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PPAR agonists inhibit TGF- induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis

Departments of ¹Environmental Medicine, ²Medicine, ³Pediatrics, and ⁴Lung Biology and Disease Program, and ⁵the Cancer Center, University of Rochester School of Medicine, Rochester, New York

Submitted 12 October 2004 ; accepted in final form 14 February 2005

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)- is a transcription factor that upon ligation with PPAR agonists activates target genes containing PPAR response elements. PPAR agonists have anti-inflammatory activities and may have potential as antifibrotic agents. In this study, we examined the abilities of PPAR agonists to block two of the most important profibrotic activities of TGF- on pulmonary fibroblasts: myofibroblast differentiation and production of excess collagen. Both natural (15d-PGJ₂) and synthetic (ciglitazone and rosiglitazone) PPAR agonists inhibited TGF--driven myofibroblast differentiation, as determined by -smooth muscle actin-specific immunocytochemistry and Western blot analysis. PPAR agonists also potently attenuated TGF--driven type I collagen protein production. A dominant-negative PPAR partially reversed the inhibition of myofibroblast differentiation by 15d-PGJ₂ and rosiglitazone, but the irreversible PPAR antagonist GW-9662 did not, suggesting that the antifibrotic effects of the PPAR agonists are mediated through both PPAR-dependent and independent mechanisms. Thus PPAR 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.

peroxisome proliferator-activated receptor-; myofibroblasts; 15d-PGJ₂; ciglitazone; rosiglitazone

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