Cyclooxygenase-2 deficiency results in a loss of the anti-proliferative response to transforming growth factor-beta in human fibrotic lung fibroblasts and promotes bleomycin-induced pulmonary fibrosis in mice

Prostaglandin E-2 (PGE(2)) inhibits fibroblast proliferation and collagen p roduction. Its synthesis by fibroblasts is induced by profibrotic mediators including transforming growth factor (TGF)-beta (1). However, in patients with pulmonary fibrosis, PGE(2) levels are decreased. In this study we exam ined the effect of TGF-beta (1) on PGE(2) synthesis, proliferation, collage n production, and cyclooxygenase (COX) mRNA levels in fibroblasts derived f rom fibrotic and nonfibrotic human lung. In addition, we examined the effec t of bleomycin-induced pulmonary fibrosis in COX-2-deficient mice. We demon strate that basal and TGF-beta (1)-induced PGE(2) synthesis is limited in f ibroblasts from fibrotic lung. Functionally, this correlates with a loss of the anti-proliferative response to TGF-beta (1). This failure to induce PG E(2) synthesis Is because of an inability to up-regulate COX-2 mRNA levels in these fibroblasts, Furthermore, mice deficient in COX-2 exhibit an enhan ced response to bleomycin, We conclude that a decreased capacity to up-regu late COX-2 expression and COX-2-derived PGE(2) synthesis in the presence of increasing levels of profibrotic mediators such as TGF-beta (1) may lead t o unopposed fibroblast proliferation and collagen synthesis and contribute to the pathogenesis of pulmonary fibrosis.