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D.M. McDonald, A.W. Stitt, T.A. Gardiner; TNF–alpha Depletion Modulates Angiogenesis in Ischaemic Retinopathy Through a Mechanism Involving Inhibition of Peroxynitrite . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1363.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Recently we have shown that inhibition of the pro–angiogenic inflammatory cytokine tumour necrosis factor alpha (TNFα) can modulate retinal hypoxia and pre–retinal neovascularization in a murine model of oxygen–induced retinopathy (OIR). This treatment facilitated intra–retinal angiogenesis and recovery of the ischaemic retina which was associated with a reduction in intra–vitreal neovascularisation. This is similar to the effects observed in inducible nitric oxide synthase (iNOS) knockout animals, therefore, the aim of this investigation was to determine if the mechanism via which TNFα depletion improved intravascular recovery was due in part to it’s inhibition of iNOS. Methods: Wild type animals and TNFα knockouts were subjected to OIR by exposure of neonatal mice to 75% oxygen between postnatal days 7 and 12 (P7–P12). The animals were returned to room air at P12 and the retinas removed at P17. The extent of pre–retinal neovascularization and intra–retinal re–vascularization was quantified by image analysis of retinal flat–mounts. Eyes were snap frozen and protein extracted for Western blotting. Results: NOS–2 (130kDa) immunoreactivity was negligible at P12 but increased significantly at P13 in all groups. Retinal expression of this protein had returned to baseline levels by P17. In contrast, nitrotyrosine was significantly increased at P13 in control mice (p<0.01) and significantly reduced in TNFα knock–out animals (p<0.001). Thus NOS–2 expression correlates with an increase in nitrotyrosine in wild type animals and a decrease in those without TNFα. Conclusions: The induction of iNOS expression was similar in wild type and TNFα knockout animals whereas there was a marked difference in the amount of peroxynitrite production during ischaemia. These data strongly suggest that the improved intra retinal recovery mediated by the absence of TNFα is due to a decrease in peroxynitrite production via a mechanism which does not involve a decrease in iNOS expression.
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