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D.S. Gibson, A.W. Stitt, T.A. Gardiner; Cytokine Inhibition Reduces Intra-retinal Angiogenesis but Increases Extra-retinal Neovascularisation in Oxygen-induced Retinopathy . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2917.
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Purpose: Neovascular retinopathies collectively represent a major cause of blindness in developed countries and are characterised by hypoxia-driven angiogenesis in which new blood vessels escape the confines of the retina and grow on the retinal surface. However, it is not known why such new vessels proliferate outside the retina in preference to infiltration of the hypoxic tissue. The present study tests whether inhibition of the pro-angiogenic inflammatory cytokines tumour necrosis factor alpha (TNFα) and interleukin-1 beta (IL-1ß) can reduce retinal neovascularization in the murine model of oxygen-induced retinopathy. Methods: C57 B6 mice were exposed to 80% oxygen between postnatal day 7 (P7) and P12 producing vaso-obliteration and cessation of vascular development in the capillary beds of the central retina. Return of the animals to room air at P12 renders the central retina ischaemic and hypoxic, and results in retinal neovascularization (NV) between P15 and P21 with maximal NV at P17. Half the pups in each oxygen treated litter were treated with CNI-1493 (dose of 5mg/Kg/day), a translational inhibitor of TNFα and Interleukin-1ß, by intra-peritoneal injection between P12 and P17. Groups of hyperoxia-exposed mice were injected with the bio-reductive drug pimonidazole (Hypoxyprobe-HP) at 60 mg/kg, 3 hours prior to sacrifice to assess the relative degree of retinal hypoxia in CNI-1493 treated v untreated animals. Results: Treatment with CNI-1493 greatly increased intra-vitreal NV with >100% increase in the number of NV cell nuclei lying outside the internal limiting membrane of the retina. However, intra-retinal angiogenesis within the ischaemic central retina was markedly inhibited, a feature reflected by significantly greater inner retinal hypoxia as indicated by immunostaining for hypoxyprobe and SDS-PAGE/Western blotting for HP-protein adducts. The florid angiogenic response in CNI-1493-treated animals was also qualitatively different from oxygen-treated controls in that neovascular complexes were seen to arise directly from the major retinal veins traversing ischaemic retina as well as from the perfused peripheral capillary beds and the optic disc. Conclusions: It may be that the physical barriers within the dense tissue matrix of the retina present a more formidable challenge to the migration of vascular endothelial cells than the fluid medium at the vitreous interface. We hypothesise that inhibition of cytokine-activation of cell-associated proteases may offer an explanation of the observed alteration in the angiogenic response.
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