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From the Centre for Respiratory Research,* University College London, London; the Department of Veterinary Basic Sciences, Royal Veterinary College, London; the Neuroscience Research Centre, Merck Sharp and Dohme, Harlow; Molecular Immunology Unit, Institute of Child Health, London; and the Department of Pathology,¶ Research and Development, AstraZeneca, Charnwood, United Kingdom
Levels of prostaglandin E2 (PGE2), a potent inhibitor of fibroblast function, are decreased in the lungs of patients with pulmonary fibrosis, which has been shown to be because of limited expression of cyclooxygenase-2 (COX-2). To further investigate the relative importance of COX-2 and PGE2 in the development of fibrosis we have used a selective COX-2 inhibitor and COX-2-deficient (–/– and +/–) mice in studies of bleomycin-induced lung fibrosis. We demonstrate in wild-type mice that bleomycin-induced lung PGE2 production is predominantly COX-2 mediated. Furthermore, COX-2+/– mice show limited induction of PGE2 and an enhanced fibrotic response with increased lung collagen content compared with wild-type mice after bleomycin injury (P < 0.001). In contrast, COX-2–/– mice show increased levels of lung PGE2, compared with wild-type mice after injury (P < 0.05), because of compensatory up-regulation of COX-1, which appears to be associated with macrophage/monocytes but not fibroblasts derived from these mice. COX-2–/– mice show an enhanced and persistent inflammatory response to bleomycin, however the fibrotic response to injury was unaltered compared with wild-type animals. These data provide further direct evidence for the importance of up-regulating COX-2 and PGE2 expression in protecting against the development of fibrosis after lung injury.
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