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Title: PPARgamma agonists inhibit TGF-beta induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis.

Authors: Burgess, Heather A; Daugherty, Louis Eugene; Thatcher, Thomas H; Lakatos, Heather F; Ray, Denise M; Redonnet, Michelle; Phipps, Richard P; Sime, Patricia J

Published In Am J Physiol Lung Cell Mol Physiol, (2005 Jun)

Abstract: Pulmonary fibrosis is a progressive life-threatening disease for which no effective therapy exists. Myofibroblasts are one of the key effector cells in pulmonary fibrosis and are the primary source of extracellular matrix production. Drugs that inhibit the differentiation of fibroblasts to myofibroblasts have potential as antifibrotic therapies. Peroxisome proliferator-activated receptor (PPAR)-gamma is a transcription factor that upon ligation with PPARgamma agonists activates target genes containing PPAR response elements. PPARgamma agonists have anti-inflammatory activities and may have potential as antifibrotic agents. In this study, we examined the abilities of PPARgamma agonists to block two of the most important profibrotic activities of TGF-beta on pulmonary fibroblasts: myofibroblast differentiation and production of excess collagen. Both natural (15d-PGJ2) and synthetic (ciglitazone and rosiglitazone) PPARgamma agonists inhibited TGF-beta-driven myofibroblast differentiation, as determined by alpha-smooth muscle actin-specific immunocytochemistry and Western blot analysis. PPARgamma agonists also potently attenuated TGF-beta-driven type I collagen protein production. A dominant-negative PPARgamma partially reversed the inhibition of myofibroblast differentiation by 15d-PGJ2 and rosiglitazone, but the irreversible PPARgamma antagonist GW-9662 did not, suggesting that the antifibrotic effects of the PPARgamma agonists are mediated through both PPARgamma-dependent and independent mechanisms. Thus PPARgamma agonists have novel and potent antifibrotic effects in human lung fibroblasts and may have potential for therapy of fibrotic diseases in the lung and other tissues.

PubMed ID: 15734787 Exiting the NIEHS site

MeSH Terms: Actins/metabolism; Anilides/pharmacology; Cell Differentiation/drug effects*; Collagen Type I/metabolism*; Fibroblasts/cytology; Fibroblasts/drug effects*; Fibroblasts/metabolism; Humans; Hypoglycemic Agents/pharmacology; Lung/cytology; Lung/drug effects*; Lung/metabolism; Muscle, Smooth/cytology; Muscle, Smooth/drug effects*; Muscle, Smooth/metabolism; PPAR gamma/agonists*; Prostaglandin D2/analogs & derivatives*; Prostaglandin D2/pharmacology; Pulmonary Fibrosis/therapy; Rosiglitazone; Thiazolidinediones/pharmacology; Transforming Growth Factor beta/pharmacology*

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