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agonists inhibit TGF-
induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis
1 Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY, USA; Lung Biology and Disease Program, University of Rochester School of Medicine, Rochester, NY, USA
2 Department of Medicine, University of Rochester School of Medicine, Rochester, NY, USA; Department of Pediatrics, University of Rochester School of Medicine, Rochester, NY, USA; Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY, USA
3 Department of Medicine, University of Rochester School of Medicine, Rochester, NY, USA; Lung Biology and Disease Program, University of Rochester School of Medicine, Rochester, NY, USA
4 Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY, USA; Lung Biology and Disease Program, University of Rochester School of Medicine, Rochester, NY, USA; Cancer Center, University of Rochester School of Medicine, Rochester, NY, USA
5 Department of Medicine, University of Rochester School of Medicine, Rochester, NY, USA; Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY, USA; Lung Biology and Disease Program, University of Rochester School of Medicine, Rochester, NY, USA
* To whom correspondence should be addressed. E-mail: Patricia_Sime{at}urmc.rochester.edu.
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 anti-fibrotic therapies. Peroxisome proliferators-activated receptor-gamma (PPAR
) is a transcription factor that upon ligation with PPAR agonists activates target genes containing PPAR response elements (PPRE). PPAR agonists have anti-inflammatory activities and may have potential as anti-fibrotic agents. In this study, we examined the abilities of PPAR agonists to block two of the most important pro-fibrotic activities of TGF-
on pulmonary fibroblasts, namely myofibroblast induction 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 GW9662 did not, suggesting that the antifibrotic effects of the PPAR agonists are mediated both through PPAR-dependent and independent mechanisms. Thus, PPAR agonists have novel and potent anti-fibrotic effects in human lung fibroblasts and may have potential for therapy of fibrotic diseases in the lung and other tissues.
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