COX-2 lack of function in hypoxia-induced ocular surface inflammation.
Injury to the ocular surface increases corneal epithelial production of cyclooxygenase (COX)-derived eicosanoids but this increase correlates poorly to the inflammatory sequelae. Moreover, corticosteroids are effective in treatment of this inflammation but NSAIDs are not. The discovery of COX-2 that is differentially affected by common NSAIDs reopened the question of the role of prostaglandins in ocular surface inflammation. We examined the presence and inducibility of COX-2 in the corneal epithelium following hypoxia-induced injury in vivo and in vitro. COX-2, but not COX-1, protein levels markedly increased following hypoxia. Use of the selective COX-2 inhibitor, NS-398, indicated that COX activity in hypoxic corneas or cells is essentially that of COX-2; in control cells, both COX-1 and COX-2 contributed equally to the production of PGE2. COX-2 protein overexpression induced by hypoxia was not associated with a parallel increase in PGE2 accumulation but the enzyme regained full catalytic activity when cells were re-exposed to normoxia in the presence of heme and arachidonic acid. Decreases in the levels of oxygen and heme, essential substrates/cofactors for COX catalytic activity, contributed to a diminished prostanoid production during hypoxia. These results suggest that in hypoxic injury, molecules other than COX-derived prostanoids play a major pro-inflammatory role. Furthermore, this study provides an explanation for the ineffectiveness of classical NSAIDs in the treatment of hypoxia-related ocular surface inflammation.
Schwartzman
Michal Laniado
ML
Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA. michal_Schwartzmann@nymc.edu
Bonazzi
Albino
A
Mieyal
Paul
P
Mezentsev
Alexandre
A
Abraham
Nader G
NG
Dunn
Michael W
MW
D000818:Animals; D015687:Cell Hypoxia / Q000276:immunology*; D002460:Cell Line; D046508:Culture Techniques; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000276:immunology / Q000378:metabolism; D019573:Epithelium, Corneal / Q000201:enzymology* / Q000276:immunology*; D007527:Isoenzymes / Q000276:immunology* / Q000378:metabolism*; D007634:Keratitis / Q000201:enzymology* / Q000276:immunology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000276:immunology* / Q000378:metabolism*; D011817:Rabbits
D007527:Isoenzymes; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone