Triamcinolone reduces neovascularization, capillary density and IGF-1 receptor phosphorylation in a model of oxygen-induced retinopathy

Increasing evidence links inflammation to retinovascular diseases. Several studies have shown that ocular fluid from diabetics have measurable inflammatory cytokines,1,2 and in an animal model of retinal neovascularization (NV), IL-6, and TNF-αwere temporally associated with subsequent release of angiogenic growth factors and the development of intravitreous NV.3 Inflammatory cells, such as leukocytes, have been implicated in the creation of avascular retinal areas in animal models of diabetes through endothelial cell apoptosis.4,5 These avascular retinal regions have been postulated to be the stimulus for NV6 through the overexpression of angiogenic growth factors,7 including vascular endothelial growth factor (VEGF). Conversely, an isoform of VEGF has been shown to increase leukocyte adherence to endothelial cells (ECs) leading to apoptosis and retinal avascularity.8 Thus, inflammation has been shown to cause NV through release of inflammatory cytokines and through the creation of avascularity, both linked to the increased expression of angiogenic factors. Anti-inflammatory therapy has been used to reduce NV in clinical inflammatory diseases such as posterior uveitis.9 Corticosteroids have been shown to downregulate induced VEGF in cultured Muller cells and in an RPE cell line.10,11 In addition, in a mouse model of oxygen-induced vaso-obliteration,12 the corticosteroid triamcinolone (TA) reduced capillary proliferation into the vitreous. Based on these findings, local delivery of corticosteroids into the eye has been considered to treat several retinovascular diseases.13–15 Clinical trials are under way to test intravitreous TA (1 mg/mL in vitreous) for macular edema in diabetic retinopathy and retinal vein occlusion.13 In addition, some investigators have tested the effects of TA in persistent NV after laser treatment in retinopathy of prematurity (ROP; Tawansy KA, et al. IOVS 2005;46:ARVO E-Abstract 3493). Besides the known clinical risks of cataract formation and increased intraocular pressure, recent studies have shown a toxic effect of TA on several retinal cell lines.16 To understand further the effect of TA in vivo, we used a well-accepted animal model of oxygen-induced retinopathy (OIR)17 that uses oxygen extremes similar to that of a preterm infant at risk for severe ROP,18 to study the effect of intravitreous injection of TA on NV, capillary density, and EC viability. In our short-term study, we found a dose-related decrease in NV and capillary density of the vascularized retina that appeared to be related to a delay in vascularization and the signaling pathway of insulin-like growth factor (IGF)-1. We also found a significant dose-dependent decrease in systemic weight gain of pups given intravitreous TA. Our findings may be relevant to the use of intravitreous TA in the management of retinovascular diseases, particularly those with ongoing intraretinal vascular development, such as ROP.