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B. Kim, Q. Tang, B.T. Rouse; Application of Plasmid DNA Encoding IL–18 and Sirna Targeting Vascular Endothelial Growth Factor Pathway Genes Inhibits Ocular Angiogenesis; Therapeutic Approaches for Herpetic Stromal Kertitis . Invest. Ophthalmol. Vis. Sci. 2005;46(13):4500.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Herpes simplex virus–1 (HSV–1) infection of the eye can cause a blinding immunoinflammatory stromal keratitis (SK) lesion. Using the mouse model, we have demonstrated that angiogenesis is a necessary step in lesion pathogenesis since its inhibition results in diminished severity. The molecules involved in causing corneal angiogenesis are multiple and appear to include the vascular endothelial growth factor (VEGF) family of proteins. The aim of this study was to evaluate whether IL–18 cytokine and siRNA targeting VEGF family genes can inhibit SK pathogenesis by suppression of angiogenesis. Methods: We treated IL–18 plasmid onto the cornea prior to HSV–1 infection or CpG implantation, or systemically injected siRNA targeting VEGF pathway genes after HSV–1 infection or CpG implantation, and then measured angiogenesis and VEGF levels in the cornea. Results: We showed that the systemic administration of siRNA directed at VEGF and two of its receptors resulted in diminished angiogenesis caused by both HSV infection as well as by CpG oligodeoxynucleotides inserted into corneal micropockets. Additionally, we demonstrated that the cytokine IL–18 expresses antiangiogenic activity, and that this appears to occur by an inhibitory effect on VEGF production. This was shown both in vivo, when IL–18 expression was achieved by a DNA plasmid encoding IL–18, as well as in vitro by IL–18 protein to inhibit VEGF production. Additionally, IL–18 used in vivo was shown to significantly reduce the severity of SK lesions. Conclusions: These findings demonstrated that application of IL–18 or siRNA targeting VEGF pathway genes suppressed angiogenesis by inhibiting their target growth factor, VEGF. Our results are discussed in terms of the multiple approaches that will be needed for the control of unwanted angiogenesis.
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