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Severity of lung injury in cyclooxygenase-2-deficient mice is dependent on reduced prostaglandin E-2 production

Hodges, RJ; Jenkins, RG; Wheeler-Jones, CPD; Copeman, DM; Bottoms, SE; Bellingan, GJ; Nanthakumar, CB; ... McAnulty, RJ; + view all (2004) Severity of lung injury in cyclooxygenase-2-deficient mice is dependent on reduced prostaglandin E-2 production. AM J PATHOL , 165 (5) 1663 - 1676. Green open access

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Abstract

Levels of prostaglandin E-2 (PGE(2)), 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. p lung PGE(2) 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 PGE(2), 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 PGE(2) expression in protecting against the development of fibrosis after lung injury.

Type: Article
Title: Severity of lung injury in cyclooxygenase-2-deficient mice is dependent on reduced prostaglandin E-2 production
Open access status: An open access version is available from UCL Discovery
Keywords: IDIOPATHIC PULMONARY-FIBROSIS, SYNTHASE-DEFICIENT MICE, GROWTH-FACTOR-BETA, FIBROBLAST PROLIFERATION, COLLAGEN PRODUCTION, ARACHIDONIC-ACID, CYCLIC-AMP, EXPRESSION, BLEOMYCIN, INFLAMMATION
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Internal Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH Genetics and Genomic Medicine Prog
URI: http://discovery.ucl.ac.uk/id/eprint/8623
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