Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy

Abstract

Diabetes causes metabolic and physiologic abnormalities in the retina, and these changes suggest a role for inflammation in the development of diabetic retinopathy. These changes include upregulation of iNOS, COX-2, ICAM-1, caspase 1, VEGF, and NF-kappaB, increased production of nitric oxide, prostaglandin E2, IL-1beta, and cytokines, as well as increased permeability and leukostasis. Using selective pharmacologic inhibitors or genetically modified animals, an increasing number of therapeutic approaches have been identified that significantly inhibit development of at least the early stages of diabetic retinopathy, especially occlusion and degeneration of retinal capillaries. A common feature of a number of these therapies is that they inhibit production of inflammatory mediators. The concept that localized inflammatory processes play a role in the development of diabetic retinopathy is relatively new, but evidence that supports the hypothesis is accumulating rapidly. This new hypothesis offers new insight into the pathogenesis of diabetic retinopathy, and offers novel targets to inhibit the ocular disease.

Figure 1

Capillary degeneration in a rat diabetic for 10 months. Large arrow: acellular (degenerate) capillary; small arrow: pericyte ghost.

Figure 2

Adherence of white blood cells to the wall of retinal blood vessels (leukostasis). The vasculature of anesthetized animals was perfused with fluorescein-coupled concanavalin A lectin, resulting in stain of all vessel walls and more intense stain of the white blood cells. Occasionally, staining of a capillary was arrested where white blood cells were trapped in the vessel (arrow), suggesting that the blood cell might have occluded the vessel.

Figure 3

PARP inhibitor inhibits retinal capillary cell death and development of lesions of diabetic retinopathy ((a) TUNEL-positive cells, (b) acellular capillaries, and (c) pericyte ghosts). (N: nondiabetic rats; D: diabetic rats; D+PJ-34: diabetic rats treated with PJ-34. ^* $P<.005$ compared to nondiabetic control, ^** $P<.0001$ compared to diabetic control, and ^*** $P<.02$ compared to diabetic control.) Reprinted by permission from Diabetes Vol. 53; pp. 2960—2967; 2004©The American Diabetes Association.

Figure 4

Working hypothesis of the contribution of inflammatory processes in the pathogenesis of capillary degeneration and other lesions of early diabetic retinopathy. The capillary degeneration can be inhibited in diabetic animals at any of several different points along this pathway.