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

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 PPAR gamma agonists activates target genes containing PPAR response elements. PPAR gamma agonists have anti- inflammatory activities and may have potential as antifibrotic agents. In this study, we examined the abilities of PPAR gamma 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- PGJ(2)) and synthetic (ciglitazone and rosiglitazone) PPAR gamma agonists inhibited TGF-beta-driven myofibroblast differentiation, as determined by alpha-smooth muscle actin- specific immunocytochemistry and Western blot analysis. PPAR gamma agonists also potently attenuated TGF-beta-driven type I collagen protein production. A dominant-negative PPAR gamma partially reversed the inhibition of myofibroblast differentiation by 15d- PGJ2 and rosiglitazone, but the irreversible PPAR gamma antagonist GW-9662 did not, suggesting that the antifibrotic effects of the PPAR gamma agonists are mediated through both PPAR gamma-dependent and independent mechanisms. Thus PPAR gamma 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.