Goodhead 1994). Consequently, alpha and other high LET particles penetrate less deeply into tissue, interactions are densely focused on a narrow track, and individual energy depositions can be large (Goodhead 1988). These different energy deposition patterns can lead to differences in radiation effects including the pattern of DNA damage.

Exposure to ionizing radiation can come from natural and industrial sources. Space and terrestrial radiation includes a range of LET particles, while diagnostic radiation methods such as X-ray imaging, mammography and CT scans use low LET X-rays. Radiation therapy can use an external beam to direct radiation on a focused tissue area, or deposit solid or liquid radioactive materials in the body that release (mostly gamma) radiation internally. External radiotherapy typically uses X-rays but is moving towards higher LET charged particles such as protons and heavy ions (Durante, Orecchia et al. 2017).

2019-05-03T12:36:36

2019-05-07T12:12:13

WikiUser_17

mammals

WCS_9606

common toxicological species human

10090

NCBI mouse

10116

NCBI rats

WikiUser_28

Vertebrates

10116

NCBI rat

Frustrated phagocytosis

Cellular

Phagocytosis is the first line of defence of the organism against foreign matter and therefore is essential for the maintenance of the homeostasis [1]. This process, mainly performed by macrophages, is dividing in two steps, first after recognition and internalization of the foreign matter, the phagosome is formed, and second, this structure is mature in a degradative compartment [1]. In the lung tissue, macrophages located in the alveolar space are involved in the clearance of foreign matter inhaled. After phagocytosis, cells migrate out of the alveolar space via the mucociliary escalator or the lymphatic system. High aspect ratio nanoparticles (HARN) are particles with a ratio length – diameter ≥ 3 [2] [3]. Their fibre-shaped, similar to asbestos, is causing concern about their toxicity [4]. HARN include nanotubes, nanorods, nanowires and nanofibers in which carbon nanotubes (CNTs) are the most known and studied. CNT could enter in cells and interact with mitotic spindles as well as nuclei [5]. Macrophages try to phagocytose these particles, however the phagocytosis if incomplete leading to a frustrated phagocytosis. Consequently, the foreign matter is retained in the body because it cannot be cleared by macrophages [6].

Using in vitro cell models, such as macrophages or epithelial cells, the analysis of interaction between HARN and cells could be performed in time-lapse microscopy [7] or backscatter electron microscopy [8].  The frustrated phagocytosis could be measure by different type of microscopy analysis allowing a direct measurement. For examples, time-lapse video microscopy [7], light microscopy [9], scanning electron microscopy [6, 9], bright-field microscopy [8] and backscatter electron microscopy [8] are used in the literature.  The analysis of phagocytic receptor expression such as MARCO, MSR-1, CD36, TLR4 is an indirect measurement [6]. The study of the capacity of macrophages to complete phagocytosis process could be performed in vitro using different type of macrophage cell lines (THP-1, NR8383, RAW267) and analysis by microscopy or gene expression or in vivo after exposure of rodents to different type of high aspect ratio nanoparticles and analysis of the remaining quantity of material in the body or the ability of macrophages to phagocyte foreign matter.

The frustrated phagocytosis of high aspect ratio particle can occur in mammals, male or female, and is generally measured in adults.

Not Specified Unspecific

Not Specified

Adult

Not Specified

1.         Montano F, Grinstein S, Levin R. Quantitative Phagocytosis Assays in Primary and Cultured Macrophages. 2018;1784:151-63; doi: 10.1007/978-1-4939-7837-3_15. 2.         safenano.org. 3.         Oberdorster G, Oberdorster E, Oberdorster J. Concepts of nanoparticle dose metric and response metric. 2007;115 6:A290; doi: 10.1289/ehp.115-1892118. 4.         Donaldson K, Poland CA. Inhaled nanoparticles and lung cancer - what we can learn from conventional particle toxicology. 2012;142:w13547; doi: 10.4414/smw.2012.13547. 5.         Sargent LM, Shvedova AA, Hubbs AF, Salisbury JL, Benkovic SA, Kashon ML, et al. Induction of aneuploidy by single-walled carbon nanotubes. 2009;50 8:708-17; doi: 10.1002/em.20529. 6.         Sweeney S, Grandolfo D, Ruenraroengsak P, Tetley TD. Functional consequences for primary human alveolar macrophages following treatment with long, but not short, multiwalled carbon nanotubes. International journal of nanomedicine. 2015;10:3115-29; doi: 10.2147/IJN.S77867. 7.         Padmore T, Stark C, Turkevich LA, Champion JA. Quantitative analysis of the role of fiber length on phagocytosis and inflammatory response by alveolar macrophages. Biochimica et biophysica acta. 2017;1861 2:58-67; doi: 10.1016/j.bbagen.2016.09.031. 8.         Schinwald A, Donaldson K. Use of back-scatter electron signals to visualise cell/nanowires interactions in vitro and in vivo; frustrated phagocytosis of long fibres in macrophages and compartmentalisation in mesothelial cells in vivo. Particle and fibre toxicology. 2012;9:34; doi: 10.1186/1743-8977-9-34. 9.         Murphy FA, Schinwald A, Poland CA, Donaldson K. The mechanism of pleural inflammation by long carbon nanotubes: interaction of long fibres with macrophages stimulates them to amplify pro-inflammatory responses in mesothelial cells. Particle and fibre toxicology. 2012;9:8; doi: 10.1186/1743-8977-9-8.            10.       Donaldson K, Murphy FA, Duffin R, Poland CA. Asbestos, carbon nanotubes and the pleural mesothelium:            a review of the hypothesis regarding the role of long fibre retention in the parietal pleura, inflammation and                        mesothelioma. 2010;7:5; doi: 10.1186/1743-8977-7-5. AOPWiki 2019-07-03T11:46:23

2022-09-16T09:03:44

Release, Cytokine

Cellular

Cytokines are small, soluble molecules secreted by cells to enable intercellular communication. Cytokines may act on the cells that secrete them (autocrine action), on nearby cells (paracrine action), as well as on distant cells (endocrine action). Cytokines can act synergistically or antagonistically, and secretion from one cell can trigger upregulation of a further range of cytokines from the same cell or others <a href="#cite_note-1">[1]</a>. Most cells in the body are able to secrete them, and several subfamilies belong to the group of cytokines, such as chemokines, interferons, interleukins, tumor necrosis factors (TNF), transforming growth factors (TGF) and colony-stimulating factors. They are important players in modulating fundamental biological processes, including body growth, adiposity, lactation, hematopoiesis, and also inflammation and immunity<a href="#cite_note-Braunersreuther2012-2">[2]</a>. Damaged cells, such as apoptotic cells, can trigger the upregulation and release of cytokines to induce the inflammatory response. An important receptor responsible for cell death-related cytokine regulation is Fas, a cell surface glycoprotein which belongs to the tumor necrosis factor (TNF) receptor family. The role of Fas in the onset of inflammation by upregulating inflammatory cytokines is increasingly discussed. Fas-activation can trigger the production of MCP-1 and IL-8 and its associated chemotaxis of phagocytes toward apoptotic cells<a href="#cite_note-Cullen2013-3">[3]</a>. TNF-α is an inflammatory mediator that can be secreted by many cell types, including hepatocytes and Kupffer cells. TNF-induced cytokines and chemokines, such as IL-6, IL-8, GMCSF, CXCL1, and RANTES, can trigger immune responses by producing acute phase proteins and recruitment of inflammatory cells such as neutrophils, macrophages, and basophils to the site of inflammation. Moreover, an increased production of monocytes/macrophages from bone marrow is triggered<a href="#cite_note-Cullen2013-3">[3]</a>. On the other hand, inflammation can be suppressed by cytokines and mediators such as IL-10 and TGF-β. In the liver, TGF-β1 is the most abundant isoform and is secreted by immune cells, stellate cells, and epithelial cells. IL-10 inhibits T cell-, monocyte-, and macrophage-mediated functions and has been detected in several liver cells, in¬cluding hepatocytes, stellate cells, and Kupffer cells <a href="#cite_note-Braunersreuther2012-2">[2]</a>.

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible? mRNA expression levels of inflammatory cytokines can be determined by using real-time PCR as described in <a href="#cite_note-Cui2011-4">[4]</a>. Equally, In Situ Hybridization of mRNA in liver tissue can be used <a href="#cite_note-Faouzi2001-5">[5]</a>. Plasma levels of pro-inflammatory cytokines, or levels in cell supernatants can be analysed by enzyme linked immunosorbent assay (ELISA) using commercial kits <a href="#cite_note-Ma2009-6">[6]</a><a href="#cite_note-Cullen2013-3">[3]</a>. A more advanced system was described recently by using a multiplex immunoassay platform. In a 96 well plate format the authors describe the analysis of blood, urine and breath samples of human volunteers in a Meso Scale Discovery (MSD) multiplex electrochemiluminescent immunoassay system <a href="#cite_note-Stiegel2015-7">[7]</a>.

<a href="#cite_note-Cui2011-4">[4]</a><a href="#cite_note-Ma2009-6">[6]</a><a href="#cite_note-Faouzi2001-5">[5]</a>: mouse <a href="#cite_note-Cullen2013-3">[3]</a><a href="#cite_note-Stiegel2015-7">[7]</a>: human

CL:0000255

CL eukaryotic cell

High High

<ol class="references"> <li id="cite_note-1"><a href="#cite_ref-1">↑</a> Zhang JM, An J. Cytokines, inflammation, and pain. Int Anesthesiol Clin. 2007 Spring;45(2):27-37 </li> <li id="cite_note-Braunersreuther2012-2">↑ <a href="#cite_ref-Braunersreuther2012_2-0">2.0</a> <a href="#cite_ref-Braunersreuther2012_2-1">2.1</a> Braunersreuther V, Viviani GL, Mach F, Montecucco F. Role of cytokines and chemokines in non-alcoholic fatty liver disease. World J Gastroenterol. 2012 Feb 28;18(8):727-35 </li> <li id="cite_note-Cullen2013-3">↑ <a href="#cite_ref-Cullen2013_3-0">3.0</a> <a href="#cite_ref-Cullen2013_3-1">3.1</a> <a href="#cite_ref-Cullen2013_3-2">3.2</a> <a href="#cite_ref-Cullen2013_3-3">3.3</a> Cullen SP, Henry CM, Kearney CJ, Logue SE, Feoktistova M, Tynan GA, Lavelle EC, Leverkus M, Martin SJ. Fas/CD95-induced chemokines can serve as "find-me" signals for apoptotic cells. Mol Cell. 2013 Mar 28;49(6):1034-48 </li> <li id="cite_note-Cui2011-4">↑ <a href="#cite_ref-Cui2011_4-0">4.0</a> <a href="#cite_ref-Cui2011_4-1">4.1</a> Cui Y, Liu H, Zhou M, Duan Y, Li N, Gong X, Hu R, Hong M, Hong F. Signaling pathway of inflammatory responses in the mouse liver caused by TiO2 nanoparticles. 2011; J. Biomed. Mater. Res. - Part A 96 A:221–229 </li> <li id="cite_note-Faouzi2001-5">↑ <a href="#cite_ref-Faouzi2001_5-0">5.0</a> <a href="#cite_ref-Faouzi2001_5-1">5.1</a> Faouzi S, Burckhardt BE, Hanson JC, Campe CB, Schrum LW, Rippe RA, Maher JJ. Anti-Fas induces hepatic chemokines and promotes inflammation by an NF-kappa B-independent, caspase-3-dependent pathway. J Biol Chem. 2001 Dec 28;276(52):49077-82 </li> <li id="cite_note-Ma2009-6">↑ <a href="#cite_ref-Ma2009_6-0">6.0</a> <a href="#cite_ref-Ma2009_6-1">6.1</a> Ma L, Zhao J, Wang J, Liu J, Duan Y, Liu H, Li N, Yan J, Ruan J, Wang H, Hong F. The Acute Liver Injury in Mice Caused by Nano-Anatase TiO2. Nanoscale Res Lett. 2009 Aug 1;4(11):1275-85 </li> <li id="cite_note-Stiegel2015-7">↑ <a href="#cite_ref-Stiegel2015_7-0">7.0</a> <a href="#cite_ref-Stiegel2015_7-1">7.1</a> Stiegel MA, Pleil JD, Sobus JR, Morgan MK, Madden MC. Analysis of inflammatory cytokines in human blood, breath condensate, and urine using a multiplex immunoassay platform. Biomarkers. 2015 Feb;20(1):35-46 </li> </ol> AOPWiki 2016-11-29T18:41:22

2017-09-16T10:14:42

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

Increased, Reactive oxygen species

Cellular

Biological State: increased reactive oxygen species (ROS) Biological compartment: an entire cell -- may be cytosolic, may also enter organelles. Reactive oxygen species (ROS) are O2- derived molecules that can be both free radicals (e.g. superoxide, hydroxyl, peroxyl, alcoxyl) and non-radicals (hypochlorous acid, ozone and singlet oxygen) (Bedard and Krause 2007; Ozcan and Ogun 2015). ROS production occurs naturally in all kinds of tissues inside various cellular compartments, such as mitochondria and peroxisomes (Drew and Leeuwenburgh 2002; Ozcan and Ogun 2015). Furthermore, these molecules have an important function in the regulation of several biological processes – they might act as antimicrobial agents or triggers of animal gamete activation and capacitation (Goud et al. 2008; Parrish 2010; Bisht et al. 2017).  However, in environmental stress situations (exposure to radiation, chemicals, high temperatures) these molecules have its levels drastically increased, and overly interact with macromolecules, namely nucleic acids, proteins, carbohydrates and lipids, causing cell and tissue damage (Brieger et al. 2012; Ozcan and Ogun 2015).

Photocolorimetric assays (Sharma et al. 2017; Griendling et al. 2016) or through commercial kits purchased from specialized companies. Yuan, Yan, et al., (2013) described ROS monitoring by using H2-DCF-DA, a redox-sensitive fluorescent dye. Briefly, the harvested cells were incubated with H2-DCF-DA (50 µmol/L final concentration) for 30 min in the dark at 37°C. After treatment, cells were immediately washed twice, re-suspended in PBS, and analyzed on a BD-FACS Aria flow cytometry. ROS generation was based on fluorescent intensity which was recorded by excitation at 504 nm and emission at 529 nm. Lipid peroxidation (LPO) can be measured as an indicator of oxidative stress damage Yen, Cheng Chien, et al., (2013). Chattopadhyay, Sukumar, et al. (2002) assayed the generation of free radicals within the cells and their extracellular release in the medium by addition of yellow NBT salt solution (Park et al., 1968). Extracellular release of ROS converted NBT to a purple colored formazan. The cells were incubated with 100 ml of 1 mg/ml NBT solution for 1 h at 37 °C and the product formed was assayed at 550 nm in an Anthos 2001 plate reader. The observations of the ‘cell-free system’ were confirmed by cytological examination of parallel set of explants stained with chromogenic reactions for NO and ROS.

ROS is a normal constituent found in all organisms.

High Unspecific

High

All life stages

High

B.H. Park, S.M. Fikrig, E.M. Smithwick Infection and nitroblue tetrazolium reduction by neutrophils: a diagnostic aid Lancet, 2 (1968), pp. 532-534 Bedard, Karen, and Karl-Heinz Krause. 2007. “The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology.” Physiological Reviews 87 (1): 245–313. Bisht, Shilpa, Muneeb Faiq, Madhuri Tolahunase, and Rima Dada. 2017. “Oxidative Stress and Male Infertility.” Nature Reviews. Urology 14 (8): 470–85. Brieger, K., S. Schiavone, F. J. Miller Jr, and K-H Krause. 2012. “Reactive Oxygen Species: From Health to Disease.” Swiss Medical Weekly 142 (August): w13659. Chattopadhyay, Sukumar, et al. "Apoptosis and necrosis in developing brain cells due to arsenic toxicity and protection with antioxidants." Toxicology letters 136.1 (2002): 65-76. Drew, Barry, and Christiaan Leeuwenburgh. 2002. “Aging and the Role of Reactive Nitrogen Species.” Annals of the New York Academy of Sciences 959 (April): 66–81. Goud, Anuradha P., Pravin T. Goud, Michael P. Diamond, Bernard Gonik, and Husam M. Abu-Soud. 2008. “Reactive Oxygen Species and Oocyte Aging: Role of Superoxide, Hydrogen Peroxide, and Hypochlorous Acid.” Free Radical Biology & Medicine 44 (7): 1295–1304. Griendling, Kathy K., Rhian M. Touyz, Jay L. Zweier, Sergey Dikalov, William Chilian, Yeong-Renn Chen, David G. Harrison, Aruni Bhatnagar, and American Heart Association Council on Basic Cardiovascular Sciences. 2016. “Measurement of Reactive Oxygen Species, Reactive Nitrogen Species, and Redox-Dependent Signaling in the Cardiovascular System: A Scientific Statement From the American Heart Association.” Circulation Research 119 (5): e39–75. Ozcan, Ayla, and Metin Ogun. 2015. “Biochemistry of Reactive Oxygen and Nitrogen Species.” In Basic Principles and Clinical Significance of Oxidative Stress, edited by Sivakumar Joghi Thatha Gowder. Rijeka: IntechOpen. Parrish, A. R. 2010. “2.27 - Hypoxia/Ischemia Signaling.” In Comprehensive Toxicology (Second Edition), edited by Charlene A. McQueen, 529–42. Oxford: Elsevier. Sharma, Gunjan, Nishant Kumar Rana, Priya Singh, Pradeep Dubey, Daya Shankar Pandey, and Biplob Koch. 2017. “p53 Dependent Apoptosis and Cell Cycle Delay Induced by Heteroleptic Complexes in Human Cervical Cancer Cells.” Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 88 (April): 218–31. Yen, Cheng Chien, et al. "Inorganic arsenic causes cell apoptosis in mouse cerebrum through an oxidative stress-regulated signaling pathway." Archives of toxicology 85 (2011): 565-575. Yuan, Yan, et al. "Cadmium-induced apoptosis in primary rat cerebral cortical neurons culture is mediated by a calcium signaling pathway." PloS one 8.5 (2013): e64330. AOPWiki 2016-11-29T18:41:29

2023-07-26T14:34:09

Increased, DNA damage and mutation

Cellular

DNA damages are alteration of the DNA backbone including abasic site, single or double strand breaks or inter-strand crosslinks. These damages could be recognized and repaired by specialized enzymes. However, if damages persist, mutation in the DNA sequences can occur. Unlike DNA damages, DNA mutations when both strands are modified cannot be repaired and are heritable. Mutations affect the genotype and could affect phenotype. Different mechanisms are implicated in DNA damage such as oxidative burst, DNA repair dysfunction or centrosome amplification and chromosome instability [1].

DNA damages could be measured using different assays, such as micronucleus formation (OECD n°487) [2], comet assay with different protocols for the detection of double and single-strand breaks, DNA-DNA and DNA-protein crosslinks, adduct and oxidized nucleotides (OECD n°489) [3, 4] and γH2AX for the analysis of DNA strand breaks [5]. DNA mutation could be analyzed with Ames test or via the analysis of frequencies of mutations (OECD n°471) [6].

The DNA damages and mutations can occur in mammals, male or female, and is generally measured in adults.

Not Specified Unspecific

Not Specified

Adult

Not Specified

1.         Zhang Y. Cell toxicity mechanism and biomarker. 2018;7 1:34; doi: 10.1186/s40169-018-0212-7. 2.         Kato T, Totsuka Y, Ishino K, Matsumoto Y, Tada Y, Nakae D, et al. Genotoxicity of multi-walled carbon nanotubes in both in vitro and in vivo assay systems. Nanotoxicology. 2013;7 4:452-61; doi: 10.3109/17435390.2012.674571. 3.         Pacurari M, Yin XJ, Zhao J, Ding M, Leonard SS, Schwegler-Berry D, et al. Raw single-wall carbon nanotubes induce oxidative stress and activate MAPKs, AP-1, NF-kappaB, and Akt in normal and malignant human mesothelial cells. 2008;116 9:1211-7; doi: 10.1289/ehp.10924. 4.         Hiraku Y, Guo F, Ma N, Yamada T, Wang S, Kawanishi S, et al. Multi-walled carbon nanotube induces nitrative DNA damage in human lung epithelial cells via HMGB1-RAGE interaction and Toll-like receptor 9 activation. Particle and fibre toxicology. 2016;13:16; doi: 10.1186/s12989-016-0127-7. 5.         Catalan J, Siivola KM, Nymark P, Lindberg H, Suhonen S, Jarventaus H, et al. In vitro and in vivo genotoxic effects of straight versus tangled multi-walled carbon nanotubes. Nanotoxicology. 2016;10 6:794-806; doi: 10.3109/17435390.2015.1132345.            6.         Fukai E, Sato H, Watanabe M, Nakae D, Totsuka Y. Establishment of an in vivo simulating co-culture assay            platform for genotoxicity of multi-walled carbon nanotubes. Cancer science. 2018; doi: 10.1111/cas.13534. AOPWiki 2019-07-03T11:49:50

2019-08-13T05:41:05

Increase, Cell Proliferation

Cellular

Throughout their life, cells replicate their organelles and genetic information before dividing to form two new daughter cells, in a process known as cellular proliferation. This replicative process is known as the cell cycle and is subdivided into various stages notably, G1, S, G2, and M in mammals. G1 and G2 are gap phases, separating mitosis and DNA synthesis. Differentiated cells typically remain in G1; however, quiescent cells reside in an optional phase just before G1, known as G0.   Progression through the cycle is dependent on sufficient nutrient availability to provide optimal nucleic acid, protein, and lipid levels, as well as sufficient cell mass. To this end, the cell cycle is mediated by three major checkpoints: the restriction (R) point, or G1/S checkpoint, controlling entry into S phase, the G2/M checkpoint, controlling entry into mitosis, and one more controlling entry into cytokinesis. If conditions are ideal for division, cells will pass the restriction point (G1/S) and begin the activation and expression of genes used for duplicating centrosomes and DNA, eventually leading to proliferation (Cuyàs et al., 2014).   Various protein complexes, known as cyclins, cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CKIs) regulate passage through each phase by activating and inhibiting specific processes (Lovicu et al., 2014). The CDKs are responsible for controlling progression through the cell cycle. They promote DNA synthesis and mitosis, and therefore cell division (Barnum & O’Connell, 2014). Furthermore, growth factors are required to stimulate cell division, but after passing through the restriction point at G1 they are no longer necessary (Lovicu et al., 2014).   In the context of cancer, one hallmark is the sustained and uncontrolled cell proliferation (Hanahan et al., 2011, Portt et al., 2011). When cells obtain a growth advantage due to mutations in critical genes that regulate cell cycle progression, they may begin to proliferate excessively, resulting in hyperplasia and potentially leading to the development of a tumor. This is often achieved through oncogene activation and inactivation of tumor suppressor genes (Hanahan et al., 2011). Cell inactivation and the replacement of these cells can initiate clonal expansion (Heidenreich adn Paretzke et al., 2008).  Sustained atrophy/degeneration olfactory epithelium under the influence of a cytotoxic agent leads to adaptive tissue remodeling. Cell types unique to olfactory epithelium, e.g. olfactory neurons, sustentacular cells and Bowmans glands, are replaced by cell types comprising respiratory epithelium or squamous epithelium.

Two common methods of measuring cell proliferation in vivo are the use of Bromodeoxyuridine (5-bromo-2'-deoxyuridine, BrdU) labeling (Pera, 1977), and Ki67 immunostaining (Grogan, 1988). BrdU is a synthetic analogue of the nucleoside Thymidine. BrDu is incorporated into DNA synthesized during the S1 phase of cell replication and is stable for long periods. Labeling of dividing cells by BrdU is accomplished by infusion, bolus injection, or implantation of osmotic pumps containing BrdU for a period of time sufficient to generate measureable numbers of labeled cells. Tissue sections are stained immunhistochemically with antibodies for BrdU and labeled cells are counted as dividing cells. Ki67 is a cellular marker of replication not found in quiescent cells (Roche, 2015). Direct immunohistochemical staining of cells for protein Ki67 using antibodies is an alternative to the use of BrdU, with the benefit of not requiring a separate treatment (injection for pulse-labeling). Cells positive for Ki67 are counted as replicating cells. Replicating cell number is reported per unit tissue area or per cell nuclei (Bogdanffy, 1997). Listed below are common methods for detecting the KE, however there may be other comparable methods that are not listed. <table border="1" cellpadding="1" cellspacing="1" style="height:298px; width:595px"> <tbody> <tr> <td style="background-color:#dddddd; text-align:center">Assay Name</td> <td style="background-color:#dddddd; text-align:center">References</td> <td style="background-color:#dddddd; text-align:center">Description</td> <td style="background-color:#dddddd; text-align:center">OECD Approved Assay</td> </tr> <tr> <td>CyQuant Cell Proliferation Assay</td> <td>Jones et al., 2001</td> <td>DNA-binding dye is added to cell cultures, and the dye signal is measured directly to provide a cell count and thus an indication of cellular proliferation</td> <td>N/A</td> </tr> <tr> <td>Nucleotide Analog Incorporation Assays (e.g. BrdU, EdU)</td> <td>Romar et al., 2016, Roche; 2013</td> <td>Nucleoside analogs are added to cells in culture or injected into animals and become incorporated into the DNA at different rates, depending on the level of cellular proliferation; Antibodies conjugated to a peroxidase or fluorescent tag are used for quantification of the incorporated nucleoside analogs using techniques such as ELISA, flow cytometry, or microscopy</td> <td>Yes (No. 442B)</td> </tr> <tr> <td>Cytoplasmic Proliferation Dye Assays</td> <td>Quah & Parish, 2012</td> <td>Cells are incubated with a cytoplasmic dye of a certain fluorescent intensity; Cell divisions decrease the intensity in such a way that the number of divisions can be calculated using flow cytometry measurements</td> <td>N/A</td> </tr> <tr> <td>Colourimetric Dye Assays</td> <td>Vega-Avila & Pugsley, 2011; American Type Culture Collection</td> <td>Cells are incubated with a dye that changes colour following metabolism; Colour change can be measured and extrapolated to cell number and thus provide an indication of cellular proliferation rates</td> <td>N/A</td> </tr> </tbody> </table>

Cell proliferation is a central process supporting development, tissue homeostasis and carcinogenesis, each of which occur in all vertebrates. This key event has been observed nasal tissues of rats exposed to the chemical initiator vinyl acetate. In general, cell proliferation is necessary in the biological development and reproduction of most organisms. This KE is thus relevant and applicable to all multicellular cell types, tissue types, and taxa. Life stage applicability: This key event is not life stage specific (Fujimichi and Hamada, 2014; Barnard et al., 2022). Sex applicability: This key event is not sex specific (Markiewicz et al., 2015). Evidence for perturbation by a stressor: There is a large body of evidence supporting the effectiveness of ionizing radiation, UV, and mechanical wounding as stressors for increased cell proliferation. These stressors can be subdivided into X-rays (van Sallmann, 1951; Ramsell and Berry, 1966; Richards, 1966; Riley et al., 1988; Riley et al., 1989; Kleiman et al., 2007; Pendergrass et al., 2010; Fujimichi and Hamada, 2014, Markiewicz et al., 2015; Bahia et al., 2018), 60Co γ-rays (Hanna and O’Brien, 1963; Barnard et al., 2022; McCarron et al., 2021), 137Cs γ-rays (Andley and Spector, 2005), neutrons (Richards, 1966; Riley et al., 1988; Riley et al., 1989), 40Ar (Worgul et al., 1986), 56Fe (Riley et al., 1989), UVB (Söderberg et al., 1986; Andley et al., 1994; Cheng et al., 2019), UVC (Trenton and Courtois, 1981), and mechanical wounding (Riley et al., 1989).

High Unspecific

High

All life stages

High High High

Andley, U. P. et al. (1994), “Modulation of lens epithelial cell proliferation by enhanced prostaglandin synthesis after UVB exposure”, Investigative Ophthalmology & Visual Science, Vol. 35/2, Rockville, pp. 374-381   Andley, U. and A. Spector (2005), “Peroxide resistance in human and mouse lens epithelial cell lines is related to long-term changes in cell biology and architecture”, Free Radical Biology & Medicine, Vol. 39/6, Elsevier B.V, United States, https://doi.org/10.1016/j.freeradbiomed.2005.04.028  Bahia, S. et al. (2018), “Oxidative and nitrative stress-related changes in human lens epithelial cells following exposure to X-rays”, International journal of radiation biology, Vol. 94/4, England, <a href="https://doi.org/10.1080/09553002.2018.1439194" rel="noreferrer noopener" target="_blank">https://doi.org/10.1080/09553002.2018.1439194</a>  Barnard, S. et al. (2022), “Lens Epithelial Cell Proliferation in Response to Ionizing Radiation.”, Radiation Research, Vol. 197/1, Radiation Research Society, United States, <a href="https://doi.org/10.1667/RADE-20-00294.1" rel="noreferrer noopener" target="_blank">https://doi.org/10.1667/RADE-20-00294.1</a>  Barnum, K. and M. O’Connell (2014), “Cell cycle regulation by checkpoints”, in Cell cycle control, Springer, New York, http://doi.org/ 10.1007/978-1-4939-0888-2  Bogdanffy. et al. (1997). “FOUR-WEEK INHALATION CELL PROLIFERATION STUDY OF THE EFFECTS OF VINYL ACETATE ON RAT NASAL EPITHELIUM”, Inhalation Toxicology, Taylor & Francis. 9: 331-350. Cheng, T. et al. (2019), “lncRNA H19 contributes to oxidative damage repair in the early age-related cataract by regulating miR-29a/TDG axis”, Journal of cellular and molecular medicine, Vol. 23/9, Wiley Subscription Services, Inc. England, https://doi.org/10.1111/jcmm.14489  Cuyàs, E. et al. (2014), “Cell cycle regulation by the nutrient-sensing mammalian target of rapamycin (mTOR) pathway”, in Cell cycle control, Springer, New York, http://dx.doi.org/ 10.1007/978-1-4939-0888-2  Fujimichi, Y. and N. Hamada (2014), “Ionizing irradiation not only inactivates clonogenic potential in primary normal human diploid lens epithelial cells but also stimulates cell proliferation in a subset of this population”, PloS one, Vol. 9/5, e98154, Public Library of Science, United States, <a href="https://doi.org/10.1371/journal.pone.0098154" rel="noreferrer noopener" target="_blank">https://doi.org/10.1371/journal.pone.0098154</a>  Grogan. et al. (1988). “Independent prognostic significance of a nuclear proliferation antigen in diffuse large cell lymphomas as determined by the monoclonal antibody Ki-67”, Blood. 71: 1157-1160. Hanna, C. and J. E. O’Brien (1963), “Lens epithelial cell proliferation and migration in radiation cataracts”, Radiation research, Academic Press, Inc, United States, <a href="https://doi.org/10.2307/3571405" rel="noreferrer noopener" target="_blank">https://doi.org/10.2307/3571405</a>  Hanahan, D. & R. A. Weinberg, (2011),” Hallmarks of cancer: the next generation”, Cell. 144(5):646-74. doi: 10.1016/j.cell.2011.02.013. Heidenreich WF, Paretzke HG. (2008) Promotion of initiated cells by radiation-induced cell inactivation. Radiat Res. Nov;170(5):613-7. doi: 10.1667/RR0957.1. PMID: 18959457. Jones, J. L. et al. (2001), Sensitive determination of cell number using the CyQUANT cell proliferation assay. Journal of Immunological Methods. 254(1-2), 85-98. Doi:10.1016/s0022-1759(01)00404-5. Kleiman, N. J. et al. (2007), “Mrad9 and Atm haplinsufficiency enhance spontaneous and X-ray-induced cataractogenesis in mice”, Radiation research, Vol. 168/5, Radiation Research Society, United States, <a href="https://doi.org/10.1667/rr1122.1" rel="noreferrer noopener" target="_blank">https://doi.org/10.1667/rr1122.1</a>  Lovicu, J. et al (2014), “Lens epithelial cell proliferation”, in Lens epithelium and posterior capsular opacification, Springer, Tokyo, http://dx.doi.org/ 10.1007/978-4-431-54300-8_4  Markiewicz, E. et al. (2015), “Nonlinear ionizing radiation-induced changes in eye lens cell proliferation, cyclin K1 expression and lens shape”, Open biology, Vol. 5/4, The Royal Society, England, <a href="https://doi.org/10.1098/rsob.150011" rel="noreferrer noopener" target="_blank">https://doi.org/10.1098/rsob.150011</a>  McCarron, R. A. et al. (2021), “Radiation-induced lens opacity and cataractogenesis: a lifetime study using mice of varying genetic backgrounds”, Radiation research, Vol. 197/1, Radiation Research Society, United States, https://doi.org/10.1667/RADE-20-00266.1  Pendergrass, W. et al. (2010), “X-ray induced cataract is preceded by LEC loss, and coincident with accumulation of cortical DNA, and ROS; similarities with age-related cataracts”, Molecular vision, Vol. 16, Molecular Vision, United States, pp. 1496-1513  Pera, Mattias and Detzer (1977). “Methods for determining the proliferation kinetics of cells by means of 5-bromodeoxyuridine”, Cell Tissue Kinet.10: 255-264. Doi: 10.1111/j.1365-2184.1977.tb00293.x. Portt, L. et al. (2011), “Anti-apoptosis and cell survival: a review”, Biochim Biophys Acta. 21813(1):238-59. doi: 10.1016/j.bbamcr.2010.10.010. Quah, J. C. B. & R. C. Parish (2012), “New and improved methods for measuring lymphocyte proliferation in vitro and in vivo using CFSE-like fluorescent dyes”, Journal of Immunological Methods. 379(1-2), 1-14. doi: 10.1016/j.jim.2012.02.012. Ramsell, T. G. and R. J. Berry (1966), “Recovery from X-ray damage to the lens. The effects of fractionated X-ray doses observed in rabbit lens epithelium irradiated in vivo”, British Journal of Radiology, Vol. 39/467, England, pp. 853-858  Riley, E. F. et al. (1988), “Recovery of murine lens epithelial cells from single and fractionated doses of X rays and neutrons”, Radiation Research, Vol. 114/3, Academic Press Inc, Oak Brook, https://doi.org/10.2307/3577127  Riley, E. F. et al. (1989), “Comparison of recovery from potential mitotic abnormality in mitotically quiescent lens cells after X, neutron, and 56Fe irradiations”, Radiation Research, Vol. 119/2, United States, pp. 232-254  Richards, R. D. (1966), “Changes in lens epithelium after X-ray or neutron irradiation (mouse and rabbit)”, Transactions of the American Ophthalmological Society, Vol. 64, United States, pp. 700-734  Roche Applied Science, (2013), “Cell Proliferation Elisa, BrdU (Colourmetric) ». Version 16 Romar, A. G., S. T. Kupper & J. S. Divito (2015), “Research Techniques Made Simple: Techniques to Assess Cell Proliferation”,  Journal of Investigative Dermatology. 136(1), e1-7. doi: 10.1016/j.jid.2015.11.020. Söderberg, P. G. et al. (1986), “Unscheduled DNA synthesis in lens epithelium after in vivo exposure to UV radiation in the 300 nm wavelength region”, Acta Ophthalmologica, Vol. 64/2, Blackwell Publishing Ltd, Oxford, UK, https://doi.org/10.1111/j.1755-3768.1986.tb06894.x  Trenton, J. A. and Y. Courtois (1981), “Evolution of the distribution, proliferation and ultraviolet repair capacity of rat lens epithelial cells as a function of maturation and aging”, Mechanisms of Ageing and Development, Vol. 15/3, Elsevier, Ireland, https://doi.org/1016/0047-6374(81)90134-2  Vega-Avila, E. & K. M. Pugsley (2011), “An Overview of Colorimetric Assay Methods Used to Assess Survival or Proliferation of Mammalian Cells”, Proc. West. Pharmacol. Soc. 54, 10-4. von Sallmann, L. (1951), “Experimental studies on early lens changes after x-ray irradiation III. Effect of X-radiation on mitotic activity and nuclear fragmentation of lens epithelium in normal and cysteine-treated rabbits”, Transactions of the American Ophthalmological Society, Vol. 48, United States, pp. 228-242  Worgul, B. V. et al. (1986), “Accelerated heavy particles and the lens II. Cytopathological changes”, Investigative Ophthalmology and Visual Science, Vol 27/1, pp. 108-114  AOPWiki 2016-11-29T18:41:27

2023-05-15T08:54:03

Lung cancer

Organ

Lung cancer is one of the most prevalent cancer in the world. This cancer occur mainly at the level of bronchial cells and affect more rarely at the level of alveoli. Lung cancer affects more men rather than women because of tabacco consumption (trend is reversing). This disease is at the first place on terms of mortality due to the late detection (Cancer League, WHO).

Lung cancer can be measured in human by analysis of the sputum cytology, the chest X-ray and all the techniques usually used in this medical field. In animal experiments, the OECD guidelines n°451 provide the procedure for the study of carcinogenesis development.

Lung cancer can occur in mammals, male or female, generally in adults

Not Specified Unspecific

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Adult

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AOPWiki 2019-07-03T11:51:27

2019-08-13T05:34:23

<upstream-id>68adf450-1702-4f45-8793-8556e1522692</upstream-id> <downstream-id>4d5783eb-41b7-4d75-a5d3-0d3039deb913</downstream-id> Phagocytosis allow the clearance of foreign matter. Incomplete phagocytosis, or frustrated phagocytosis, leads to the persistence of foreign matter. Therefore, in order to clear these substances, phagocytes secretes signals including cytokines for the recruitment of other phagocytes.

The main function of professional phagocytes is to clear the tissue of the foreign matter by phagocytosis [<a href="#_ENREF_1" title="Murray, 2011 #45">1</a>]. Following exposure to foreign matter, macrophages are activated and therefore secrete pro-inflammatory mediators including cytokines [<a href="#_ENREF_1" title="Murray, 2011 #45">1</a>].

In the study of Murphy et al, the human monocytic THP-1 cells treated with carbon nanotubes (CNTs) that induce frustrated phagocytosis showed an increase production of IL-1β, IL-6 and IL-8 whereas treatment by CNTs that did not induce this process did not induce production of these cytokines [<a href="#_ENREF_2" title="Murphy, 2012 #3">2</a>]. Similarly, it was shown that exposure to fibres that induced frustrated phagocytosis of primary human alveolar macrophages is accompanied by induction of IL-6 and IL-8 [<a href="#_ENREF_3" title="Sweeney, 2015 #9">3</a>], and exposure of immortalized MH-S murine alveolar macrophage is accompanied by induction of TNFα and IL-1α [<a href="#_ENREF_4" title="Padmore, 2017 #1">4</a>, <a href="#_ENREF_5" title="Ye, 1999 #47">5</a>]. The induction of cytokines was observed in lesser extend after cell treatment with fibres that did not cause frustrated phagocytosis. Indeed, the ratio of the dose-response for TNFα and IL-1α of long fibres to short fibres was about 11 [<a href="#_ENREF_4" title="Padmore, 2017 #1">4</a>, <a href="#_ENREF_5" title="Ye, 1999 #47">5</a>].

In very few studies it was analysed the release of cytokines in the same samples as the frustrated phagocytosis. A study of Zeidler-Erdely et al 2006 showed that human alveolar macrophages are able to engulf fibres with a length of 20 µm and explained this difference with rat alveolar macrophages are smaller than human cells [<a href="#_ENREF_6" title="Zeidler-Erdely, 2006 #48">6</a>]. However, these data are not in accordance with those obtained by Sweeney et al 2015 were they used primary human alveolar macrophages  and by Murphy et al 2012 were they used monocytic cells THP-1 differentiated in macrophages [<a href="#_ENREF_2" title="Murphy, 2012 #3">2</a>, <a href="#_ENREF_3" title="Sweeney, 2015 #9">3</a>].

The length of fibres that induced frustrated phagocytosis accompanied by cytokines production were comprised between 13 and 39.3 µm, whereas fibres with length between 1 and 7 µm were completely phagocytosed and did not induce cytokine production [<a href="#_ENREF_2" title="Murphy, 2012 #3">2</a>, <a href="#_ENREF_3" title="Sweeney, 2015 #9">3</a>, <a href="#_ENREF_4" title="Padmore, 2017 #1">4</a>].

The frustrated phagocytosis and cytokine production were observed after 16 to 24h of treatment [<a href="#_ENREF_2" title="Murphy, 2012 #3">2</a>, <a href="#_ENREF_3" title="Sweeney, 2015 #9">3</a>, <a href="#_ENREF_4" title="Padmore, 2017 #1">4</a>, <a href="#_ENREF_5" title="Ye, 1999 #47">5</a>].

Not Specified Unspecific

Not Specified

Adult

Not Specified

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb8a1135368> AOPWiki 2019-07-03T11:52:25

2019-08-13T05:25:46

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb8a1329fc0> AOPWiki 2019-07-03T11:52:45

2019-07-03T11:52:45

<upstream-id>c41db4d8-d495-4bc7-a662-308eef4a0b8d</upstream-id> <downstream-id>9000f577-7ab5-4253-864b-ad0fd15b0109</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb8a18a7f88> AOPWiki 2019-07-03T11:53:04

2019-07-03T11:53:04

<upstream-id>9000f577-7ab5-4253-864b-ad0fd15b0109</upstream-id> <downstream-id>86720c17-d31d-45c3-bd3a-8a3ae27545a1</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb8a0d76268> AOPWiki 2019-07-03T11:53:23

2019-07-03T11:53:23

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb8a0772e20> AOPWiki 2019-07-03T11:53:38

2019-07-03T11:53:38

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb8a17a2160> AOPWiki 2019-07-03T11:53:50

2019-07-03T11:53:50

Frustrated phagocytosis-induced lung cancer

Arthur Author

Carole Seidel Sarah Valentino Laurent Gaté Institut National de Recherche et de Sécurité, Rue du Morvan, CS 60027, F-54519 Vand&oelig;uvre, Cedex, France.

BY-SA

Under Development

1.86

2.0

Inhalation of materials, including fibres and particles, represents the main route of occupational exposure. The main issue is the biopersistance of these materials in lungs that could lead to chronic pulmonary pathologies such as fibrosis and cancer. Lung tumour is one of the most prevalent cancer in the world and, in general, is often detected at a late stage. The knowledge related to the induction of lung disease following asbestos exposure led to study the toxicity of high aspect ratio materials (HARMs) in general. It is now well documented that exposure to HARMs could lead to pulmonary inflammation and ROS overproduction. Some studies suggest that lung biopersistence of HARMs is associated with frustrated phagocytosis and material length. The identified gaps regarding the induction of lung cancer following the exposure to HARMs is mainly on the interaction with cells, and no study demonstrated all the key events presented here in the same samples.

High aspect ratio nanoparticles are not completely engulfed by macrophages due to their long shape (> 10µm) [8, 10].  Some studies analysed the effect of the length of nanoparticles (NPs) on the capacity of macrophages to phagocytose them. The study of Sweeney et al 2015 demonstrated that treatment of primary human alveolar macrophages by multi-walled carbon nanotubes (MWCNT) similar in term of diameter, specific surface area and purity but differ by their length differentially alter phagocytosis [6]. Indeed, treatment by the longer CNT (median length 19.3 µm) induced frustrated phagocytosis and receptor expression (MARCO) as well as decreased phagocytic ability and migratory capacity in a more extend manner than the shorter CNT (median length 1.1 µm) [6]. Another study analysed the effect of particle morphology on the ability of human monocytic cell line THP-1 to engulf carbon nanotubes [9]. Cells were treated for 24h by two longs CNTs (men length 13 and 36 µm, dimeter 84.89 and 165.02 nm), two tangled CNTs (length 1-5 and 5-20 µm, dimeter 14.84 and 10.40 nm) and one short CNT (length 1-2 µm, diameter 25.7 nm). The authors observed by light microscopy that only the two long CNTs are protruding from the cells. A study on THP-1 cells treated for 4h was conducted with silver nanowires that possess similar diameter but different length (average length: 3, 5, 10, 14 and 28 µm) [8]. The authors observed by bright-field microscopy that the shorter NPs (3 and 5) were fully enclosed by macrophages, while the longer NPs (14 and 28) caused frustrated phagocytosis. In addition, injection of NPs in mouse pleural cavity followed by pleural lavage demonstrated that the shorter (3 and 5) were fully phagocytosed whereas the longer (10) caused frustrated phagocytosis. The authors observed differences between in vitro and in vivo studies in term of sensitivity for the determination of the length threshold that caused frustrated phagocytosis [8]. Finally, Padmore et al showed by time-lapse video microscopy that immortalized MH-S murine alveolar macrophages were able to internalized short glass fibres (mean length 7 µm) whereas the longer fibres were not (mean length 39.3 µm) [7].  All together, these studies could suggest that the threshold for frustrated phagocytosis should be around 10 µm, close to the suggestion formulated by Donaldson et al that fibres longer than 15 µm cause this process [10].

adjacent

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Not Specified Unspecific

Not Specified

Adult

Not Specified

This AOP is applicable to adult (at least to mature lung tissue), to many vertebrate taxons, and to both genders.

Not Specified

AOPWiki 2019-07-03T11:26:45

2023-09-25T16:27:00