Severity of lung injury in cyclooxygenase-2-deficient mice is dependent on reduced prostaglandin E(2) production.
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 PGE(2) 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 PGE(2) production is predominantly COX-2 mediated. Furthermore, COX-2(+/-) mice show limited induction of PGE(2) 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.
Hodges
Rebecca J
RJ
Centre for Respiratory Research, University College London, Rayne Bldg., 5 University St., London WC1E 6JJ, UK.
Jenkins
R Gisli
RG
Wheeler-Jones
Caroline P D
CP
Copeman
Danielle M
DM
Bottoms
Stephen E
SE
Bellingan
Geoffrey J
GJ
Nanthakumar
Carmel B
CB
Laurent
Geoffrey J
GJ
Hart
Stephen L
SL
Foster
Martyn L
ML
McAnulty
Robin J
RJ
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D015153:Blotting, Western; D018893:Bronchoalveolar Lavage; D003094:Collagen / Q000378:metabolism; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000473:pathology; D006579:Heterozygote; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D015289:Leukotrienes / Q000378:metabolism; D008168:Lung / Q000473:pathology; D055370:Lung Injury; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000502:physiology*; D013997:Time Factors; D015854:Up-Regulation
D007527:Isoenzymes; D015289:Leukotrienes; D001761:Bleomycin; D003094:Collagen; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone