COX-2-derived prostacyclin protects against bleomycin-induced pulmonary fibrosis.
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.
Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, 27599, USA.
Alysia Kern
AK
Lovgren
Leigh A
LA
Jania
John M
JM
Hartney
Kelly K
KK
Parsons
Laurent P
LP
Audoly
Garret A
GA
Fitzgerald
Stephen L
SL
Tilley
Beverly H
BH
Koller
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001761:Bleomycin / Q000633:toxicity*; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D011464:Epoprostenol / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000473:pathology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011453:Prostaglandins / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D011453:Prostaglandins; D001761:Bleomycin; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2