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 (PPAR gamma), a ligand-activated transcription factor of the nuclear receptor superfamily, has received particular attention in recent years, because the activation of PPAR gamma by both natural and synthetic agonists could effectively inhibit TGF-beta-induced profibrotic effects in many organs. DATA SOURCES: The English-language medical databases, PubMed, Elsevier and SpringerLink were searched for articles on PPAR gamma, 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 PPAR gamma 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 PPAR gamma agonists is to suppress the TGF-beta signaling pathway by so-called PPAR gamma-dependent effect. In addition, PPAR gamma agonists, especially 15d-PGJ2, also exert potentially antifibrotic activity independent of PPAR gamma activation. TGF-beta 1/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 PPAR gamma agonists certainly affects the cytokine networks and causes non-suspected side-effects. Anti-TGF-beta therapies with PPAR gamma 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. (Hepatobiliary Pancreat Dis Int 2012;11:467-478)