COX-2-derived prostacyclin protects against bleomycin-induced pulmonary fibrosis

1 Curriculum in Genetics and Molecular Biology, 2 Department of Medicine, Division of Pulmonary and Critical Care Medicine, and 3 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; 4 Department of Pharmacology, Merck Frosst Canada, Kirkland, Quebec, Canada; and 5 Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania Submitted 21 November 2005 ; accepted in final form 8 February 2006 Prostacyclin is one of a number of lipid mediators elaborated from the metabolism of arachidonic acid by the cyclooxygenase (COX) enzymes. This prostanoid is a potent inhibitor of platelet aggregation, and its production by endothelial cells and protective role in the vasculature are well established. In contrast, much less is known regarding the function of this prostanoid in other disease processes. We show here that COX-2-dependent production of prostacyclin plays an important role in the development of fibrotic lung disease, limiting both the development of fibrosis and the consequential alterations in lung mechanics. In stark contrast, loss of prostaglandin E 2 synthesis and signaling through the G s -coupled EP2 and EP4 receptors had no effect on the development of disease. These findings suggest that prostacyclin analogs will protect against bleomycin-induced pulmonary fibrosis in COX-2 –/– mice. If such protection is observed, investigation of these agents as a novel therapeutic approach to pulmonary fibrosis in humans may be warranted. prostaglandin; IP; lung mechanics; EP2; microsomal prostaglandin E 2 synthase 1 Address for reprint requests and other correspondence: B. H. Koller, Univ. of North Carolina, Dept. of Medicine, 4341 Molecular Biomedical Research Bldg., Chapel Hill, NC 27599 (e-mail: treawouns{at}aol.com )