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J Biol Chem, Vol. 275, Issue 4, 2837-2844, January 28, 2000

Regulation of Cyclooxygenase-2 by Hypoxia and Peroxisome Proliferators in the Corneal Epithelium*

Albino BonazziDagger , Vladimir Mastyugin, Paul A. Mieyal, Michael W. Dunn, and Michal Laniado-Schwartzman§

From the Department of Pharmacology, New York Medical College, Valhalla, New York 10595

Hypoxic injury provokes inflammation of many tissues including the ocular surface. In rabbit corneal epithelial cells, both peroxisome proliferator-activated receptor (PPAR)-inducible cytochrome P450 4B1 and cyclooxygenase-2 (COX-2) mRNAs were increased by hypoxia. PPAR alpha  and beta  but not gamma  mRNAs were detected in these cells. The PPAR activator, WY-14,643 increased COX-2 expression. Similarly, non-steroidal anti-inflammatory drugs with the ability to activate PPARs induced COX-2 independently of prostaglandin synthesis inhibition. COX-2 protein overexpression by hypoxia and PPAR activation was not associated with a parallel increase in prostaglandin E2 accumulation. However, the enzyme regained full catalytic activity when: 1) hypoxic cells were re-exposed to normoxic conditions in the presence of heme and arachidonic acid, and 2) WY-14,643-treated cells were depleted of intracellular GSH. Consistent with previous observations showing that the corneal production of cytochrome P450-derived inflammatory eicosanoids is elevated by hypoxia and inflammation, the current data suggest that hypoxic injury is a model of inflammation in which molecules other than COX-derived arachidonic acid metabolites play a major proinflammatory role. This study also suggests that increased cellular GSH may be the mechanism responsible for the characteristic dissociation of PPAR-induced COX-2 expression and activity. Moreover, we provide new insights into the commonly observed lack of efficacy of classical non-steroidal anti-inflammatory drugs in the treatment of hypoxia-related ocular surface inflammation.


* This work was supported in part by National Institutes of Health Grant EY05613.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Supported in part by a student fellowship from the Institute of Pharmacological Sciences (Prof. Giancarlo Folco), University of Milan, Milan, Italy.

§ To whom correspondence should be addressed. Tel.: 914-594-4153; Fax: 914-594-4303; E-mail: michal_schwartzman@nymc.edu.


Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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