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S.A. Vinores, W.–H. Xiao, J. Shen, P.A. Campochiaro; TNF Is Critical for Retinal Leukostasis Mediated by VEGF, IL–1ß, and PAF and for Blood–Retinal Barrier (BRB) Breakdown in Ischemic Retinopathy . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1723.
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Diabetic retinopathy (DR) has been described as an ischemic retinopathy and an inflammatory disorder. Tumor necrosis factor–α (TNFα) is a potent proinflammatory and vasculo–reactive molecule that has been implicated in the development of complications of DR. This study was conducted to determine if TNFα is critical in mediating retinal leukostasis, BRB breakdown, and retinal neovascularization (NV), which are characteristic of DR, following exposure to various proinflammatory factors.
TNFα knockout mice and controls received a 1µl intravitreal injection of the lowest dose of vascular endothelial growth factor (VEGF), interleukin–1ß (IL–1ß), or platelet activating factor (PAF) that elicits maximum BRB breakdown or vehicle. Oxygen–induced ischemic retinopathy (OIR) was also induced in TNFα knockout mice and controls. Six hours after intravitreal injections and at P17 in mice with OIR, retinal leukostasis was assessed using FITC–conjugated concanavalin–A and BRB breakdown was assessed using 3H–mannitol. Retinal NV was evaluated using griffonia simplicifolia isolectin–B4 (GSA) labeling with image analysis.
Retinal leukostasis induced by VEGF, IL–1ß, or PAF was significantly reduced by 80%, 84%, and 92%, respectively, in TNFα knockouts compared to controls, but BRB breakdown induced by these proinflammatory agents was not significantly inhibited. In mice with OIR, BRB breakdown was significantly reduced by 25% in TNFα knockouts compared to controls, but retinal leukostasis and NV were not.
The data shows that TNFα is critical in mediating leukostasis induced by various proinflammatory factors and suggests that BRB breakdown is augmented by inflammation, but not dependent on it. In ischemic retinopathy, TNFα contributes to BRB breakdown, but is not critical to it and BRB breakdown can occur without a significant increase in leukostasis. VEGF has been identified as a key molecule for BRB breakdown and NV in OIR, but the data suggest that its interaction with TNFα is not implicated in the development of retinal NV and increased leukostasis and plays a limited role in BRB breakdown in this model.
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