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      Diabetic Retinopathy: Vascular and Inflammatory Disease

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          Abstract

          Diabetic retinopathy (DR) is the leading cause of visual impairment in the working-age population of the Western world. The pathogenesis of DR is complex and several vascular, inflammatory, and neuronal mechanisms are involved. Inflammation mediates structural and molecular alterations associated with DR. However, the molecular mechanisms underlying the inflammatory pathways associated with DR are not completely characterized. Previous studies indicate that tissue hypoxia and dysregulation of immune responses associated with diabetes mellitus can induce increased expression of numerous vitreous mediators responsible for DR development. Thus, analysis of vitreous humor obtained from diabetic patients has made it possible to identify some of the mediators (cytokines, chemokines, and other factors) responsible for DR pathogenesis. Further studies are needed to better understand the relationship between inflammation and DR. Herein the main vitreous-related factors triggering the occurrence of retinal complication in diabetes are highlighted.

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          Most cited references 180

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          A central role for inflammation in the pathogenesis of diabetic retinopathy.

          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.
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            An endotoxin-induced serum factor that causes necrosis of tumors.

            In studying "hemorrhagic necrosis" of tumors produced by endotoxin, it was found that the serum of bacillus Calmette--Guerin (BCG)-infected mice treated with endotoxin contains a substance (tumor necrosis factor; TNF) which mimics the tumor necrotic action of endotoxin itself. TNF-positive serum is as effective as endotoxin itself in causing necrosis of the sarcoma Meth A and other transplanted tumors. A variety of tests indicate that TNF is not residual endotoxin, but a factor released from host cells, probably macrophages, by endotoxin. Corynebacteria and Zymosan, which like BCG induce hyperplasia of the reticulo-endothelial system, can substitute for BCG in priming mice for release of TNF by endotoxin. TNF is toxic in vitro for two neoplastic cell lines; it is not toxic for mouse embryo cultures. We propose that TNF mediates endotoxin-induced tumor necrosis, and that it may be responsible for the suppression of transformed cells by activated macrophages.
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              The role of cyclooxygenases in inflammation, cancer, and development.

              The cyclooxygenase (COX) enzymes catalyze a key step in the conversion of arachidonate to PGH2, the immediate substrate for a series of cell specific prostaglandin and thromboxane synthases. Prostaglandins play critical roles in numerous biologic processes, including the regulation of immune function, kidney development, reproductive biology, and gastrointestinal integrity. There are two COX isoforms, which differ mainly in their pattern of expression. COX-1 is expressed in most tissues, whereas COX-2 usually is absent, but is induced by numerous physiologic stimuli. Surprisingly, disruption of Cox1 (Ptgs1) in the mouse did not result in gastrointestinal abnormalities. cox-2 (Ptgs2) null mice show reproductive anomalies and defects in kidney development. Epidemiologic, animal, and human data indicate that NSAIDs, inhibitors of cyclooxygenase, are chemopreventive for colon cancer. COX-2 is overexpressed in 50% of benign polyps and 80-85% of adenocarcinomas. Offspring from cox-2 null by Apcdelta716 matings exhibit an 86% reduction in polyp number when compared to offspring from control animals, thus providing genetic evidence that COX-2 contributes to tumor formation or growth. The in vivo mechanism by which COX-2 affects tumor growth has not been determined. It is possible that both tumor and stromally derived COX-2 could influence tumor angiogenesis and/ or immune function.
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                Author and article information

                Journal
                J Diabetes Res
                J Diabetes Res
                JDR
                Journal of Diabetes Research
                Hindawi Publishing Corporation
                2314-6745
                2314-6753
                2015
                7 June 2015
                : 2015
                Affiliations
                1Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
                2Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy
                3Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
                4Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples, Italy
                5ICRRS Neuromed, Pozzilli, Isernia, Italy
                Author notes

                Academic Editor: Harald Sourij

                Article
                10.1155/2015/582060
                4475523
                Copyright © 2015 F. Semeraro et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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