Neutrophil Elastase Contributes to the Early Molecular Abnormalities of the Retina in Diabetes

Abstract

Introduction: Previous studies by our lab indicate that neutrophils are involved with capillary degeneration in diabetic retinopathy (DR). The elastase is a serine protease in neutrophils that plays an important role in a variety of inflammatory diseases, such as chronic obstructive pulmonary disease. We are investigating the potential role of NE in the development of DR. Method: The activity of neutrophil elastase (NE) was selectively inhibited (by daily sivelestat) or deleted (Elane-/-) from diabetic mice, and the effects of NE loss were compared to the effects of inhibition of general protease activity (over-expression of protease inhibitor, alpha-1 antitrypsin). Molecular abnormalities associated with the development of DR, including retinal superoxide production, expression of proteins associated with inflammation, and leukocyte-mediated cytotoxicity of retinal endothelial cells were used to determine the effects of NE in diabetic mice. Result: At two months of diabetes, selective inhibition of NE or deletion of the elastase both inhibited diabetes-induced superoxide production and inflammation in the retina. Both also inhibited leukostasis and/or leukocyte mediated damage to endothelial cells in cell cytotoxicity assays. In contrast, over-expression of alpha-1 antitrypsin resulted in increased retinal superoxide production and leukocyte activity in cytotoxicity assays in both diabetic and nondiabetic animals. Conclusion: NE may play an important role in the development of DR. Disclosure H. Liu: None. T. Kern: None.