Human Retinopathy Of Prematurity Research Articles

Hyperoxia inhibits several critical aspects of vascular development

Normal human retinal vascular development uses angiogenesis and vasculogenesis, both of which are interrupted in the vaso-obliteration phase of retinopathy of prematurity (ROP). Canine oxygen-induced retinopathy (OIR) closely resembles human ROP. Canine retinal endothelial cells (ECs) and angioblasts were used to model OIR and characterize the effects of hyperoxia on angiogenesis and vasculogenesis. Cell cycle analysis showed that hyperoxia reduced the number of G1 phase cells and showed increased arrest in S phase for both cell types. Migration of ECs was significantly inhibited in hyperoxia (P < 0.01). Hyperoxia disrupted the cytoskeleton of angioblasts but not ECs after 2 days. Differentiation of angioblasts into ECs (determined by acetylated low-density lipoprotein uptake) was evaluated after basic fibroblast growth factor treatment. Differentiation of angioblasts into pericytes was determined by smooth muscle actin expression after treatment with platelet-derived growth factor. Differentiation into ECs was significantly inhibited by hyperoxia (P < 0.0001). The percentage of CXCR4(+) cells (a marker for retinal vascular precursors) increased in both treatment groups after hyperoxia. These data show novel mechanisms of hyperoxia-induced disruption of vascular development.

Incidence and severity of neovascularization in oxygen- and metabolic acidosis-induced retinopathy depend on rat source

Purpose. We have previously described oxygen-induced retinopathy (OIR) and metabolic acidosis-induced retinopathy (MAIR) in the neonatal rat, both of which are analogous to human retinopathy of prematurity (ROP). Given that rats of identical strain from two commercial suppliers are phenotypically different, we investigated the incidence and severity of preretinal neovascularization (NV) in rats from different suppliers using the OIR and MAIR models. Methods. Using our established models for OIR and MAIR, 400 newborn Sprague-Dawley rats, obtained from Harlan Laboratories (HSD) and Charles River Laboratories (CRSD), were raised in 16 expanded litters of 25 (6 OIR and 10 MAIR). Beginning at day 1 of life, OIR litters (3 HSD, 3 CRSD) were exposed to 7 daily cycles of hyperoxia (80% O 2, 20.5 hours) and hypoxia (10% O 2, 0.5 hours) with a gradual return to 80% O 2 over 3 hours. OIR rats were sacrificed after 5 days of room air recovery. MAIR litters (5 HSD, 5 CRSD) were raised in room air and gavaged twice daily with NH 4 Cl (10 mM/kg body weight) from day 2 through day 4. MAIR rats were sacrificed after 3 days of recovery. For both OIR and MAIR litters, retinae from left eyes were dissected, ADPase-stained, and flatmounted. Presence and severity of NV was scored and retinal vascular areas measured by a masked observer. Results. In OIR rats, the incidence of NV was higher in CRSD rats than HSD rats (73% vs. 45%, p= 0.002). NV was more severe in CRSD rats than HSD rats (median clock hours 2 vs. 0, p= 0.0001). In MAIR rats, the incidence of NV was comparable between CRSD and HSD rats (29% vs. 34%, p = 0.53) and there was no significant difference in the severity of NV. Conclusions. Sprague-Dawley rats obtained from two independent commercial sources differed in their incidence and severity of NV associated with OIR, but not with MAIR. Future genetic studies are warranted to investigate the differences between CRSD and HSD rats, which might yield further clues into the pathogenesis of ROP.

Oxygen-induced retinopathy in the newborn rat: effects of hyperbarism and topical administration of timolol maleate.

Lesions resembling those of human retinopathy of prematurity can be provoked in newborn Wistar rats by exposure to an FiO2 of 80% for the first 5 days of life followed by 5 days recovery under room-air conditions. We evaluated the effects of moderate hyperbarism (+60.75 kPa, i.e. 455 mmHg or 0.6 atm) and topical administration of 0.25% timolol maleate on oxygen-induced retinopathy (OIR) in this experimental model. OIR (including neovascularization in most cases) was observed in 100% of the retinas of normobaric oxygen-reared ratlings that did not receive timolol. OIR was less frequent in oxygen-reared ratlings treated with hyperbarism (60%) or timolol (65%). Hyperbaric oxygen supplementation combined with timolol treatment during both the hyperoxic and room-air phases reduced the incidence of OIR to 30%. There was no sign of vasoproliferation in any of the retinas from the latter three groups. The highly significant protective effects of hyperbarism and timolol observed in this study are not fully understood. We speculate that vasoconstriction induced by the hyperbarism reduces the amount of oxygen that reaches the retina from the choroid during O2 supplementation, while an increased ocular perfusion pressure caused by timolol-induced reduction of the intraocular pressure might decrease the stimulus to vasoproliferation that normally occurs with room-air recovery.