COX-2 lack of function in hypoxia-induced ocular surface inflammation.

Abstract 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 PGE 2 . COX-2 protein overexpression induced by hypoxia was not associated with a parallel increase in PGE 2 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.