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AM Joussen, V Poulaki, S Döhmen, K Koizumi, B Kirchhof, AP Adamis; Non-steroid Alanti-inflammatory Drugs Prevent Early Diabetic Retinopathy: Aspirinand COX-2 Inhibition Prevent Blood-retinal Barrier Breakdown and Leukocyte Adhesion Via TNF-asuppression . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2969.
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Purpose: Leukocyte adhesion to the diabetic retinal vasculature results in early blood-retinal barrier breakdown, capillary non-perfusion, and endothelial cell injury and death. Previous work has shown that intercellular adhesion molecule-1 (ICAM-1) and the leukocyte integrin CD18 are required for these processes. In this study we investigated the effect of non-steroidal antiinflammatory drugs to prevent early diabetic changes in the retina. Methods: In this study, diabetes was induced in Long Evans rats with streptozotocin, resulting in a 2- to 3-fold increase in retinal leukocyte adhesion. Neutrophil expression of the surface integrins CD11a, CD11b, and CD18 was significantly increased following one week of diabetes, as were retinal ICAM-1 levels. Animals were then treated with aspirin, a selective COX-2 inhibitor (meloxicam), or a soluble TNFa-receptor/Fc construct (TNFR-Fc, etanercept). Results: High-dose aspirin, etanercept, and high-dose meloxicam each reduced leukocyte adhesion in the diabetic retinal vasculature and suppressed blood-retinal barrier breakdown. High-dose aspirin downregulated the expression of neutrophil integrins CD11a, CD11b and CD18, whereas meloxicam and etanercept did not. High dose aspirin, etanercept and high-dose meloxicam each signficantly reduced retinal ICAM-1 expression. Aspirin and meloxicam each reduced TNFa levels in the diabetic retina. Notably, aspirin, meloxicam, or etanercept did not change retinal VEGF levels. The retinal expression of eNOS, and the DNA-binding capacity of retinal NF-kB, the latter a potential downstream mediator of TNFa activity, were increased in the diabetic retina and were potently suppressed by high-dose aspirin, etanercept and high-dose meloxicam. Lastly, high-dose aspirin suppressed Erk kinase activity, which is involved in CD18 upregulation. Conclusion: Taken together, these data identify COX-2 and TNFa as being operative in the early signature pathologies of diabetic retinopathy, a newly recognized inflammatory disease.
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