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Originally published In Press as doi:10.1167/iovs.08-1755 on March 31, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:3239-3244.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.08-1755
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Role of NADPH Oxidase in Retinal Vascular Inflammation

Mohamed Al-Shabrawey,*,1,2 Modesto Rojas,2 Tammy Sanders,1 Ali Behzadian,2,3 Azza El-Remessy,3,4 Manuela Bartoli,2,5 Abdul Kader Parpia,6 Gregory Liou,7 and Ruth B. Caldwell*,2,7,8,9

1From the Oral Biology and Anatomy, School of Dentistry, the 2Vascular Biology Center, and the 3Departments of Pharmacology and Toxicology, 6Internal Medicine, 7Ophthalmology, and 8Cellular Biology and Anatomy, Medical College of Georgia, Augusta, Georgia; the 4Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, Georgia; the 5Department of Ophthalmology, University of South Carolina, Columbia, South Carolina; and the 9VA Medical Center, Augusta, Georgia.

PURPOSE. In another study, it was demonstrated that NADPH oxidase-derived reactive oxygen species (ROS) are important for ischemia–induced increases in vascular endothelial growth factor (VEGF) and retinal neovascularization. Diabetes–induced increases in retinal ROS, VEGF expression, and vascular permeability are accompanied by increases in the NADPH oxidase catalytic subunit NOX2 within the retinal vessels. The goal of this study was to evaluate the potential role of NOX2 and NADPH oxidase activity in the development of retinal vascular inflammation.

METHODS. Studies were performed in wild-type mice, mice lacking NOX2, and mice treated with the NADPH oxidase inhibitor apocynin in models of endotoxemia and streptozotocin-induced diabetes. Intracellular adhesion molecule (ICAM)-1 expression was determined by Western blot analysis. Leukocyte adhesion was assessed by labeling adherent leukocytes with concanavalin A. Vascular permeability was assessed by extravasation of FITC-conjugated albumin. ROS production was determined by dichlorofluorescein imaging.

RESULTS. Both endotoxemia- and diabetes-induced increases in ICAM-1 expression and leukostasis were significantly inhibited by deletion of NOX2, indicating that this enzyme is critically involved in both conditions. Moreover, apocynin treatment and deletion of NOX2 were equally effective in preventing diabetes-induced increases in ICAM-1, leukostasis, and breakdown of the blood–retinal barrier, suggesting that NOX2 is primarily responsible for these early signs of diabetic retinopathy.

CONCLUSIONS. These data suggest that NOX2 activity has a primary role in retinal vascular inflammation during acute and chronic conditions associated with retinal vascular inflammatory reactions. Targeting this enzyme could be a novel therapeutic strategy for treatment of the retinopathies associated with vascular inflammation.






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