Joussen A. M.

Dept. of Vitreoretinal Surgery, University of Cologne, Germany and Massachusetts Eye and Ear Infirmary, Harvard Medical School; Boston MA, USA

The development of a rational therapy for diabetic retinopathy that targets specific molecular pathways requires a detailed knowledge of the molecular pathophysiology of the disease. This presentation reviews the cellular aspects as well as the therapeutical consequences of early diabetic retinopathy. Endothelial cell death is a hallmark of diabetic retinopathy. Its occurrence is required for the formation of acellular (devitalized) capillaries, lesions that produce irreversible retinal ischemia through their inability to support blood flow. Adherent leukocytes are temporally and spatially associated with retinal endothelial cell injury and death within one week of streptozotocin-induced experimental diabetes in rats. The diabetic leukostasis coincides with the development of blood-retinal barrier breakdown and capillary non-perfusion. Intercellular adhesion molecule-1 (ICAM-1) and CD18 are shown to be operative in these events. Neutrophils from diabetic, but not from control rats induced endothelial cell apoptosis, which was inhibited by specific reagents blocking Fas/FasL interaction. In vivo inhibition of FasL resulted in a significant reduction of vascular leakage and retinal vascular endothelial cell death. This indicates that neutrophils from diabetic rats are capable of inducing Fas-mediated endothelial cell death, resulting in capillary damage and obstruction. This strengthens the possibility for a beneficial effect of anti-inflammatory drugs in diabetic retinopathy. Aspirin as well as TNF-inhibitor Enbrel reduced the expression of leukocytes surface integrins and potently suppressed diabetic leukocyte adhesion in retinal vessels. High dose COX-2 inhibitors led to similar effects. Furthermore these drugs were able to significantly reduce diabetic vascular leakage. The expression of eNOS, a likely downstream mediator of VEGF activity, was increased in diabetic retina, but was potently suppressed with aspirin as well as with treatment with the TNFa inhibitor. Endogenous VEGF seems to be causal in initiating the altered leukocyte-endothelial cell interactions in diabetes. Angiopoietin-1belongs to a newly described growth factor family comprising ang-1, ist antagonist ang-2 and TIE-2 as their common receptor. Angiopoietin-1 promotes endothelial cell survival in vitro without causing endothelial cell proliferation, blocks the leak-inducing action of VEGF in vivo, and stabilizes endothelial interactions with surrounding support cells. Angiopoietin-1 can prevent and reverse these early diabetic retinal vascular changes. In conclusion, these data highlight the inflammatory component of diabetic retinopathy, offering several new treatment possibilities. Persuing the goal to prevent diabetic retinal vasuclar changes, further studies need to adress possibilities of drug delivery.

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