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

Am J Pathol. 2001 Apr;158(4):1411-22. doi: 10.1016/s0002-9440(10)64092-8.


Prostaglandin E(2) (PGE(2)) inhibits fibroblast proliferation and collagen production. 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 examined the effect of TGF-beta(1) on PGE(2) synthesis, 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-beta(1)-induced PGE(2) synthesis is limited in fibroblasts from fibrotic lung. Functionally, this correlates with a loss of the anti-proliferative response to TGF-beta(1). This failure to induce PGE(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 enhanced response to bleomycin. We conclude that a decreased capacity to up-regulate 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 to unopposed fibroblast proliferation and collagen synthesis and contribute to the pathogenesis of pulmonary fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bleomycin
  • Cell Division / drug effects
  • Cell Line
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology
  • Dinoprostone / biosynthesis
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology*
  • Humans
  • Indomethacin / pharmacology
  • Isoenzymes / deficiency*
  • Isoenzymes / genetics
  • Membrane Proteins
  • Procollagen / biosynthesis
  • Prostaglandin-Endoperoxide Synthases / deficiency*
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / enzymology*
  • Pulmonary Fibrosis / pathology*
  • RNA, Messenger / metabolism
  • Transforming Growth Factor beta / pharmacology*


  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Isoenzymes
  • Membrane Proteins
  • Procollagen
  • RNA, Messenger
  • Transforming Growth Factor beta
  • Bleomycin
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • PTGS1 protein, human
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Dinoprostone
  • Indomethacin