The role of 12-hydroxyeicosanoids in the corneal inflammatory response.

摘要

The corneal epithelium of several species, has the capacity to metabolize arachidonic acid via an NADPH-dependent cytochrome P450 mechanism. The major metabolites are 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) and 12-hydroxy-5,8,14-eicosatrienoic acid (12-HETrE), both of which exist in stereoisomeric configurations. However, the R enantiomers are predominantly produced by this enzyme system and exhibit potent biological activities. 12(R)-HETE inhibits Na-K-ATPase, increases corneal thickness and reduces intraocular pressure. 12(R)-HETrE causes vasodilation, neutrophil chemoattraction and angiogenesis. The formation of these metabolites is unaffected by cyclooxygenase or lipoxygenase inhibitors (indomethacin, diclofenac and BW755C) but inhibited by cytochrome P450 enzyme inhibitors such as carbon monoxide, SKF-525A and clotrimazole.; The capacity of the normal corneal epithelium to metabolize arachidonic acid via cytochrome P450 is very low although under certain conditions this enzymatic pathway may become greatly induced. Corneal epithelial hypoxia in response to closed eye-hydrogel contact lens wear results in the time-dependent formation of NADPH-cytochrome P450-dependent arachidonate metabolites, 12(R)-HETE and 12(R)-HETrE. Under this condition, metabolite production correlates strongly with the in situ inflammatory reponse and the development of corneal edema. A potential cause-effect relationship between the cytochrome P450-dependent formation of 12(R)-HETE and 12(R)-HETrE and the in situ inflammatory response, was established through the use of SnCl{dollar}sb2{dollar} in the closed eye contact lens model. SnCl2 proved to be selective in its ability to inhibit cytochrome P450 activity both directly as an enzyme inhibitor and indirectly through the induction of heme oxygenase. Induction of this enzyme results in the enhanced metabolism of microsomal heme with subsequent depletion of various heme containing enzymes, particularly those with a more rapid turnover such as cytochrome P450. Through treatment of the hydrogel lenses with SnCl{dollar}sb2{dollar}, the time-dependent production of 12(R)-HETE and 12(R)-HETrE was significantly attenuated. Coinciding with these events was a significant induction in corneal epithelial heme oxygenase mRNA and alleviation of both the in situ inflammatory response and the development of corneal edema.; These findings are novel in providing pharmacological evidence for a role of the corneal epithelial cytochrome P450 enzyme system, specifically 12(R)-HETE and 12(R)-HETrE production, in the inflammatory response to closed eye-hydrogel contact lens wear. The inhibition of their synthesis by SnCl{dollar}sb2{dollar} was selective without evidence of corneal toxicity. This finding could provide a unique basis for the treatment of the adverse effects of contact lens wear, especially in the closed eye.