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Severity of Lung Injury in Cyclooxygenase-2-Deficient Mice Is Dependent on Reduced Prostaglandin E2 Production

https://doi.org/10.1016/S0002-9440(10)63423-2Get rights and content

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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Supported by The Wellcome Trust (grant no. 071124), Aventis Pharmaceuticals Inc., the Arthritis Research Campaign (grant no. JO520), and the British Lung Foundation (grant nos. P01/04 and P03/12).

R.J.H. and R.G.J. contributed equally to this work.

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