This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Peroxisome proliferator-activated receptors γ inactivation leading to lung fibrosis
Point of Contact
- Jinhee Choi
- Brendan Ferreri-Hanberry
|Author status||OECD status||OECD project||SAAOP status|
|Under development: Not open for comment. Do not cite||Under Development||1.54||Included in OECD Work Plan|
This AOP was last modified on April 05, 2021 18:16
|Inactivation of PPARγ||December 26, 2017 02:12|
|Activation of TGF-β signaling||February 15, 2017 02:45|
|Collagen Deposition||February 15, 2017 02:55|
|Lung fibrosis||December 26, 2017 02:10|
|Increase, Inflammation||January 30, 2019 10:26|
|Induction, Epithelial Mesenchymal Transition||January 30, 2019 10:27|
|Inactivation of PPARγ leads to Activation of TGF-β signaling||February 15, 2017 02:57|
|Increase, Inflammation leads to EMT||January 30, 2019 10:58|
|Collagen Deposition leads to Lung fibrosis||February 15, 2017 02:58|
|Activation of TGF-β signaling leads to Increase, Inflammation||March 18, 2018 09:46|
|EMT leads to Collagen Deposition||November 20, 2018 20:57|
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 inactivation, 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.
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Sequence||Type||Event ID||Title||Short name|
|1||MIE||1270||Inactivation of PPARγ||Inactivation of PPARγ|
|3||KE||1271||Activation of TGF-β signaling||Activation of TGF-β signaling|
|4||KE||149||Increase, Inflammation||Increase, Inflammation|
|6||KE||1275||Collagen Deposition||Collagen Deposition|
|7||KE||1457||Induction, Epithelial Mesenchymal Transition||EMT|
|8||AO||1276||Lung fibrosis||Lung fibrosis|
Relationships Between Two Key Events (Including MIEs and AOs)
Life Stage Applicability
|All life stages|
|Homo sapiens||Homo sapiens||NCBI|
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Considerations for Potential Applications of the AOP (optional)
- Lakatos HF, Thatcher TH, Kottmann RM, Garcia TM, Phipps RP, Sime PJ. The Role of PPARs in Lung Fibrosis. PPAR Research. 2007; 2007:71323.
- Belvisi MG, Hele DJ. Peroxisome Proliferator-Activated Receptors as Novel Targets in Lung Disease. Chest. 2008; 134(1):152-157.
- 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.
- Sakai N, Tager AM. Fibrosis of Two: Epithelial Cell-Fibroblast Interactions in Pulmonary Fibrosis. Biochim Biophys Acta. 2013; 1832(7): 911–921.
- Limjunyawong N, Mitzner W, Horton MR. A mouse model of chronic idiopathic pulmonary fibrosis. Physiol Rep. 2014; 2(2): e00249.
- Brown T. Silica exposure, smoking, silicosis and lung cancer—complex interactions. Occup Med (Lond). 2009; 59(2):89-95.
- Holt DJ, Chamberlain LM, Grainger DW. Cell-cell signaling in co-cultures of macrophages and fibroblasts. Biomaterials. 2010; 31(36):9382-9394.
- 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
- 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.
- Todd NW, Luzina IG, Atamas SP. Molecular and cellular mechanisms of pulmonary fibrosis. Fibrogenesis Tissue Repair. 2012; 5(1):11.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.