Inactivation of PPARγ

GO:0006954

GO inflammatory response

WIKI increased

9606

NCBI Homo sapiens

10090

NCBI Mus musculus

10116

NCBI Rattus norvegicus

Inactivation of PPARγ

Molecular

Following pulmonary exposure, the stressor interacts with cellular membranes of alveolar macrophages, other inflammatory cells, epithelial cells and proteins (lung surfactants) in the lung space. The stressor acts as an antagonist of PPARγ of epithelial and inflammatory cells in the lung.

AOPWiki 2017-02-15T02:43:41

2017-12-26T02:12:06

Activation of TGF-β signaling

Cellular

AOPWiki 2017-02-15T02:45:16

2017-02-15T02:45:16

Collagen Deposition

Tissue

AOPWiki 2017-02-15T02:55:23

2017-02-15T02:55:23

Lung fibrosis

Organ

This consecutive KE resulting in the acquisition of the accumulation of excess fibrous connective tissue, the adverse outcome on pulmonary fibrosis. Scar formation, the accumulation of excess fibrous connective tissue (the process called fibrosis), leads to thickening of the walls, and causes reduced oxygen supply in the blood. As a consequence patients suffer from perpetual shortness of breath.

AOPWiki 2017-02-15T02:55:56

2017-12-26T02:10:27

Increase, Inflammation

Cellular

Inflammation is complex to define.  Villeneuve et al. (2018) analyzed the varied biological responses, provided guidance to simplify the  process representing inflammation in adverse outcome pathways, and recommended 3 key steps: 1. Tissue resident cell activation 2. Increased Pro-inflammatory mediators 3. Leukocyte recruitment/activation.  Tissue resident cell activation generally occurs when healthy tissue is exposed to a stressor, or when damage occurs, initiating a signal response of pro-inflammatory mediators (ex. cytokines).  Pro-inflammatory mediators result in the production of lipids and proteins, signaling, and initiate leukocyte recruitment/activation.  Leukocyte recruitment/activation initiate inflammation and other morphological changes.  Some empirical research studies that illustrate inflammation pathways: <ul> <li>A review of inflammation caused by microplastics in mammals (Wright and Kelly, 2017).  Inflammation and immune responses are caused by irritation via microplastics inhalation.</li> <li>Increased inflammatory interleukin gene expression in lab mice brains with damaged hypoglossal nerves (Gamo et al., 2008).  Inflammatory genes interleukin-1beta and interleukin-6, and tumor necrosis factor-alpha levels were increased after physical injury.</li> <li>Increased inflammation in the freshwater fish Danio rerio exposed to polystyrene microplastics (Lu et al., 2016).  Oxidative stress indicator enzymes superoxide dismutase and catalase were increased in livers, along with histopathological changes in inflammation and necrosis, in response to accumulation of microplastics.</li> <li>Inhibited inflammatory interleukin gene expression in guts and increased mucus production in guts in the freshwater fish Danio rerio exposed to polystyrene microplastics (Jin et al., 2018).  Gene expression of tumor necrosis factor-alpha, interleukin-1alpha, interleukin-1beta, interferon, interleukin-6, interleukin-8, interleukin-10 were changed, with most genes showing statistically significant increases and a dose-response relationship, due to exposure to polystyrene microplastics.  In additional, gut microbiota was altered.</li> <li>Significant intestinal damage including intestinal fold disruption, enterocyte damage, broken tissue, and inflammation in the freshwater fish Danio rerio exposed to microplastics (Lei et al., 2018).  Growth and reproductive effects were seen in addition to the histology observations, and associated with accumulation of microplastics.</li> </ul> In cancer, inflammation is a cascade of events created by the host in response to the spread of the cancer (Coussens and Werb, 2002). In response to an injury or the presence of cancer, the host heals itself through inflammation. Indeed, the activation and the migration of  leukocytes (neutrophils, monocytes and eosinophils) to the wound induces the healing process. These inflammatory cells provide an extracellular matrix that forms upon which fibroblast and endothelial cells proliferate and migrate in order to recreate a normal environment. Damage to the epithelial layer initiate inflammatory reactions (Palmer et al. 2011).  In cancer, this inflammatory state induces cell proliferation, increases the production of reactive oxygen species leading to oxidative DNA damage, and reduces DNA repair (Coussens and Werb, 2002).

Inflammation is generally detected in histopathological examination of organs (ex. liver, intestines) or in changes in gene expression (ex. interleukins).  Activation of the innate immune response and the release of various inflammatory cytokines can also be assessed (Flake and Morgan, 2017).

Taxonomic: appears to be present broadly, with representative studies focused on mammals (humans, lab mice, lab rats).

CL:0000255

CL eukaryotic cell

High Unspecific

High

All life stages

High High High

Flake, G.P., and Morgan, D.L. 2017. Pathology of diacetyl and 2,3-pentanedione airway lesions in a rat model of obliterative bronchiolitis. Toxicology, 388, 40–47. <a href="https://doi.org/10.1016/j.tox.2016.10.013">https://doi.org/10.1016/j.tox.2016.10.013</a> Palmer, S.M., Flake, G.P., Kelly, F.L., Zhang, H.L., Nugent, J.L., Kirby, P.J., Zhang, H.L., Nugent, J.L., Kirby, P.J., Foley, J.F., Gwinn, W.M., and Morgan, D.L. 2011. Severe airway epithelial injury, aberrant repair and Bronchiolitis obliterans develops after diacetyl instillation in rats. PLoS ONE, 6(3). <a href="https://doi.org/10.1371/journal.pone.0017644">https://doi.org/10.1371/journal.pone.0017644</a> Coussens L.M. and Werb Z. Inflammation and cancer. Nature. 2002 Dec 19-26;420(6917):860-7. doi: 10.1038/nature01322. PMID: 12490959; PMCID: PMC2803035. Gamo, K., Kiryu-Seo, S., Konishi, H., Aoki, S., Matushima, K., Wada, K., and Kiyama, H.  2008.  G-protein-coupled receptor screen reveals a role for chemokine recepteor CCR5 in suppressing microglial neurotoxicity.  Journal of Neuroscience 28: 11980-11988. Jin, Y., Xia, J., Pan, Z., Yang, J., Wang, W., and Fu, Z.  2018.  Polystyrene microplastics induce microbiota dysbiosis and inflammation in the gut of adult zebrafish.  Environmental Pollution 235: 322-329. Lei, L., Wu, S., Lu, S., Liu, M., Song, Y., Fu, Z., Shi, H., Raley-Susman, K.M., and He, D.  2018.  Microplastic particles cause intestinal damage and other adverse effects in zebrafish Danio rerio and nematode Caenorhabditis elegans.  Science of the Total Environment 619-620: 1-8. AOPWiki 2016-11-29T18:41:23

2023-08-10T14:43:51

Induction, Epithelial Mesenchymal Transition

EMT

Cellular

Inflammatory reactions result in the release of various cytokines which in turn can stimulate the transition of epithelial cells to a mesenchymal phenotype acquiring function characteristics of fibroblasts and myofibroblasts.

Loss of <a href="https://en.wikipedia.org/wiki/E-cadherin">E-cadherin</a> and cell polarity is considered to be a fundamental event in epithelial-mesenchymal transition. The simultaneous expression of epithelial (e.g. E-cadherin) and mesenchymal markers (e.g. N-cadherin and vimentin) within the airway epithelium are indicative for ongoing transition (Borthwick et al. 2009, 2010).

Borthwick, L. A., Parker, S. M., Brougham, K. A., Johnson, G. E., Gorowiec, M. R., Ward, C., … Fisher, A. J. (2009). Epithelial to mesenchymal transition (EMT) and airway remodelling after human lung transplantation. Thorax, 64(9), 770–777. <a href="https://doi.org/10.1136/thx.2008.104133">https://doi.org/10.1136/thx.2008.104133</a> Borthwick, L. A., McIlroy, E. I., Gorowiec, M. R., Brodlie, M., Johnson, G. E., Ward, C., … Fisher, A. J. (2010). Inflammation and epithelial to mesenchymal transition in lung transplant recipients: Role in dysregulated epithelial wound repair. American Journal of Transplantation, 10(3), 498–509. <a href="https://doi.org/10.1111/j.1600-6143.2009.02953.x">https://doi.org/10.1111/j.1600-6143.2009.02953.x</a> AOPWiki 2017-07-26T19:11:33

2019-01-30T10:27:22

<upstream-id>86bd5535-d2a5-41bc-8d5f-121191f4e7f0</upstream-id> <downstream-id>78afeafb-a086-40b3-befe-912fc8ee99c8</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42cc2c64a8> AOPWiki 2017-02-15T02:57:01

2017-02-15T02:57:01

<upstream-id>56d636e7-9961-423f-9773-b561a44a6ff2</upstream-id> <downstream-id>0f4ca77f-3400-400b-b062-7eb13283a8ab</downstream-id> The inflammatory reactions initiated by the damaged airway epithelium might stimulate the transition of fibroblasts present in the underlying mesenchymal tissue to myofibroblasts.

Fibroblast to myofibroblast transition might represent an alternative way, besides EMT, to close wounds in the epithelial layer. Under the influence of inflammatory signals, fibroblast present in the mesenchymal tissue beneath the damage epithelium might be stimulated to differentiate into myofibroblasts. Especially in regions of the airways that became completely denuded from an epithelial layer this might form an alternative for EMT to repair the wound in the epithelium.

Studying airway fibroblasts in vitro, myofibroblast transdifferentiation in response to TGF-beta1 signaling was observed, evidenced by increased alpha-smooth muscle actin mRNA and protein expression (Ramirez et al. 2006).

Both the transition of epithelial cells to mesenchymal cells as well as the transition of mesenchymal fibroblasts to myofibroblast are possible mechanisms leading to dysregulated repair of damage airway epithelium. At present it is unclear which transition is the most prominent.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb89dc0bd40> AOPWiki 2018-03-18T09:50:09

2019-01-30T10:58:48

<upstream-id>d1fd52b5-5625-402d-918a-6c830077c4a4</upstream-id> <downstream-id>5254d340-4a86-47a7-8644-7d1e3a3dc6d9</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb89f83b240> AOPWiki 2017-02-15T02:58:46

2017-02-15T02:58:46

<upstream-id>78afeafb-a086-40b3-befe-912fc8ee99c8</upstream-id> <downstream-id>56d636e7-9961-423f-9773-b561a44a6ff2</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb8a03d8990> AOPWiki 2018-03-18T09:46:23

2018-03-18T09:46:23

<upstream-id>0f4ca77f-3400-400b-b062-7eb13283a8ab</upstream-id> <downstream-id>d1fd52b5-5625-402d-918a-6c830077c4a4</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb89f2fac68> AOPWiki 2018-11-20T20:57:41

2018-11-20T20:57:41

Peroxisome proliferator-activated receptors γ inactivation leading to lung fibrosis

PPARγ inactivation leading to lung fibrosis

Brendan Ferreri-Hanberry

Jinhee Choi, University of Seoul, Republic of Korea Nivedita Chatterjee, University of Seoul, Republic of Korea Jaeseong Jeong, University of Seoul, Republic of Korea Ji-yeon Rho, Knoell Korea, Republic of Korea Eun-Young Kim, Kyung Hee University, Republic of Korea Seung Min Oh, Hoseo University, Republic of Korea Natàlia Garcia-Reyero, Mississippi State University, USA Edward J. Perkins, U.S. Army Engineer Research and Development Center, USA Lyle D. Burgoon, U.S. Army Engineer Research and Development Center, USA

Under Development

1.54

1.0

Pulmonary fibrosis is a respiratory disease in which scars are formed in the lung tissues, leading to serious breathing problems. It is an immunological process that is known to be regulated by the immune modulator Peroxisome proliferator-activated receptors γ (PPARγ) and transforming growth factor β (TGF-β). PPARγ ligands antagonize the profibrotic effects of TGF-β in which induce differentiation of fibroblasts to myofibroblasts, a critical effector cell in fibrosis. These sequential set of events are described in this Adverse Outcome Pathway (AOP). The molecular initiating event (MIE) is inactivation of PPARγ which leads to TGF-β activation, a key event (KE) at molecular level. Next, key event at cellular level is differentiation of Myofibroblast and expression of collagen gene by activated TGF-β signaling pathway. Differentiated myofibroblast subsequently produce α-smooth muscle actin (α-SMA) and overexpressed collagen deposits in lung tissue. This consecutive KE resulting in the acquisition of the accumulation of excess fibrous connective tissue, the adverse outcome on pulmonary fibrosis. Scar formation, the accumulation of excess fibrous connective tissue (the process called fibrosis), leads to thickening of the walls, and causes reduced oxygen supply in the blood. As a consequence patients suffer from perpetual shortness of breath.

adjacent

Not Specified

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Not Specified

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Not Specified

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Not Specified

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Not Specified

Not Specified Unspecific

Not Specified

All life stages

Not Specified

<ol> <li>Lakatos HF, Thatcher TH, Kottmann RM, Garcia TM, Phipps RP, Sime PJ. The Role of PPARs in Lung Fibrosis. PPAR Research. 2007; 2007:71323.</li> <li>Belvisi MG, Hele DJ. Peroxisome Proliferator-Activated Receptors as Novel Targets in Lung Disease. Chest. 2008; 134(1):152-157.</li> <li>Belvisi MG, Mitchell JA. Targeting PPAR receptors in the airway for the treatment of inflammatory lung disease. Br J Pharmacol. 2009; 158(4):994–1003.</li> <li>Sakai N, Tager AM. Fibrosis of Two: Epithelial Cell-Fibroblast Interactions in Pulmonary Fibrosis. Biochim Biophys Acta. 2013; 1832(7): 911–921.</li> <li>Limjunyawong N, Mitzner W, Horton MR. A mouse model of chronic idiopathic pulmonary fibrosis. Physiol Rep. 2014; 2(2): e00249.</li> <li>Brown T. Silica exposure, smoking, silicosis and lung cancer—complex interactions. Occup Med (Lond). 2009; 59(2):89-95.</li> <li>Holt DJ, Chamberlain LM, Grainger DW. Cell-cell signaling in co-cultures of macrophages and fibroblasts. Biomaterials. 2010; 31(36):9382-9394.</li> <li>Mishra A, Rojanasakul Y, Chen BT, Castranova V, Mercer RR, Wang L. Assessment of Pulmonary Fibrogenic Potential of Multiwalled Carbon Nanotubes in Human Lung Cells. J Nanomater. 2012; 2012: 18</li> <li>Ye Z, Zhang J. Mechanism study is needed for better understanding of crystalline silica-induced silicosis and lung cancer. theHealth 2012; 3(1): 5-6.</li> <li>Todd NW, Luzina IG, Atamas SP. Molecular and cellular mechanisms of pulmonary fibrosis. Fibrogenesis Tissue Repair. 2012; 5(1):11.</li> <li>Tsukada T, Fushida S, Harada S, Yagi Y, Kinoshita J, Oyama K et al. The role of human peritoneal mesothelial cells in the fibrosis and progression of gastric cancer. Int J Oncol. 2012; 41(2):476-482.</li> <li>Moore BB, Lawson WE, Oury TD, Sisson TH, Raghavendran K, Hogaboam CM. Animal Models of Fibrotic Lung Disease. Am J Respir Cell Mol Biol. 2013; 49(2):167-179.</li> <li>Loubaki L, Hadj-Salem I, Fakhfakh R, Jacques E, Plante S, Boisvert M et al. Co-Culture of Human Bronchial Fibroblasts and CD4+ T Cells Increases Th17 Cytokine Signature. PLoS One. 2013; 8(12):e81983.</li> <li>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; 7:7.</li> <li>Haubner F, Muschter D, Pohl F, Schreml S, Prantl L, Gassner HG. A Co-Culture Model of Fibroblasts and Adipose Tissue-Derived Stem Cells Reveals New Insights into ImpairedWound Healing After Radiotherapy. Int J Mol Sci. 2015; 16(11):25947-25958.</li> <li>Jonsdottir HR, Arason AJ, Palsson R, Franzdottir SR, Gudbjartsson T, Isaksson HJ et al. Basal cells of the human airways acquire mesenchymal traits in idiopathic pulmonary fibrosis and in culture. Lab Invest. 2015; 95(12):1418-1428.</li> <li>Iskandar AR, Xiang Y, Frentzel S, Talikka M, Leroy P, Kuehn D et al. Impact Assessment of Cigarette Smoke Exposure on Organotypic Bronchial Epithelial Tissue Cultures: A Comparison of Mono-Culture and Coculture Model Containing Fibroblasts. Toxicol Sci. 2015; 147(1):207-221.</li> <li>Rajangam T, Park MH, Kim SH. 3D Human Adipose-Derived Stem Cell Clusters as a Model for In Vitro Fibrosis. Tissue Eng Part C Methods. 2016; 22(7):679-690.</li> <li>Pozzolini M, Vergani L, Ragazzoni M, Delpiano L, Grasselli E, Voci A et al. Different reactivity of primary fibroblasts and endothelial cells towards crystalline silica: A surface radical matter. Toxicology. 2016; 361-362:12-23.</li> <li>Clippinger AJ, Ahluwalia A, Allen D, Bonner JC, Casey W, Castranova V et al. Expert consensus on an in vitro approach to assess pulmonary fibrogenic potential of aerosolized nanomaterials. Arch Toxicol. 2016; 90(7):1769-1783.</li> <li>Vietti G, Lison D, van den Brule S. Mechanisms of lung fibrosis induced by carbon nanotubes: towards an Adverse Outcome Pathway (AOP). Part Fibre Toxicol. 2016; 13:11.</li> </ol> AOPWiki 2017-02-15T02:34:56

2023-09-25T16:26:55