Long-term Leukocyte-mediated Vascular Pathology in the Diabetic Retina

Abstract

Abstract: : Purpose: Diabetic retinopathy is a leading cause of adult vision loss and blindness. Much of the retinal damage that characterizes the disease results from retinal vascular leakage and nonperfusion. Diabetic retinal vascular leakage, capillary nonperfusion and endothelial cell damage are secondary, in part, to ICAM-1 and CD18 mediated-retinal leukocyte adhesion in early experimental diabetes. However, little is known about the consequences of leukocyte adhesion on the long-term funcational and anatomic changes associated with diabetic retinpathy. Methods: Using a mouse models of STZ induced diabetic retinopathy and experimental galacosemia, we examined the role of CD18 and intercellular adhesion molecule-1 (ICAM-1) in long term diabetes on the development of retinal vascular lesions. Results: CD18 and ICAM-1 deficient mice demonstrated significantly fewer adherent leukocytes in the retinal vasculature 11 and 15 months following the induction of diabetes. Significantly fewer injured endothelial cells were observed and this was associated with markedly less blood-retinal barrier brekadown. VEGF expression in the retina was not altered in diabetic CD18 and ICAM-1 deficient mice. Galactosemia of up to 24 months led to pericyte and endothelial cell loss and the formation of acellular capillaries. These changes are significantly reduced in CD18 and ICAM-1 deficient mice. Retinal vascular basement membrane thickening was increased in long-term galactosemic animals and was not altered in the the ICAM-1 -/- and CD18 -/- mice. Conclusions: The current study demonstrates that the inhibition of leukocyte-endothelial cell interactions prevents many of the functional and anatomic consequences that are the signature of diabetic retinopathy. These data highlight the central and causal role of adherent leukocytes in the pathogenesis of diabetic retinopathy. They also underscore the potential utility of anti-inflammatory agents in the treatment of the disease.

Keywords: diabetic retinopathy • inflammation • transgenics/knock-outs