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From the Centre for Cardiopulmonary Biochemistry and Respiratory
Medicine,*
Royal Free and University College London Medical
School, London, United Kingdom; the Respiratory
Unit,
Morriston Hospital, Swansea, United
Kingdom; the Division of Clinical
Investigation,
National Cancer Institute,
Mexico City, Mexico; the Molecular Immunology
Unit,§
Institute of Child Health, London,
United Kingdom; and the Discovery Biology,¶
Aventis Pharmaceuticals, Dagenham, United Kingdom
Prostaglandin E2 (PGE2) inhibits fibroblast proliferation and collagen production. Its synthesis by fibroblasts is induced by profibrotic mediators including transforming growth factor (TGF)-ß1. However, in patients with pulmonary fibrosis, PGE2 levels are decreased. In this study we examined the effect of TGF-ß1 on PGE2 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-ß1-induced PGE2 synthesis is limited in fibroblasts from fibrotic lung. Functionally, this correlates with a loss of the anti-proliferative response to TGF-ß1. 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 PGE2 synthesis in the presence of increasing levels of profibrotic mediators such as TGF-ß1 may lead to unopposed fibroblast proliferation and collagen synthesis and contribute to the pathogenesis of pulmonary fibrosis.
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V. Lama, B. B. Moore, P. Christensen, G. B. Toews, and M. Peters-Golden Prostaglandin E2 Synthesis and Suppression of Fibroblast Proliferation by Alveolar Epithelial Cells Is Cyclooxygenase-2-Dependent Am. J. Respir. Cell Mol. Biol., December 1, 2002; 27(6): 752 - 758. [Abstract] [Full Text] [PDF]
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 A. Papafili, M. R. Hill, D. J. Brull, R. J. McAnulty, R. P. Marshall, S. E. Humphries, and G. J. Laurent Common Promoter Variant in Cyclooxygenase-2 Represses Gene Expression: Evidence of Role in Acute-Phase Inflammatory Response Arterioscler. Thromb. Vasc. Biol., October 1, 2002; 22(10): 1631 - 1636. [Abstract] [Full Text] [PDF]
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J. C. Bonner, A. B. Rice, J. L. Ingram, C. R. Moomaw, A. Nyska, A. Bradbury, A. R. Sessoms, P. C. Chulada, D. L. Morgan, D. C. Zeldin, et al. Susceptibility of Cyclooxygenase-2-Deficient Mice to Pulmonary Fibrogenesis Am. J. Pathol., August 1, 2002; 161(2): 459 - 470. [Abstract] [Full Text] [PDF]
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G. Jenkins, S. L. Hart, R. J. Hodges, Q.-H. Meng, C. Kinnon, G. J. Laurent, and R. J. McAnulty Cyclooxygenase-2 Overexpression, Using an Integrin-Targeted Gene Delivery System (the LID Vector), Inhibits Fibroblast Proliferation In Vitro and Leads to Increased Prostaglandin E2 in the Lung Chest, March 1, 2002; 121(2007): 102S - 104S. [Abstract] [Full Text] [PDF]
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D. C. Zeldin The 5-Lipoxygenase Pathway . A New Therapeutic Target for the Treatment of Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., January 15, 2002; 165(2): 146 - 147. [Full Text] [PDF]
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