Abstract
Purpose:
Retinopathy of prematurity (ROP) is a significant cause of visual morbidity in very preterm infants (born < 32 weeks of gestation), with the incidence of ROP having increased globally as a result of advances in neonatal care. Due to the increased survival of neonates born after shorter lengths of gestation, the primary aim of this study was to determine the long-term ocular pathology following neonatal exposure to hyperoxia, starting earlier than in the traditional ROP mouse model.
Methods:
Neonatal (C57BL/6J) mice were raised in either 40% or 65% oxygen from birth until postnatal day 7 followed by room air until early adulthood (8 weeks) or middle-age (10 months). Control animals were raised in normoxia for the duration of the experiment. Eyes were collected for resin histology and immunofluorescence staining was performed on retinal whole mounts using anti-Iba-1 and anti-CD31 (PECAM) antibodies for the visualization of macrophages/microglia and vessels respectively. The density of vitreal hyalocytes and subretinal macrophages was calculated.
Results:
Histological examination of mice 8 weeks after exposure to 65% oxygen from day 0 to day 7 revealed marked disruption of the nuclear layers of the retina, with displacement of nuclei and photoreceptor loss, retinal thinning, retinal folds, the presence of pseudorosettes and neovascular tufts, and persistent hyaloid vasculature. The degree of pathology in the 40% oxygen group at 8 weeks was less severe than in the 65% oxygen group. Confocal microscopic analysis of retinal whole mounts at 8 weeks and 10 months revealed microglial activation and the accumulation of hyalocytes and subretinal macrophages in response to 40% and 65% oxygen. Analysis of CD31 staining in the 65% oxygen group revealed retinal vessel loss in the periphery at 8 weeks, which was persistent at 10 months of age.
Conclusions:
These data demonstrate that early neonatal exposure to hyperoxic conditions results in oxygen concentration-dependent pathology and long-term retinal injury, resembling various features of human ROP and hyperplastic vitreous. These novel findings may be particularly relevant for infants that are born at earlier gestational ages.
Keywords: 706 retinopathy of prematurity •
688 retina •
595 microglia