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JM Holmes, Y Chen, N Loewen, DA Leske, EM Poeschla; Subretinal Injection Increases Neovascularization in Oxygen-Induced Retinopathy in the Neonatal Rat . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1263.
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Purpose: In pilot studies, we found paradoxically that subretinal injection of potentially therapeutic agents increased the incidence and severity of neovascularization (NV) in a neonatal rat model for retinopathy of prematurity (ROP). We hypothesized that subretinal injection per se causes more severe NV. Methods: Using one of our established models for OIR, 75 newborn Sprague-Dawley rats (Charles River), were raised in 3 expanded litters of 25 and exposed to 7 daily cycles of hyperoxia (80% O2, 20.5 hours) and hypoxia (10% O2, 0.5 hours) with a gradual return to 80% O2 over 3 hours. The environment was also maintained at 10% inspired CO2. On day 5 of life (after the completion of the 4th cycle) right eyes were injected subretinally with 2µl PBS. Control left eyes were not injected. After cyclic oxygen, rats recovered in room air for 5 days and were sacrificed on day 13. Eyes were fixed and retinae from both eyes dissected, ADPase-stained, and flat-mounted. Presence and severity (clockhours, 0-12) of NV in experimental retinae, control retinas, and room air grading controls was scored by a masked observer. Comparisons of incidence and severity between eyes with and without subretinal injection were made using Chi-square and Wilcoxon signed-rank tests. Results: Incidence of NV was higher in eyes receiving a subretinal injection than uninjected eyes (93% vs 62%, p=0.005). NV was also more severe in eyes receiving an injection than uninjected eyes (median = 6 clockhours vs 1 clockhour, p=0.0001). None of the grading controls were graded positive for NV. Conclusion: Subretinal injection per se increases the incidence and severity of NV in a neonatal rat model of OIR. We hypothesize that the mechanism may be induction of a retinal detachment, which may render the hypoxic avascular retina even more hypoxic. These findings are important when planning and interpreting results of all experiments involving subretinal injections, including OIR models, and are important for consideration of future treatments in human ROP.
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