Choroidal Involution Is Associated with a Progressive Degeneration of the Outer Retinal Function in a Model of Retinopathy of Prematurity

Abstract

Retinopathy of prematurity (ROP), the most common cause of blindness in premature infants, has long been associated with inner retinal alterations. However, recent studies reveal outer retinal dysfunctions in patients formerly afflicted with ROP. We have recently demonstrated that choroidal involution occurs early in retinopathy. Herein, we investigated the mechanisms underlying the choroidal involution and its long-term impact on retinal function. An oxygen-induced retinopathy (OIR) model was used. In vitro and ex vivo assays were applied to evaluate cytotoxic effects of IL-1β on choroidal endothelium. Electroretinogram was used to evaluate visual function. We found that proinflammatory IL-1β was markedly increased in retinal pigment epithelium (RPE)/choroid and positively correlated with choroidal degeneration in the early stages of retinopathy. IL-1β was found to be cytotoxic to choroid in vitro, ex vivo, and in vivo. Long-term effects on choroidal involution included a hypoxic outer neuroretina, associated with a progressive loss of RPE and photoreceptors, and visual deterioration. Early inhibition of IL-1β receptor preserved choroid, decreased subretinal hypoxia, and prevented RPE/photoreceptor death, resulting in life-long improved visual function in IL-1 receptor antagonist-treated OIR animals. Together, these findings suggest a critical role for IL-1β-induced choroidal degeneration in outer retinal dysfunction. Neonatal therapy using IL-1 receptor antagonist preserves choroid and prevents protracted outer neuroretinal anomalies in OIR, suggesting IL-1β as a potential therapeutic target in ROP.

VEGF‐Trap is a potent modulator of vasoregenerative responses and protects dopaminergic amacrine network integrity in degenerative ischemic neovascular retinopathy

“…Suggesting a beneficial effect for neurotransmission, we assessed the potential impact of these molecular changes on light responsiveness in young adult mice (P50). In agreement with previous findings (Vessey et al ; Zhou et al ), we detected significantly reduced a‐wave and b‐wave amplitudes in OIR mice relative to normoxic controls (Fig. a and b).…”

“…Thus, electroretinography aberrations, including oscillatory potential abnormalities, are useful tools for early diabetic retinopathy diagnosis (Bearse et al ; Simo et al ). In OIR models, which largely recapitulate the pathomorphological alterations of proliferative diabetic retinopathy, visual perturbations are also detectable by electroretinography even after neovascular tufts resolve (Dorfman et al ; Vessey et al ; Zhou et al ). Such perturbations include reduced a‐wave and b‐wave amplitudes, as well as altered oscillatory potentials.…”

“…Yet, outer segment damage or molecular cascade dysfunction within these cells cannot be discarded. Recently, involution of the chroroidal vasculature was linked to long‐lasting photoreceptor dysfunction (Zhou et al ). Whereas changes to cone outer segments were reported in the central retina of OIR mice (Vessey et al ), little is known about how the two cone populations of the murine retina react to Afibercept.…”

Review of the mechanisms and therapeutic avenues for retinal and choroidal vascular dysfunctions in retinopathy of prematurity

“…). Early neonatal treatment with an IL‐1 receptor antagonist preserved choroidal vessels, decreased outer retinal hypoxia and decreased significantly RPE and photoreceptor loss in OIR animals . These observations suggest a critical role for IL‐1 β , which is known to trigger prostaglandin synthase expression, in inducing choroidal degeneration and long‐term subretinal and outer retinal disorder following OIR/ROP.…”

“…Additionally, our laboratory recently explored the role of IL-1b on choroidal involution and consequently on subretinal dysfunction in a rodent model of ROP (55). It is well established that oxidant stress is intimately intertwined with inflammation.…”