The Role of Inflammation in the Pathophysiology of Diabetic Retinopathy

Abstract

The inflammatory nature of diabetic retinopathy (DR) was first suggested by the finding that it occurred less frequently among diabetic patients taking salicylates for rheumatoid arthritis. Subsequent work has identified many features that are characteristic of inflammation, including increased blood flow, vascular permeability, and edema, as well as the influx of cells that are associated With inflammatory responses. While DR involves defects in many retinal cell types, the retinal vasculature appears to be the principal locus of the inflammation-linked damage. In experimental studies employing rodent models of diabetes, diabetic retinal vascular leakage, capillary nonperfusion, and endothelial cell damage are temporally and spatially correlated with a low-level leukocyte influx and persistent retinal leukostasis. This leukostasis is mediated by retinal upregulation of intercellular adhesion molecule-1 (ICAM-1), together with an increased expression of its cognate integrin ligands on neutrophils. Subsequently, endothelial cell injury and death result from Fas/FasL-rnediated apoptosis. In response to this injury, the endothelium maintains a sustained high rate of cell division, which is believed to result in exhaustion of its regenerative capacity. This stress is further exacerbated by a diabetes-induced defect in the ability of endothelial precursor cells to repair the damaged vasculature. While the vascular damage is primarily a function of infiltrating leukocytes, DR also is associated with ischemic neovascularization, a process that is amplified by the influx of macrophages. Numerous cytokines are upregulated in DR, and two of these, vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (INF-alpha), are believed to play important roles in the inflammation-linked retinal damage. Upregulation of VEGF causes much of the increase in retinal ICAM-1 and the resultant leukostasis, with the VEGF(165) isoform being especially important in promoting inflammatory responses. TNF-alpha also is involved in the upregulation of ICAM-1, and preclinical studies have established that inhibitors of both VEGF and TNF-alpha are able to reduce the DR-associated pathology. The concept that DR is a low-grade inflammatory condition has proved useful in the clinic. Inhibitors of VEGF and TNF-alpha have shown efficacy in reducing the DR-related vision loss while high-dose aspirin has proved effective in reducing the number of DR-associated microaneurysms. There is thus reason for hope that further elucidation of the underlying cellular and molecular mechanisms of DR-associated inflammation will lead to the development of new molecularly targeted therapies and to the rational use of approaches employing more than one therapeutic agent.