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. DATA SOURCES: 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.
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. DATA SOURCES: 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.
Authors: Saeid Ghavami; Behzad Yeganeh; Amir A Zeki; Shahla Shojaei; Nicholas J Kenyon; Sean Ott; Afshin Samali; John Patterson; Javad Alizadeh; Adel Rezaei Moghadam; Ian M C Dixon; Helmut Unruh; Darryl A Knight; Martin Post; Thomas Klonisch; Andrew J Halayko Journal: Am J Physiol Lung Cell Mol Physiol Date: 2017-10-26 Impact factor: 5.464
Authors: Eugene Makarev; Evgeny Izumchenko; Fumiaki Aihara; Piotr T Wysocki; Qingsong Zhu; Anton Buzdin; David Sidransky; Alex Zhavoronkov; Anthony Atala Journal: Cell Cycle Date: 2016-06-07 Impact factor: 4.534