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Yun-Zheng Le, Zhiming Song, Huizuo Xu, Dan J. Carr, Meili Zhu; Modulating The Severity Of Uveitis By Altering RPE Barrier Function: Implication In Therapeutics. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3220.
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Uveitis is responsible for approximately 10% of cases of severe vision impairment in the United States. We previously demonstrated that RPE-specific disruption of vascular endothelial growth factor (VEGF) significantly reduced the severity of RPE barrier-specific leakage in the subretinal gap and the level of exudative retinal detachment in a mouse model of endotoxin-induced uveitis (EIU). To determine the underlining mechanism of this observation and to develop therapeutic strategy for uveitis, we analyzed retinal inflammation, RPE barrier leakage, and severity of exudative retinal detachment in RPE-specific VEGF receptor-2 (VEGFR2) knockout (KO) mice or mice injected with VEGF neutralizing antibody using an EIU model.
Expression of retinal inflammatory markers was analyzed by immunoblotting and the number of infiltrating leukocytes was quantified by flow cytometry. The severity of RPE barrier breakdown and exudative retinal detachment was examined with our recently established fluorescent microscopic assay.
Loss of VEGF signaling in the RPE by disrupting VEGFR2 significantly reduced the expression of inflammatory biomarkers (MCP1 and CD68) and the infiltration of neutrophils, activated monocytes, macrophages, and microglia in the retina of EIU mice. Treatment of EIU mice with VEGF neutralizing antibody resulted in a substantial reduction of RPE barrier-specific leakage and exudative retinal detachment.
Although uveitis is traditionally considered as an inflammatory disorder, our results clearly suggest that breakdown of the RPE barrier function is a major contributing factor for the severity of the disease. The RPE barrier is therefore a potential cellular target of posterior uveitis with anti-VEGF agents applicable for the treatment of the disease.
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