Apoptosis in the cornea in response to epithelial injury: significance to wound healing and dry eye.

Abstract

Chronic ocular surface injury is a hallmark of dry eye disease. The extent of objective surface abnormality is highly variable between patients, and roughly correlates with the severity of the disease. These surface changes extend from mild conjunctival rose bengal staining to diffuse conjunctival and corneal rose bengal and fluorescein staining. Previous studies have demonstrated that corneal surface injury triggers keratocyte apoptosis and a subsequent wound healing response in the stroma. However, the majority of patients with mild to moderate surface abnormalities from dry eye have no evidence of stromal haze, unstable refractive error, or other changes that would be expected if significant ongoing stromal wound healing were triggered by the surface changes. Superficial injury to the corneal or conjunctival epithelium probably does not induce stromal wound healing because of the intact barrier function of the epithelium and lack of penetration of proapoptotic cytokines into the corneal stroma and subconjunctival tissues. New data suggest in response to IL-1 or tumor necrosis factor (TNF) alpha is monocyte chemotactic and activating factor (MCAF)18 (also Hong, Liu, and Wilson, unpublished data, 2000). This upregulation of MCAF in response to IL-1 or TNF alpha stimulation was confirmed by RNAse protection assay (mRNA) and western blotting (protein). MCAF has chemotactic effects on monocyte and macrophage cells. This observation has led us to formulate a model to explain factors attracting inflammatory cells into corneal stroma or subconjunctival connective tissue in response to epithelial injury. This hypothesis holds that: 1) Significant injury to the epithelium (mechanical or other) results in the release of IL-1 and TNF alpha from the epithelial cells. 2) If the injury to the epithelium is sufficient to break down the epithelial barrier function, then IL-1 and TNF alpha penetrate into the stroma or subconjunctival tissues. Some types of injury might directly trigger release of IL-1 or TNF alpha from the basal epithelial cells. 3) IL-1 or TNF alpha that penetrates into the subepithelial tissues binds to receptors expressed by keratocytes or conjunctival fibroblasts, and triggers MCAF production. 4) MCAF attracts and activates macrophages. Work is in progress to characterize the effects of MCAF. We also hope to identify other cytokines released by keratocytes or conjunctival fibroblasts that attract T cells and polymorphonuclear cells in response to epithelial injury or other pathophysiological triggers.