Oxygen-induced retinopathy in the rat: hemorrhages and dysplasias may lead to retinal detachment

Abstract

Rearing neonatal rats in hyperoxia induces the development of retinal hemorrhages and retinal dysplasia. Albino rats were placed in 80% oxygen immediately after birth and were exposed for either 5, 10, or 14 days, followed by sacrifice or exposure to normoxia for an additional 2, 4, 5, 7, 8, 10, 38, 45 or 56 days. Control rats were simultaneously raised in room air and sacrificed at the same times. All animals were enucleated and their eyes processed for light and electron microscopy. Eyecups were trimmed to facilitate cross-sectioning of the retina in the vertical meridian. No control rats showed signs of retinal hemorrhages or of dysplastic folds or rosettes. Nor did the retinas of rats killed immediately after oxygen exposure contain hemorrhages, but the incidence of retinal folds or rosettes in this group was 54%. For rats exposed to combinations of hyperoxia and brief normoxia (10 days or less), 40% suffered hemorrhages and 50% developed retinal folds or rosettes. Although hemorrhages were more prominent in rats subjected to longer periods of oxygen (73% of all rats exposed for 14 days followed by brief normoxia vs. 6% of those exposed for 5 days followed by brief normoxia), the incidence decreased with time post-exposure in room air. Hemorrhages occurred in 100% of the rats raised in oxygen for 14 days followed by 2 days in room air, and decreased to 50% by 7 days in room air and to 0% by 38 days, indicating a spontaneous resolution with time. In each case, the blood appeared to leak from the newly-forming vessels of the deep capillary net, with most of the red blood cells migrating to the subretinal space. Retinal fold or rosette formation, indicative of developmental dysplasia, occurred in a fraction of virtually all groups of exposed rats, and persisted at the longest post-exposure periods. These two manifestations of oxygen-induced retinopathy are emphasized because they lead to an abnormal separation of the retina from the epithelial layer, which may increase the likelihood of the most serious consequence of ROP--retinal detachment. In fact, all rats that endured post-exposure periods of 38 days or longer before sacrifice exhibited retinal detachment.

Retinal dysplasia in mice lacking p56lck

“…ROP is a multifactorial disease and numerous risk factors in addition to light and oxygen such as xanthine administration, vitamin E de®ciency, gestational agebirth weight (Zierler 1988;Hammer et al, 1986;Sira et al, 1985) have been reported. A number of these suggested risk factors are consistent with an oxidative mechanism of injury; the lack of su cient antioxydant, such as vitamin E (Penn et al, 1992), would be expected to exacerbate the severity of oxidative retinal damage. Indeed the prophylatic administration of vitamin E, an oxygen reactive product, reduces the incidence and severity of ROP (Quinn et al, 1990) Lck tyrosine kinase may prevent excess reactive oxygen production and thus, may be necessary for normal retinal physiology.…”

“…Retinal dysplasia with rosette formation has previously been associated with the loss or absence of retinal pigment epithelium (RPE) (Silverstein et al, 1971) or RPE function. Dysplasia and rosettes have been reported as features of oxygen-induced retinopathy in the rat model for retinopathy of prematurity (ROP) (Penn et al, 1992) and by photosensitization induced retinopathy in the newborn Beagle (Sadda et al, 1994). Rosettes have also been decribed in the retinoblastoma (Flexner 1981;Ts'o 1969).…”

Unbalanced expression of VEGF and PEDF in ischemia‐induced retinal neovascularization

“…Therefore, this model is also considered an accepted model for diabetic retinopathy [16]. Previous studies have shown that compared to mice, rats are less prone to develop ischemiainduced retinal neovascularization, and require cycling between hypoxia and normoxia to develop signi¢cant retinal neovascularization [21,22]. However, most of these previous studies used Sprague Dawley rats [22,23].…”

The significance of neuronal and glial cell changes in the rat retina during oxygen-induced retinopathy

“…When the rat pup is placed back into normal air at a later stage, the retina is rendered hypoxic because of the lack of normal vessel development, and consequently epiretinal angiogenesis develops, ultimately leading to retinal detachment and blindness [19][20][21].…”