Cyclooxygenase-2 deficiency results in a loss of the anti-proliferative response to transforming growth factor-β in human fibrotic lung fibroblasts and promotes …

CB Keerthisingam, RG Jenkins, NK Harrison… - The American journal of …, 2001 - Elsevier
CB Keerthisingam, RG Jenkins, NK Harrison, NA Hernandez-Rodriguez, H Booth…
The American journal of pathology, 2001Elsevier
Prostaglandin E2 (PGE2) inhibits fibroblast proliferation and collagen production. Its
synthesis by fibroblasts is induced by profibrotic mediators including transforming growth
factor (TGF)-β1. However, in patients with pulmonary fibrosis, PGE2 levels are decreased. In
this study we examined the effect of TGF-β1 on PGE2synthesis, proliferation, collagen
production, and cyclooxygenase (COX) mRNA levels in fibroblasts derived from fibrotic and
nonfibrotic human lung. In addition, we examined the effect of bleomycin-induced pulmonary …
Prostaglandin E2 (PGE2) inhibits fibroblast proliferation and collagen production. Its synthesis by fibroblasts is induced by profibrotic mediators including transforming growth factor (TGF)-β1. However, in patients with pulmonary fibrosis, PGE2 levels are decreased. In this study we examined the effect of TGF-β1 on PGE2synthesis, proliferation, collagen production, and cyclooxygenase (COX) mRNA levels in fibroblasts derived from fibrotic and nonfibrotic human lung. In addition, we examined the effect of bleomycin-induced pulmonary fibrosis in COX-2-deficient mice. We demonstrate that basal and TGF-β1-induced PGE2 synthesis is limited in fibroblasts from fibrotic lung. Functionally, this correlates with a loss of the anti-proliferative response to TGF-β1. This failure to induce PGE2 synthesis is because of an inability to up-regulate COX-2 mRNA levels in these fibroblasts. Furthermore, mice deficient in COX-2 exhibit an enhanced response to bleomycin. We conclude that a decreased capacity to up-regulate COX-2 expression and COX-2-derived PGE2synthesis in the presence of increasing levels of profibrotic mediators such as TGF-β1 may lead to unopposed fibroblast proliferation and collagen synthesis and contribute to the pathogenesis of pulmonary fibrosis.
Elsevier