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J. Cao, R. Renard, H. Song, E. Ioffe, V. Mosher, J.S. Rudge, E.M. Koehler-Stec, G.D. Yancopoulos, S.J. Wiegand; Inhibition of IL-1 Blocks Corneal Inflammation and Neovascularization . Invest. Ophthalmol. Vis. Sci. 2003;44(13):823.
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Purpose: Systemic administration of a novel IL-1 inhibitor, murine IL-1 Trap, was investigated in a mouse model of corneal injury in order to determine the effect of IL-1 blockade on the development of corneal inflammation and neovascularization. Methods: The murine IL-1 Trap (a chimeric protein comprising the ligand binding domains of murine IL-1R1 and IL-1RacP and mouse Fc) was incorporated into an E1E3 deleted adenovirus (Ad.IL-1 Trap). Twenty-four hours before corneal injury, C57BL/6 mice were injected intravenously with either Ad.IL-1 Trap (1 x 10^9 pfu) or a control adenovirus (adenovirus human Fc). Corneal neovascularization was induced by intrastromal placement of 3 nylon sutures in the right eye. The growth of corneal neovessels was evaluated on days 8 and 15 by slit-lamp microscopy and histology. The vasculature was labeled with an endothelial specific fluorescein conjugated lectin (lycopersicon esculentum), and neovascularization was evaluated in corneal flat-mount, as well as in cross sections using PECAM immunohistochemistry. Corneal edema was also evaluated with slit lamp microscopy and corneal thickness was measured in cross-sections. The number of polymorphonucleocytes (PMN) and macrophages were determined by staining cross-sections with HEMA-3 or rat anti-mouse F4/80 monoclonal antibody, respectively. The Scion Image program was used for analysis of the area and length of corneal neovessels. Circulating levels of murine IL-1 trap were measured on by ELISA 2, 10, and 15 days after the systemic delivery. Results: Treatment with murine IL-1 Trap significantly inhibited corneal edema and neovascularization in suture induced corneal injury (P<0.001). Histological studies showed that IL-1 Trap treatment also dramatically reduced the infiltration of PMNs and macrophages into the damaged cornea. Conclusions: IL-1Trap significantly inhibited the development of corneal neovascularization, effectively prevented edema, and markedly reduced the infiltration of leukocytes and macrophages induced by corneal suture injury. These results indicate that IL-1Trap is a potent inhibitor of inflammation and pathological angiogenesis, with potential therapeutic applications in the treatment of ocular inflammation and neovascularization.
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