The Bull’s Eye: Are We Off-Target for Corneal Endothelial Cell Physiology?

As the primary refractive surface of the eye, clarity of the cornea is essential for optimal visual acuity. Many disease processes can irreversibly disrupt corneal clarity requiring corneal transplantation to restore visual function. The most common indication for corneal transplantation is opacification from corneal edema. Corneal edema arises from dysregulation of fluid homeostasis in the cornea. The natural tendency of the cornea is to imbibe fluid from the anterior chamber to facilitate the delivery of nutrients to this avascular tissue, 1 however continuous fluid influx would lead to a constant state of corneal edema. The corneal endothelium, a monolayer of cells on the posterior surface of the cornea, regulates corneal hydration by providing a " leaky barrier ". Incomplete tight junction bands allow fluid influx while gradients formed by ion channels and transporters drive fluid efflux. 2 Loss of corneal endothelial cells is the primary reason for corneal edema. Because of the nonproliferative nature of these cells, corneal transplantation with cadaveric donor tissue is currently the only means of restoring the endothelial monolayer of cells. However, recent research is pushing towards finding non-surgical treatment options. Three alternatives are being studied. One focuses on enhancing the proliferative potential of corneal endothelial cells, and drug treatments are now emerging. 3 Another approach targets modulation of the endothelial cell barrier function. 4 The final method seeks to enhance fluid efflux from the stroma across the endothelium and is the focus of my studies. Fluid efflux across the corneal endothelium is governed by ion movement. For several decades, investigators have questioned the roles of various ions, channels and transporters in the endothelium. In 1965, Brown and Hedbys demonstrated the importance of the Na + /K + ATPase in supporting corneal deturgescence in rabbit eyes. 5 Further studies on rabbit corneal endothelium confirmed the need for ATP as well as Na + and HCO 3 −. 6,7 Initial investigations in the 1970's on transport in human cornea demonstrated that human (and monkey) as compared to rabbit corneas had different polarities and responses to changes in extracellular pH. In 1981, Wingham and Hodson showed similar responses in human and bovine corneal endothelial short-circuit current response (a measure of the rate of active ion transport) to extracellular HCO 3 − concentration and suggested that human, bovine and rabbit corneas had similar endothelial transport mechanisms. They published one final manuscript on human corneal endothelial physiology in 1987 and …