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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
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
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v1.0

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

Authors

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

Donghyeon Kim, University of Seoul, Republic of Korea

Ji-yeon Rho, Knoell Korea, 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

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

Coaches

This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help
  • Shihori Tanabe

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
1.54 Under Development
This AOP was last modified on June 03, 2024 21:00

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 February 28, 2024 06:33
Epithelial Mesenchymal Transition April 24, 2024 00:44
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

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 which induce differentiation of fibroblasts to myofibroblasts, a critical effector cell in fibrosis. This Adverse Outcome Pathway (AOP) describes these sequential sets of events. The molecular initiating event (MIE) is an antagonism of PPARγ, which increases the profibrotic effect of TGF-β/Smad3 signaling (key event, KE1). Then TGF-β signaling and oxidative stress pathways increase inflammatory cytokine production (KE2). Increased inflammatory response drives EMT (KE3), which results in the deposition of an interwoven network of fibrillar and non-fibrillar collagens (KE4). Increasing amounts of collagen lead to increased tissue stiffness, which signals increased production of extracellular matrix components (ECM) by mechanotransduction, through the rho-ROCK-actin pathways, leading to tissue damage and scarring or fibrosis, the AO.

AOP Development Strategy

Context

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

Strategy

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

Events:

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 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
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

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
Unspecific

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

This AOP applies to human and mammals as the majority of the evidence are derived from either human or rodent studies.

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
Type (Event ID) Title Description Support for the essentiality of the KE

MIE (1270)

 Inactivation of PPARγ Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor family and regulate a wide range of physiological activities. Three different isoforms have been identified: PPARα, PPARβ/δ, and PPARγ (Blanquart et al., 2003). PPARγ is expressed in many types of lung cells, including fibroblasts, and has anti-inflammatory properties (Rizzo and Fiorucci, 2006). The Essentiality of MIE is moderate. TGF-β drives the differentiation of lung fibroblasts to myofibroblasts, a key step in fibrosis formation. On the other hand, PPARγ ligands differentiate fibroblasts from fat-storing adipocytes, suggesting that PPARγ agonists may oppose the fibrogenic effects of TGF-β (Lakatos et al., 2007; Deng et al., 2012). Therefore, blocking PPARγ function would remove this opposing regulatory pathway, increasing the profibrotic effects of TGF-β (Ferguson et al., 2009; Yoon et al., 2015).

KE1 (1271)

 Activation of TGF-β signaling Lung fibrosis is the result of a TGF-β activated signaling cascade in lung fibroblasts (Kang et al., 2007; Wei et al., 2010). In this pathway, TGF-β activation leads to the phosphorylation and activation of Smad2 and Smad3, which heterodimerize with Smad4 and recruit the histone acetyltransferase p300 and the CREB binding protein (CBP) at the promoters of Smad3 dependent genes to activate transcription (Massagué et al., 2005; Chen et al., 1999; Mori et al., 2000; Ghosh et al., 2000; 2001; 2004). Smad3 activation is a necessary step in the progression of pulmonary fibrosis and myofibroblast differentiation, with knockout of Smad3 being sufficient to prevent pulmonary fibrosis and myofibroblast differentiation (Gu et al., 2007). The Smad:p300 complex causes transcription of Smad3-dependent genes, including MLK1, a key regulator of fibroblast differentiation to myofibroblasts. The Essentiality of KE1 is high, as an antagonist of TGF-β transduction signaling, significantly reduced bleomycin-induced lung fibrosis (Giri et al., 1993; Nakao et al., 1999). Knockout and knockdown experiments with MLK1 were sufficient to prevent cardiac fibrosis in mice (Small et al., 2010), reduced fibrogenesis in the lungs of rats with hypoxia-induced pulmonary hypertension (Yuan et al., 2014), and prevented bleomycin-induced lung fibrosis (Zhou et al., 2013) and skin fibrosis (Shiwen et al., 2015).

KE2 (149)

 Increase, Inflammation In general, the overproduction of cytokines leads to the infiltration of inflammatory cells and the proliferation of fibroblast-related interstitial cells (Miyazaki et al., 1995). The classical proinflammatory cytokines IL-6, IL-1β, and TNF-α released from innate immune cells like monocytes are also profibrotic. The Essentiality of KE2 is high. Experiments in various animal models, such as TNF-α blockers or TNF-receptor deficient mice, have shown that cytokine TNF-α has pro-fibrosis properties. IL-6 is an essential component of fibrosis, mainly resulting in reduced degradation of the matrix protein (Mack, 2017). Also, the attenuation of cell-related inflammation leads to a reduction of the activity of MMP (Underwood et al., 2000).

KE3 (1457)

 Induction, Epithelial-Mesenchymal Transition The EMT acquires mesenchymal markers, including neural cadherin (N-cadherin), vimentin, integrin, fibronectin, and MMPs while epithelial cells are gradually transformed into mesenchymal-like cells, losing epithelial functions and characteristics (Stone et al., 2016). The Essentiality of KE3 is high. Whereas EMT is necessary for proper re-epithelialization and extracellular matrix (ECM) deposition, an uncontrolled continued transition from epithelial cells to myofibroblasts can result in fibrosis (Stone et al., 2016; Rout-Pitt et al., 2018). Inhibition of MMP activity leads to the accumulation of matrix proteins like collagen in the extracellular space (Roeb, 2018).

KE4 (1275)

 Collagen Deposition Collagen deposition is a part of the tissue healing process induced by epithelial cell injury (Biasin et al., 2017). The Essentiality of KE4 is moderate. The disruption of the epithelial layer integrity can enhance inflammatory cell infiltration and in turn, worsen the fibrotic process (Biasin et al., 2017).

AO (1276)

 Lung fibrosis Lung fibrosis is a severe disease characterized by epithelial cell injury, inflammation, and collagen deposition (Biasin et al., 2017).  

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help
KER Support for biological plausibility of the KER Empirical support for the KER
MIE to KE1 The Biological Plausibility is moderate as the anti-inflammatory effects of PPARγ ligands are well-described (Lakatos et al., 2007), and several studies have explored the effects of PPARγ ligands as potential antifibrotic agents (Kawaguchi et al., 2004; Uto et al., 2005; Dantas et al., 2015; Ruzehaji et al., 2016). The Empirical Support of KER is moderate. In several studies, the relationship between PPARγ and TGF-β was confirmed by experiments using PPARγ ligands, and the PPARγ agonists inhibit the ability of TGF-β1 induce myofibroblast differentiation and collagen secretion (Kulkarni et al., 2011; Nuwormegbe et al., 2017; Dantas et al., 2015; Milam et al., 2007; Wu et al., 2009). For the quantitative relationship, there were studies of PPARγ ligand decreased intrinsic expression of TGF-β1 and TGF-β induced phosphorylation of Akt, and α-SMA and fibronectin expression as a marker of myofibroblast differentiation, in a dose-dependent manner (Kulkarni et al., 2011; Nuwormegbe et al., 2017; Milam et al., 2007).
KE1 to KE2 The Biological Plausibility of KER is high. The activated TGF-β signaling pathway stimulates the expression of multiple proinflammatory and fibrotic cytokines such as tumor necrosis factor-α (TNF-α), IL-1β, IL-6, and IL-13, promoting the fibrotic response (Kang et al., 2017). The Empirical Support between TGF-β and inflammation is moderate. As a result of immunohistochemical staining for lung sections of pulmonary fibrosis patients, increased production of TGF-β has been associated with chronic inflammatory and fibrotic diseases in humans and rodents (Khalil et al., 1991). There was little research on quantitative relationships between TGF-β and inflammation-related markers.
KE2 to KE3 The Biological Plausibility is high. Th-2 cytokines (IL-4, IL-5, and IL-13) and proinflammatory cytokines (IL-1β, IL-6, and TNF-α) are linked to MMP and fibrosis (Mack, 2017). The Empirical Support is moderate. TNF-α induces the expression of vimentin and MMP, and inflammatory cytokines were associated with elevated EMT genes, indicating causal relationships (Yan et al., 2010). For the quantitative relationship, there were studies that the proinflammatory cytokine, IL-17A induced dose-dependent downregulation of E-cadherin and upregulation of α-SMA (Vittal et al., 2013). And TNF-α only slightly decreases E-cadherin expression in a concentration-dependent manner (Kasai et al., 2005).
KE3 to KE4 The Biological Plausibility is high. MMPs, the EMT markers, can degrade collagen type I and III, key collagens of the irreversible scar in hepatic cirrhosis (Roeb, 2018). The Empirical Support is low. Bleomycin-induced fibrosis is reduced in transgenic animals (Kang et al., 2007; Cabrera et al., 2007). There was little research on quantitative relationships between EMT and collagen.
KE4 to AO The Biological Plausibility is high. The total amount of collagen deposited by fibroblasts is a controlled balance between collagen synthesis and catabolism. In the remodeling phase, when this balance is disrupted and collagen deposition increases, scar formation, organs or peri-implantation fibrosis occurs (Chen and Raghunath, 2009). The Empirical Support is low. Morphological analysis in the bleomycin-treated meprinβ KO mice revealed decreased collagen deposition and tissue density in lung fibrosis (Biasin et al., 2017). There was limited understanding of the quantitative relationships between collagen and fibrosis.

Most studies have demonstrated the therapeutic potential of PPARγ agonists for fibrosis, which is an opposite direction to this AOP, PPARγ antagonism leads to fibrosis. In some studies, PPARγ antagonist induces α-SMA activation (Weng et al., 2016), TGF-β activation (Ji et al., 2018), and fibrosis, but empirical evidence is insufficient for all KERs. Also, there are lack of receptor binding studies for MIE.

PPARγ agonists have been shown to induce fibrosis independently of PPARγ, suggesting a potential for other pathways. Kulkarni et al. (2011) reported that in human lung fibroblasts, PPARγ ligands potently block myofibroblast differentiation via a PPARγ-independent mechanism by targeting the TGFβ-induced PI3K-Akt pathway involving FAK (Kulkarni et al., 2011).

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
Modulating Factor (MF) Influence or Outcome KER(s) involved
     

Quantitative Understanding

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

The biological processes from PPARγ to pulmonary fibrosis are so complex that understanding quantitative relationships is not easy, especially with late KEs. To date, no studies have established a whole quantitative relationship for pulmonary fibrosis AOP. However, there is experimental evidence of some dose-response relationships between MIE and early-stage KEs or AO using MIE-related stressors. Milam et al. (2008) performed a dose-response assay using PPARγ agonists. They found that selective PPARγ agonists activate lung fibroblast PPARγ and inhibit TGF-β1-induced myofibroblast differentiation and collagen secretion in a dose-dependent manner. There are dose- and time-dependent inhibitory effects on proliferative responses of undifferentiated fibroblasts and myofibroblasts to mitogenic growth factors. In the bleomycin-induced murine model, PPARγ agonist inhibits lung fibrosis (hydroxyproline and collagen accumulation) in a dose-dependent manner (Milam et al., 2008). In the future, it will be possible to construct a computational and predictive model when data on the dose-response relationships becomes available through research on late-stage KEs.

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

Until now, there have been many uncertainties in this AOP. Quantitative AOP is expected to take a long time to complete, while AOP will improve. Ultimately, this AOP will allow a quick and simple screening of AO, pulmonary fibrosis, using in silico approaches for chemicals suspected of inhalation toxicity.

References

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

  1. Lakatos, H. F.; Thatcher, T. H.; Kottmann, R. M.; Garcia, T. M.; Phipps, R. P.; Sime, P. J. The Role of PPARs in Lung Fibrosis. PPAR Res. 2007, 2007, 71323. https://doi.org/10.1155/2007/71323.

  2. Kulkarni, A. A.; Thatcher, T. H.; Olsen, K. C.; Maggirwar, S. B.; Phipps, R. P.; Sime, P. J. PPAR-γ Ligands Repress TGFβ-Induced Myofibroblast Differentiation by Targeting the PI3K/Akt Pathway: Implications for Therapy of Fibrosis. PLoS One 2011, 6 (1), e15909. https://doi.org/10.1371/journal.pone.0015909.

  3. Deng, Y. L.; Xiong, X. Z.; Cheng, N. S. Organ Fibrosis Inhibited by Blocking Transforming Growth Factor-β Signaling via Peroxisome Proliferator-Activated Receptor γ Agonists. Hepatobiliary Pancreat. Dis. Int. 2012, 11 (5), 467–478. https://doi.org/10.1016/S1499-3872(12)60210-0.

  4. Nuwormegbe, S. A.; Sohn, J. H.; Kim, S. W. A PPAR-Gamma Agonist Rosiglitazone Suppresses Fibrotic Response in Human Pterygium Fibroblasts by Modulating the P38 MAPK Pathway. Investig. Opthalmology Vis. Sci. 2017, 58 (12), 5217–5226. https://doi.org/10.1167/iovs.17-22203.

  5. Ferguson, H. E.; Kulkarni, A.; Lehmann, G. M.; Garcia-Bates, T. M.; Thatcher, T. H.; Huxlin, K. R.; Phipps, R. P.; Sime, P. J. Electrophilic Peroxisome Proliferator-Activated Receptor-γ Ligands Have Potent Antifibrotic Effects in Human Lung Fibroblasts. Am. J. Respir. Cell Mol. Biol. 2009, 41 (6), 722–730. https://doi.org/10.1165/rcmb.2009-0006OC.

  6. Blanquart, C.; Barbier, O.; Fruchart, J. C.; Staels, B.; Glineur, C. Peroxisome Proliferator-Activated Receptors: Regulation of Transcriptional Activities and Roles in Inflammation. J. Steroid Biochem. Mol. Biol. 2003, 85 (2–5), 267–273. https://doi.org/10.1016/S0960-0760(03)00214-0.

  7. Rizzo, G.; Fiorucci, S. PPARs and Other Nuclear Receptors in Inflammation. Curr. Opin. Pharmacol. 2006, 6 (4), 421–427. https://doi.org/10.1016/j.coph.2006.03.012.

  8. Kawaguchi, K.; Sakaida, I.; Tsuchiya, M.; Omori, K.; Takami, T.; Okita, K. Pioglitazone Prevents Hepatic Steatosis, Fibrosis, and Enzyme-Altered Lesions in Rat Liver Cirrhosis Induced by a Choline-Deficient L-Amino Acid-Defined Diet. Biochem. Biophys. Res. Commun. 2004, 315 (1), 187–195. https://doi.org/10.1016/j.bbrc.2004.01.038.

  9. Uto, H.; Nakanishi, C.; Ido, A.; Hasuike, S.; Kusumoto, K.; Abe, H.; Numata, M.; Nagata, K.; Hayashi, K.; Tsubouchi, H. The Peroxisome Proliferator-Activated Receptor-γ Agonist, Pioglitazone, Inhibits Fat Accumulation and Fibrosis in the Livers of Rats Fed a Choline-Deficient, l-Amino Acid-Defined Diet. Hepatol. Res. 2005, 32 (4), 235–242. https://doi.org/10.1016/J.HEPRES.2005.05.008.

  10. Dantas, A. T.; Pereira, M. C.; de Melo Rego, M. J.; da Rocha, L. F. J.; Pitta Ida, R.; Marques, C. D.; Duarte, A. L.; Pitta, M. G. The Role of PPAR Gamma in Systemic Sclerosis. PPAR Res. 2015, 2015, 124624. https://doi.org/10.1155/2015/124624.

  11. Ruzehaji, N.; Frantz, C.; Ponsoye, M.; Avouac, J.; Pezet, S.; Guilbert, T.; Luccarini, J. M.; Broqua, P.; Junien, J. L.; Allanore, Y. Pan PPAR Agonist IVA337 Is Effective in Prevention and Treatment of Experimental Skin Fibrosis. Ann. Rheum. Dis. 2016, 75 (12), 2175–2183. https://doi.org/10.1136/annrheumdis-2015-208029.

  12. Yoon, Y. S.; Kim, S. Y.; Kim, M. J.; Lim, J. H.; Cho, M. S.; Kang, J. L. PPARγ Activation Following Apoptotic Cell Instillation Promotes Resolution of Lung Inflammation and Fibrosis via Regulation of Efferocytosis and Proresolving Cytokines. Mucosal Immunol. 2015, 8 (5), 1031–1046. https://doi.org/10.1038/mi.2014.130.

  13. Milam, J. E.; Keshamouni, V. G.; Phan, S. H.; Hu, B.; Gangireddy, S. R.; Hogaboam, C. M.; Standiford, T. J.; Thannickal, V. J.; Reddy, R. C. PPAR-γ Agonists Inhibit Profibrotic Phenotypes in Human Lung Fibroblasts and Bleomycin-Induced Pulmonary Fibrosis. Am. J. Physiol. Cell. Mol. Physiol. 2007, 294 (5), L891–L901. https://doi.org/10.1152/ajplung.00333.2007.

  14. Wu, M.; Melichian, D. S.; Chang, E.; Warner-Blankenship, M.; Ghosh, A. K.; Varga, J. Rosiglitazone Abrogates Bleomycin-Induced Scleroderma and Blocks Profibrotic Responses through Peroxisome Proliferator-Activated Receptor-β. Am. J. Pathol. 2009, 174 (2), 519–533. https://doi.org/10.2353/ajpath.2009.080574.

  15. Kang, H. R.; Soo, J. C.; Chun, G. L.; Homer, R. J.; Elias, J. A. Transforming Growth Factor (TGF)-Β1 Stimulates Pulmonary Fibrosis and Inflammation via a Bax-Dependent, Bid-Activated Pathway That Involves Matrix Metalloproteinase-12. J. Biol. Chem. 2007, 282 (10), 7723–7732. https://doi.org/10.1074/jbc.M610764200.

  16. Wei, J.; Bhattacharyya, S.; Varga, J. Peroxisome Proliferator-Activated Receptor γ: Innate Protection from Excessive Fibrogenesis and Potential Therapeutic Target in Systemic Sclerosis. Curr. Opin. Rheumatol. 2010, 22 (6), 671–676. https://doi.org/10.1097/BOR.0b013e32833de1a7.

  17. Massagué, J.; Seoane, J.; Wotton, D. Smad Transcription Factors. Trends Biochem. Sci. 2005, 19 (23), 2783–2810. https://doi.org/10.1101/gad.1350705.

  18. Chen, S. J.; Yuan, W.; Mori, Y.; Levenson, A.; Trojanowska, M.; Varga, J. Stimulation of Type I Collagen Transcription in Human Skin Fibroblasts by TGF-β: Involvement of Smad 3. J. Invest. Dermatol. 1999, 112 (1), 49–57. https://doi.org/10.1046/j.1523-1747.1999.00477.x.

  19. Mori, Y.; Chen, S. J.; Varga, J. Modulation of Endogenous Smad Expression in Normal Skin Fibroblasts by Transforming Growth Factor-β. Exp. Cell Res. 2000, 258 (2), 374–383. https://doi.org/10.1006/excr.2000.4930.

  20. Ghosh, A. K.; Yuan, W.; Mori, Y.; Varga, J. Smad-Dependent Stimulation of Type I Collagen Gene Expression in Human Skin Fibroblasts by TGF-β Involves Functional Cooperation with P300/CBP Transcriptional Coactivators. Oncogene 2000, 19 (31), 3546–3555. https://doi.org/10.1038/sj.onc.1203693.

  21. Ghosh, A. K.; Yuan, W.; Mori, Y.; Chen, S. J.; Varga, J. Antagonistic Regulation of Type I Collagen Gene Expression by Interferon-γ and Transforming Growth Factor-β: Integration at the Level of P300/CBP Transcriptional Coactivators. J. Biol. Chem. 2001, 276 (14), 11041–11048. https://doi.org/10.1074/jbc.M004709200.

  22. Ghosh, A. K.; Bhattacharyya, S.; Varga, J. The Tumor Suppressor P53 Abrogates Smad-Dependent Collagen Gene Induction in Mesenchymal Cells. J. Biol. Chem. 2004, 279 (46), 47455–47463. https://doi.org/10.1074/jbc.M403477200.

  23. Gu, L.; Zhu, Y. J.; Yang, X.; Guo, Z. J.; Xu, W. B.; Tian, X. L. Effect of TGF-β/Smad Signaling Pathway on Lung Myofibroblast Differentiation. Acta Pharmacol. Sin. 2007, 28 (3), 382–391. https://doi.org/10.1111/j.1745-7254.2007.00468.x.

  24. Kang, H. Role of Micrornas in TGF-β Signaling Pathway-Mediated Pulmonary Fibrosis. Int. J. Mol. Sci. 2017, 18 (12). https://doi.org/10.3390/ijms18122527.

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