A central role for inflammation in the pathogenesis of diabetic retinopathy

Abstract

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 temporary and spatially associated with retinal leukocyte stasis in early experimental diabetes. Retinal leukostasis increases within days of developing diabetes and correlates with the increased expression of retinal intercellular adhesion molecule-1 (ICAM-1) and CD18. Mice deficient in the genes encoding for the leukocyte adhesion molecules CD18 and ICAM-1 were studied in two models of diabetic retinopathy with respect to the long-term development of retinal vascular lesions. CD18-/- and ICAM-1-/- mice demonstrate significantly fewer adherent leukocytes in the retinal vasculature at 11 and 15 months after induction of diabetes with STZ. This condition is associated with fewer damaged endothelial cells and lesser vascular leakage. Galactosemia of up to 24 months causes pericyte and endothelial cell loss and formation of acellular capillaries. These changes are significantly reduced in CD18- and ICAM-1-deficient mice. Basement membrane thickening of the retinal vessels is increased in long-term galactosemic animals independent of the genetic strain. Here we show that chronic, low-grade subclinical inflammation is responsible for many of the signature vascular lesions 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 treatment in diabetic retinopathy.

Surface Engineering of Quantum Dots for In Vivo Vascular Imaging

“…Our in vivo imaging results are consistent with studies of ICAM and VCAM expression in diabetic and nondiabetic tissue, in which their upregulation is implicated in an inflammatory cascade that causes various complications of the disease (6,40,41). QD fluorescence due to ICAM and VCAM expression is apparent on major vessels as well as the microcirculation in disease models, which appears as an out of focus fluorescent background behind the major vessels ( Figure 4A-F).…”

Proteomic analysis of human vitreous fluid by fluorescence-based difference gel electrophoresis (DIGE): a new strategy for identifying potential candidates in the pathogenesis of proliferative diabetic retinopathy

“…In recent years evidence has accumulated indicating that inflammation is an important event in the pathogenesis of diabetic retinopathy [26][27][28]. In the present study, vitreous levels of several components of the complement system (C4b, factor B, C3 and C9) have been found, for the first time, to be simultaneously increased in PDR patients relative to control subjects.…”

Vascular endothelial growth factor in eye disease

“…Although experimental diabetes in rodent models does not progress to proliferative diabetic retinopathy, many of the early vascular changes seen in patients are evident, such as increased permeability, microaneurysm formation, and leukostasis. The latter is caused by up-regulation of inflammatory mediators including the leukocyte adhesion molecule ICAM-1 (Joussen et al, 2004). Studies have shown that VEGF requires ICAM-1 to induce early vascular changes in experimental diabetes (Lu et al, 1999;Miyamoto et al, 1999).…”

“…Studies have shown that VEGF requires ICAM-1 to induce early vascular changes in experimental diabetes (Lu et al, 1999;Miyamoto et al, 1999). Mice deficient in the genes encoding for the leukocyte adhesion molecules CD18 and ICAM-1 demonstrate significantly fewer adherent leukocytes in the retinal vasculature as well as fewer damaged RECs and less vascular leakage after 11 or 15 months of diabetes (Joussen et al, 2004). These data strongly suggest that chronic, low-grade, sub-clinical inflammation is responsible for many of the vascular lesions seen in patients with diabetic retinopathy.…”

“…The early onset of VEGF upregulation may imply a role for inflammatory and redox stimuli in promoting VEGF expression. On the other hand, it has been suggested that hyperglycemia-induced leukostasis could result in multiple foci of transient hypoxia due to reversible occlusion of the retinal capillaries by adherent leukocytes (Joussen et al, 2004).…”