This AOP is licensed under a Creative Commons Attribution 4.0 International License.

Aop: 206

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Peroxisome proliferator-activated receptors γ inactivation leading to lung fibrosis

Short name

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PPARγ inactivation leading to lung fibrosis

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool

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Authors

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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

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section. More help

Jinhee Choi (email point of contact)

Contributors

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Jinhee Choi

Status

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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 Do not cite	Under Development	1.54	Included in OECD Work Plan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 September 16, 2021 04:10

Revision dates for related pages

Page	Revision Date/Time
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	December 20, 2022 08:53
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

Abstract

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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.

AOP Development Strategy

Context

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Strategy

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Summary of the AOP

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Events:

Molecular Initiating Events (MIE)

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Key Events (KE)

A measurable event within a specific biological level of organisation. More help

Adverse Outcomes (AO)

An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Type	Event ID	Title	Short name

MIE

1270

Inactivation of PPARγ

KE	1271	Activation of TGF-β signaling	Activation of TGF-β signaling
KE	149	Increase, Inflammation	Increase, Inflammation
KE	1275	Collagen Deposition	Collagen Deposition
KE	1457	Induction, Epithelial Mesenchymal Transition	EMT

1276

Lung fibrosis

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Title	Adjacency	Evidence	Quantitative Understanding

Inactivation of PPARγ leads to Activation of TGF-β signaling	adjacent
Increase, Inflammation leads to EMT	adjacent
Collagen Deposition leads to Lung fibrosis	adjacent
Activation of TGF-β signaling leads to Increase, Inflammation	adjacent
EMT leads to Collagen Deposition	adjacent

Network View

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Prototypical Stressors

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Life Stage Applicability

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Life stage	Evidence
All life stages

Taxonomic Applicability

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Term	Scientific Term	Evidence	Link
Homo sapiens	Homo sapiens		NCBI

Sex Applicability

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Sex	Evidence
Unspecific

Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Known Modulating Factors

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

List of the literature that was cited for this AOP. More help

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.