Aop: 206


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
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
PPARγ inactivation leading to lung fibrosis

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool


The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

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)


Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Jinhee Choi


Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
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 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


A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

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


Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help


Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help


Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
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 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
AO 1276 Lung fibrosis 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

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
All life stages

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help


List of the literature that was cited for this AOP. More help
  1. Lakatos HF, Thatcher TH, Kottmann RM, Garcia TM, Phipps RP, Sime PJ. The Role of PPARs in Lung Fibrosis. PPAR Research. 2007; 2007:71323.
  2. Belvisi MG, Hele DJ. Peroxisome Proliferator-Activated Receptors as Novel Targets in Lung Disease. Chest. 2008; 134(1):152-157.
  3. 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.
  4. Sakai N, Tager AM. Fibrosis of Two: Epithelial Cell-Fibroblast Interactions in Pulmonary Fibrosis. Biochim Biophys Acta. 2013; 1832(7): 911–921.
  5. Limjunyawong N, Mitzner W, Horton MR. A mouse model of chronic idiopathic pulmonary fibrosis. Physiol Rep. 2014; 2(2): e00249.
  6. Brown T. Silica exposure, smoking, silicosis and lung cancer—complex interactions. Occup Med (Lond). 2009; 59(2):89-95.
  7. Holt DJ, Chamberlain LM, Grainger DW. Cell-cell signaling in co-cultures of macrophages and fibroblasts. Biomaterials. 2010; 31(36):9382-9394.
  8. 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
  9. 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.
  10. Todd NW, Luzina IG, Atamas SP. Molecular and cellular mechanisms of pulmonary fibrosis. Fibrogenesis Tissue Repair. 2012; 5(1):11.
  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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.