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S.X. Zhang, J.J. Wang, K. Lu, R. Mott, J.–X. Ma; Pigment Epithelium–Derived Factor: An Endogenous Anti–Inflammatory Factor in the Eye . Invest. Ophthalmol. Vis. Sci. 2005;46(13):4705.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Pigmented epithelial–derived factor (PEDF) is a potent angiogenesis inhibitor, which has also been shown to reduce vascular endothelial growth factor (VEGF)–induced permeability. However, the mechanisms underlying these effects are largely unclear. As inflammation is a key factor in angiogenesis and permeability, we hypothesize that PEDF may exert its effects through anti–inflammatory function. In this study, we have investigated the retinal and systemic PEDF levels in inflammatory and diabetic animal models, and further explored the function of PEDF on the regulation of inflammatory cytokines and permeability in vivo and in vitro. Methods: Brown Norway rats and primary bovine retinal capillary endothelial cell (BRCEC) were used in the experiment. The animal models of inflammation, diabetes and oxygen–treated retinopathy (OIR) were induced by a footpad injection of lipopolysaccharide (LPS), an intravenous injection of STZ (60 mg/kg), and a 5–day exposure to hyperoxia (75% O2 and 25% room air, P7–12), respectively. Retinal vascular permeability was evaluated using the Evans blue method. Retinal and plasma PEDF, TNF–α, sICAM–1, and MCP–1 were measured by ELISA. Retinal VEGF and VEGFR–2 levels were determined by ELISA, Western blot analysis and immunohistochemistry. The mRNA levels of PEDF were quantified by real–time PCR. Endothelial monolayer permeability was measured using FITC–albumin as a tracer. NF–ΚB activation was analyzed by immunocytochemistry. Results: In the plasma of 24 h LPS–treated rats and 12–week diabetic rats, PEDF levels were significantly decreased while TNF–α levels were significantly increased. In OIR rats and diabetic rats, intravitreal injection of PEDF at 3 µg/eye significantly decreased the retinal levels of inflammatory factors, including VEGF, TNF–α, MCP–1, and sICAM–1. Moreover, intravitreal injection of PEDF reduced retinal vascular permeability in a dose–dependent manner. Further in vitro studies using BRCEC showed that PEDF inhibited hypoxia and VEGF–induced hyper–permeability and decreased TNF–α and ICAM–1 expression in a dose–dependent manner. Immunocytochemistry study showed that PEDF effectively inhibited NF–ΚB nuclear translocation induced by hypoxia, VEGF or TNF–α, suggesting that the anti–inflammatory effect of PEDF may be mediated by the blockade of NF–ΚB activation. Conclusions: PEDF, as a negative regulator of inflammation, may be implicated in a variety of inflammation–related pathogenesis, including angiogenesis and permeability. Therefore, PEDF may have therapeutic potential in the treatment of ocular and systemic inflammatory diseases.
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