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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
Bonazzi ,
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 and but not 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.
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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Copyright © 2000 by the American Society for Biochemistry and Molecular Biology.
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