Organ fibrosis inhibited by blocking transforming growth factor-β signaling via peroxisome proliferator-activated receptor γ agonists.
BACKGROUND
Organ fibrosis has been viewed as one of the major medical problems, which can lead to progressive dysfunction of the liver, lung, kidney, skin, heart, and eventually death of patients. Fibrosis is initiated by a variety of pathological, physiological, biochemical, and physical factors. Regardless of their different etiologies, they all share a common pathogenetic process: excessive activation of the key profibrotic cytokine, transforming growth factor-beta (TGF-beta). Peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand-activated transcription factor of the nuclear receptor superfamily, has received particular attention in recent years, because the activation of PPARgamma by both natural and synthetic agonists could effectively inhibit TGF-beta-induced profibrotic effects in many organs.


METHODS
The English-language medical databases, PubMed, Elsevier and SpringerLink were searched for articles on PPARgamma, TGF-beta, and fibrosis, and related topics.


RESULTS
TGF-beta is recognized as a key profibrotic cytokine. Excessive activation of TGF-beta increases synthesis of extracellular matrix proteins and decreases their degradation, associated with a gradual destruction of normal tissue architecture and function, whereas PPARgamma agonists inhibit TGF-beta signal transduction and are effective antifibrogenic agents in many organs including the liver, lung, kidney, skin and heart.


CONCLUSIONS
The main antifibrotic activity of PPARgamma agonists is to suppress the TGF-beta signaling pathway by so-called PPARgamma-dependent effect. In addition, PPARgamma agonists, especially 15d-PGJ2, also exert potentially antifibrotic activity independent of PPARgamma activation. TGF-beta1/Smads signaling not only plays many essential roles in multiple developmental processes, but also forms cross-talk networks with other signal pathways, and their inhibition by PPARgamma agonists certainly affects the cytokine networks and causes non-suspected side-effects. Anti-TGF-beta therapies with PPARgamma agonists may have to be carefully tailored to be tissue- and target gene-specific to minimize side-effects, indicating a great challenge to the medical research at present.
Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, China.
Yi-Lei
YL
Deng
Xian-Ze
XZ
Xiong
Nan-Sheng
NS
Cheng
D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005355:Fibrosis / Q000188:drug therapy*; D006801:Humans; D007627:Keloid / Q000188:drug therapy; D007668:Kidney / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy; D009206:Myocardium / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists*; D011658:Pulmonary Fibrosis / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology
D047495:PPAR gamma; D016212:Transforming Growth Factor beta