Effects of Topical Antiglaucoma Medications on Corneal Epithelium as Evaluated by Gene Expression Patterns

Purpose: To examine the expression pattern of the stress-related genes c-fos and c-jun, which encode the 2 major components of activator protein (AP)-1, and cyclooxygenase (COX)-2 in rat corneal epithelium treated with topical antiglaucoma medications and benzalkonium chloride (BAK) preservative. Methods: Eighty-eight male Wistar rats were used. We instilled antiglaucoma eye drops (0.5% Timoptol, 0.005% Xalatan, or 0.12% Rescula), their chemical constituents (active ingredients), or BAK preservative (0.005%, 0.01%, or 0.02%) in 1 eye of each rat. Fellow eyes served as controls. The eyes were enucleated after various intervals. In situ hybridization and immunohistochemistry were used to detect expression of c-fos, c-jun, and COX-2. Results: Expression of c-fos, c-jun, and COX-2 was minimally observed in uninjured rat corneal epithelium. Thirty minutes to 1 hour after applying the antiglaucoma eye drops, signals for c-fos and c-jun mRNA were detected in the corneal epithelium. Ninety minutes after applying 0.005% Xalatan, 0.12% Rescula, or their chemical constituents, but not 0.5% Timoptol, COX-2 was detected in corneal epithelium. Expression of c-fos and c-jun seemed more marked with prostaglandins than with timolol. Thirty minutes to 1 hour after instillation of 0.02% BAK preservative, signals for c-fos and c-jun mRNA were detected in the corneal and conjunctival epithelium. COX-2 was not induced by 0.5% Timoptol or BAK preservative. COX-2 mRNA was not affected by applying 0.005% or 0.01% BAK preservative. Proteins of these components were also detected, indicating that each mRNA expression was followed by protein synthesis. Conclusions: Corneal and conjunctival epithelial cells are transcriptionally activated transiently at an early phase after topical administration of antiglaucoma medications and BAK preservative. Stimulatory effects of prostaglandin drugs on corneal epithelial cells were more marked than those with timolol. Expression of COX-2 may potentially be involved in inflammatory response in the corneal epithelium.