GO:0006954inflammatory response1increased9606Homo sapiensInactivation of PPARγInactivation of PPARγMolecular<p>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.</p>
<p>The stressor acts as an antagonist of PPARγ of epithelial and inflammatory cells in the lung.</p>
2017-02-15T02:43:412017-12-26T02:12:06Activation of TGF-β signalingActivation of TGF-β signalingCellular2017-02-15T02:45:162017-02-15T02:45:16Collagen DepositionCollagen DepositionTissue2017-02-15T02:55:232017-02-15T02:55:23Lung fibrosisLung fibrosisOrgan<p>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.</p>
2017-02-15T02:55:562017-12-26T02:10:27Increase, InflammationIncrease, InflammationCellular<p>Inflammation is compex to define.</p>
<p>In cancer, is a cascade of events created by the host in response to the spread of the cancer (Coussens). 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 re create a normal environnement. 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)</p>
<p>Damage of the epithelial layer lining the airways initiate inflammatory reactions.</p>
<ul>
<li>Activation of the innate immune response and the release of various inflammatory cytokines (Flake and Morgan, 2017).</li>
<li><span style="font-size:8.0pt"><span style="font-family:"Times New Roman",serif">Cytokines dosage</span></span></li>
<li><span style="font-size:8.0pt"><span style="font-family:"Times New Roman",serif">Chemokine dosage</span></span></li>
<li><span style="font-size:8.0pt"><span style="font-family:"Times New Roman",serif">Metalloprotesae</span></span></li>
</ul>
<p>Breast cancer cell lines</p>
<p> </p>
CL:0000255eukaryotic cellNot SpecifiedFemaleNot SpecifiedAdultNot Specified<p>Flake, G. P., & Morgan, D. L. (2017). Pathology of diacetyl and 2,3-pentanedione airway lesions in a rat model of obliterative bronchiolitis. <em>Toxicology</em>, <em>388</em>, 40–47. <a href="https://doi.org/10.1016/j.tox.2016.10.013"><u>https://doi.org/10.1016/j.tox.2016.10.013</u></a></p>
<p>Palmer, S. M., Flake, G. P., Kelly, F. L., Zhang, H. L., Nugent, J. L., Kirby, P. J., … Morgan, D. L. (2011). Severe airway epithelial injury, aberrant repair and Bronchiolitis obliterans develops after diacetyl instillation in rats. <em>PLoS ONE</em>, <em>6</em>(3). <a href="https://doi.org/10.1371/journal.pone.0017644"><u>https://doi.org/10.1371/journal.pone.0017644</u></a></p>
<p>Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002 Dec 19-26;420(6917):860-7. doi: 10.1038/nature01322. PMID: 12490959; PMCID: PMC2803035.</p>
2016-11-29T18:41:232022-12-20T08:53:06Induction, Epithelial Mesenchymal TransitionEMTCellular<p>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.</p>
<p>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).</p>
<p>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. <em>Thorax</em>, <em>64</em>(9), 770–777. <a href="https://doi.org/10.1136/thx.2008.104133"><u>https://doi.org/10.1136/thx.2008.104133</u></a></p>
<p>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. <em>American Journal of Transplantation</em>, <em>10</em>(3), 498–509. <a href="https://doi.org/10.1111/j.1600-6143.2009.02953.x"><u>https://doi.org/10.1111/j.1600-6143.2009.02953.x</u></a></p>
2017-07-26T19:11:332019-01-30T10:27:222bdbdca9-8fa4-4d03-8411-44a6cef85461cd5263db-70a3-4078-afc3-2ee3f6b04ed22017-02-15T02:57:012017-02-15T02:57:0156752e59-479e-4481-b73b-055fb66e35a1b06684c1-aa3c-4956-bc1c-4dad3bfc2e6b<p>The inflammatory reactions initiated by the damaged airway epithelium might stimulate the transition of fibroblasts present in the underlying mesenchymal tissue to myofibroblasts.</p>
<p>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.</p>
<p>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).</p>
<p>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.</p>
<p>Ramirez, A. M., Shen, Z., Ritzenthaler, J. D., & Roman, J. (2006). Myofibroblast Transdifferentiation in Obliterative Bronchiolitis: TGF-β Signaling Through Smad3-Dependent and -Independent Pathways. <em>American Journal of Transplantation</em>, <em>6</em>(9), 2080–2088. <a href="https://doi.org/10.1111/j.1600-6143.2006.01430.x"><u>https://doi.org/10.1111/j.1600-6143.2006.01430.x</u></a></p>
2018-03-18T09:50:092019-01-30T10:58:4858885303-5c63-4c41-afc8-289b9f545397ca2e1167-e5dd-4ec8-ae9a-73c9cc7ab67a2017-02-15T02:58:462017-02-15T02:58:46cd5263db-70a3-4078-afc3-2ee3f6b04ed256752e59-479e-4481-b73b-055fb66e35a12018-03-18T09:46:232018-03-18T09:46:23b06684c1-aa3c-4956-bc1c-4dad3bfc2e6b58885303-5c63-4c41-afc8-289b9f5453972018-11-20T20:57:412018-11-20T20:57:41Peroxisome proliferator-activated receptors γ inactivation leading to lung fibrosisPPARγ inactivation leading to lung fibrosis<p>Jinhee Choi, University of Seoul, Republic of Korea</p>
<p>Nivedita Chatterjee, University of Seoul, Republic of Korea</p>
<p>Jaeseong Jeong, University of Seoul, Republic of Korea</p>
<p>Ji-yeon Rho, Knoell Korea, Republic of Korea</p>
<p>Eun-Young Kim, Kyung Hee University, Republic of Korea</p>
<p>Seung Min Oh, Hoseo University, Republic of Korea</p>
<p>Natàlia Garcia-Reyero, Mississippi State University, USA</p>
<p>Edward J. Perkins, U.S. Army Engineer Research and Development Center, USA</p>
<p>Lyle D. Burgoon, U.S. Army Engineer Research and Development Center, USA</p>
Under development: Not open for comment. Do not citeUnder DevelopmentIncluded in OECD Work Plan1.54<p style="text-align:justify">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.</p>
adjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedNot SpecifiedUnspecificNot SpecifiedAll life stagesNot Specified<ol>
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