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Aop: 206

AOP Title

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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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Authors

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Jinhee Choi, University of Seoul, Republic of Korea

Nivedita Chatterjee, University of Seoul, India

Jaeseong Jeong, University of Seoul, Republic of Korea

Youngho 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

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Brendan Ferreri-Hanberry   (email point of contact)

Contributors

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  • Jinhee Choi
  • Brendan Ferreri-Hanberry

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Proposal submitted - for discussion in June 2017 Proposed for OECD Work Plan


This AOP was last modified on January 14, 2018 22:20

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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
Differentiation of Myofibroblast February 15, 2017 02:46
Production of α-smooth muscle actin February 15, 2017 02:54
Expression of Collagen February 15, 2017 02:54
Collagen Deposition February 15, 2017 02:55
Lung fibrosis December 26, 2017 02:10
Inactivation of PPARγ leads to Activation of TGF-β signaling February 15, 2017 02:57
Activation of TGF-β signaling leads to Differentiation of Myofibroblast February 15, 2017 02:57
Activation of TGF-β signaling leads to Expression of Collagen February 15, 2017 02:57
Differentiation of Myofibroblast leads to Production of α-smooth muscle actin February 15, 2017 02:57
Expression of Collagen leads to Collagen Deposition February 15, 2017 02:58
Production of α-smooth muscle actin leads to Lung fibrosis February 15, 2017 02:58
Collagen Deposition leads to Lung fibrosis February 15, 2017 02:58

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 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.


Background (optional)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
1 MIE 1270 Inactivation of PPARγ Inactivation of PPARγ
2 KE 1271 Activation of TGF-β signaling Activation of TGF-β signaling
3 KE 1272 Differentiation of Myofibroblast Differentiation of Myofibroblast
4 KE 1274 Production of α-smooth muscle actin Production of α-smooth muscle actin
5 KE 1273 Expression of Collagen Expression of Collagen
6 KE 1275 Collagen Deposition Collagen Deposition
7 AO 1276 Lung fibrosis Lung fibrosis

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Inactivation of PPARγ leads to Activation of TGF-β signaling adjacent
Activation of TGF-β signaling leads to Differentiation of Myofibroblast adjacent
Activation of TGF-β signaling leads to Expression of Collagen adjacent
Differentiation of Myofibroblast leads to Production of α-smooth muscle actin adjacent
Expression of Collagen leads to Collagen Deposition adjacent
Production of α-smooth muscle actin leads to Lung fibrosis adjacent
Collagen Deposition leads to Lung fibrosis adjacent

Network View

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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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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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