Article

Role of 4 Integrin (CD49d) in the Pathogenesis of Diabetic Retinopathy

Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, USA.
Investigative ophthalmology & visual science (Impact Factor: 3.66). 07/2009; 50(10):4898-904. DOI: 10.1167/iovs.08-2013
Source: PubMed

ABSTRACT The pathophysiology of diabetic retinopathy is mediated by leukocyte adhesion to the vascular endothelium of the diabetic retina, which results in endothelial injury, blood-retina barrier breakdown, and capillary nonperfusion. Leukocyte adhesion is triggered by the interaction of vascular endothelium adhesion molecules, such as ICAM-1, with leukocyte integrins, such as CD18. Inhibition of ICAM-1/CD18 signaling suppresses but does not completely abolish the cardinal manifestations of diabetic retinopathy, suggesting a role for additional adhesion molecules. Integrin alpha 4 (CD49d), in complex with integrin beta1, forms very late antigen-4 (VLA-4), which interacts with vascular cell adhesion molecule-1. The authors have now studied the role of integrin alpha 4/CD49d in the pathogenesis of diabetic retinopathy.
Diabetes mellitus was induced in Long Evans rats with streptozotocin, and an anti-alpha 4 integrin/CD49d neutralizing antibody was injected 5 and 10 days later. Two weeks after streptozotocin administration, vascular leakage was quantified with the Evans Blue technique. Leukostasis was measured with a static adhesion assay ex vivo and the FITC-lectin perfusion method in vivo. Retinal VEGF and TNF-alpha levels and NF-kappaB activity were measured by ELISA.
Blockade of alpha 4 integrin/CD49d attenuated the diabetes-induced upregulation of NF-kappaB activation, VEGF, and TNF-alpha protein levels and reduced significantly diabetes-induced leukocyte adhesion and vascular leakage.
These data identify alpha 4 integrin/CD49d as a mediator of leukocyte adhesion and the resultant early signature abnormalities of diabetic retinopathy. Inhibition of this signaling pathway may hold promise for clinical activity in patients with diabetes.

0 Followers
 · 
127 Views
  • Source
    • "Integrins are also among various factors that cause retinal detachment in proliferative diabetic retinopathy and proliferative vitreoretinopathy (Kupper and Ferguson 1993; Guidry et al. 2003). In rats, blockade of α4 integrin diminished diabetes-induced increase in NF-kappaB activation , VEGF and TNF-alpha levels and significantly reduced leukocyte adhesion and vascular leakage (Iliaki et al. 2009). Synthetic peptide antagonists of integrin αvβ3 inhibited retinal neovascularization in a murine model when administered as intraperitonal or periocular injections (Luna et al. 1996), inhibition of αv integrins prevented basic fibroblast growth factor-induced neovascularization of cornea (Klotz et al. 2000), and inhibition of α5β1 inhibited and regressed corneal neovascularization after alkali-burns (Muether et al. 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Several studies have established the role of activated corneal keratocytes in the fibrosis of the cornea. However, the role of keratocytes in maintaining the structural integrity of a normal cornea is less appreciated. We focus on the probable functions of integrins in the eye and of the importance of integrin-mediated keratocyte interactions with stromal matrix in the maintenance of corneal integrity. We point out that further understanding of how keratocytes interact with their matrix could establish a novel direction in preventing corneal pathology including loss of structural integrity as in keratoconus or as in fibrosis of the corneal stroma.
    Journal of Cell Communication and Signaling 03/2014; DOI:10.1007/s12079-014-0230-1
  • Source
    • "Alpha 4 integrin (Iliaki et al., 2009 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Diabetes causes a number of metabolic and physiologic abnormalities in the retina, but which of these abnormalities contribute to recognized features of diabetic retinopathy (DR) is less clear. Many of the molecular and physiologic abnormalities that have been found to develop in the retina in diabetes are consistent with inflammation. Moreover, a number of anti-inflammatory therapies have been found to significantly inhibit development of different aspects of DR in animal models. Herein, we review the inflammatory mediators and their relationship to early and late DR, and discuss the potential of anti-inflammatory approaches to inhibit development of different stages of the retinopathy. We focus primarily on information derived from in vivo studies, supplementing with information from in vitro studies were important.
    Progress in Retinal and Eye Research 05/2011; 30(5):343-58. DOI:10.1016/j.preteyeres.2011.05.002 · 9.90 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This paper presents a method of recognizing unconstrained handwritten numerals. For feature extraction, a method called crossing feature coding is proposed. The method scans through the rows and columns to obtain the horizontal and vertical crossing times of a character. The method is fast in extracting features and it can provide a large amount of information for classification. Based on the horizontal and vertical crossing feature codes and some other feature such as stroke length and slope, and density, a number of classifying rules are proposed. For classification a self-correcting classification tree is designed. A practical recognition and mail sorting system is set up to test the effectiveness of the recognition method
    Signal Processing and Its Applications, 1999. ISSPA '99. Proceedings of the Fifth International Symposium on; 02/1999
Show more

Similar Publications