Nonsteroidal anti‐inflammatory drugs prevent early diabetic retinopathy via TNF‐α suppression

Leukocyte adhesion to the diabetic retinal vasculature results in blood‐retinal barrier breakdown, capillary nonperfusion, and endothelial cell injury and death. Intercellular adhesion molecule‐1 (ICAM‐1) and the leukocyte integrin CD18 are required for these processes. Diabetes was induced in Long Evans rats, resulting in a two‐ to threefold increase in retinal leukocyte adhesion. Following one week of diabetes, neutrophil CD11a, CD11b, and CD18 expression was increased significantly, as were retinal ICAM‐1 levels. Animals were treated with aspirin, a cyclooxygenase 2 (COX‐2) inhibitor (meloxicam), or a soluble tumor necrosis factor α (TNF‐α) receptor/Fc construct (TNFR‐Fc, etanercept). High‐dose aspirin, etanercept, and high‐dose meloxicam each reduced leukocyte adhesion and suppressed blood‐retinal barrier breakdown. High‐dose aspirin also reduced the expression of CD11a, CD11b, and CD18, whereas meloxicam and etanercept did not. High‐dose aspirin, etanercept, and high‐dose meloxicam each reduced retinal ICAM‐1 expression. Aspirin and meloxicam both lowered retinal TNF‐α levels. Notably, aspirin, meloxicam, and etanercept did not change retinal vascular endothelial growth factor levels. High‐dose aspirin, etanercept and high‐dose meloxicam, each suppressed the retinal expression of eNOS and the DNA‐binding capacity of retinal nuclear factor‐κΒ. High‐dose aspirin also suppressed Erk kinase activity, which is involved in CD18 up‐regulation. Taken together, these data identify COX‐2 and TNF‐α as operative in the early signature pathologies of diabetic retinopathy, a newly recognized inflammatory disease.

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