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

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 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.

• Authors: Rebecca J Hodges, R Gisli Jenkins, Caroline P D Wheeler-Jones, Danielle M Copeman, Stephen E Bottoms, Geoffrey J Bellingan, Carmel B Nanthakumar, Geoffrey J Laurent, Stephen L Hart, Martyn L Foster, Robin J McAnulty
• Journal: The American journal of pathology (Am J Pathol) Vol. 165 Issue 5 Pg. 1663-76 (Nov 2004) ISSN: 0002-9440 [Print] United States
• PMID: 15509536 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Isoenzymes
• Leukotrienes
• Bleomycin
• Collagen
• Cyclooxygenase 2
• Prostaglandin-Endoperoxide Synthases
• Dinoprostone

Topics

• Animals
• Bleomycin (pharmacology)
• Blotting, Western
• Bronchoalveolar Lavage
• Collagen (metabolism)
• Cyclooxygenase 2
• Dinoprostone (biosynthesis, metabolism)
• Female
• Fibroblasts (metabolism)
• Fibrosis (pathology)
• Heterozygote
• Immunohistochemistry
• Isoenzymes (genetics, physiology)
• Leukotrienes (metabolism)
• Lung (pathology)
• Lung Injury
• Macrophages (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Monocytes (metabolism)
• Prostaglandin-Endoperoxide Synthases (genetics, physiology)
• Time Factors
• Up-Regulation