Although alterations of the underlying basement membrane,
21,22 the lack of sufficient innervation,
23,24 and/or low tear production
25,26 are likely contributing factors, prolonged hyperglycemia including elevated glucose in tears
27 may directly affect epithelial cells through elevated reactive oxygen species, resulting in epithelial defects and abnormalities. Using cultured human corneal epithelial cells (CECs), pig corneas, and human diabetic corneas, we recently showed that high glucose impairs epidermal growth factor receptor (EGFR) signaling and suppresses basal and wound-induced AKT phosphorylation, resulting in delayed wound healing in cultured porcine corneas in a ROS-related manner.
28 The AKT signaling pathway was also perturbed in the epithelia of human diabetic corneas, but not in the corneas of nondiabetic, age-matched donors, suggesting that hyperglycemia specifically targets the EGFR phosphatidylinositol 3′-kinase (PI3K)-AKT signaling pathway.
28 Hence, weakened EGFR signaling may contribute to the pathogenesis of diabetic keratopathy and epitheliopathy in diabetic patients. Of interest, it was recently reported that 4 weeks of hyperglycemia are sufficient to cause epithelial thinning and basal epithelial cell shape changes, and systematic administration of the EGFR inhibitor AG1478 attenuates these alterations.
29 Recent reports have shown the surprising result that cancer treatments with EGFR-targeting drugs such as cetuximab (an EGFR monoclonal antibody) and an EGFR kinase inhibitor, gefitinib, cause ocular abnormalities in some patients, including diffuse punctate keratitis and corneal erosion,
30,31 that have been observed frequently in diabetic corneas. Moreover, topical application of EGF is an effective therapy for persisting corneal erosion during cetuximab treatment,
32 suggesting a potential use for EGFR agonists for impaired corneal epithelial wound healing. To date, the question of whether EGFR-mediated wound response in vivo is also compromised remains unanswered.