Abstract
Bronchopulmonary dysplasia (BPD) is a major cause of neonatal morbidity in premature infants, occurring as a result of arrested lung development combined with multiple postnatal insults. Infants with BPD exposed to supplemental oxygen are at risk of retinopathy of prematurity as well. Thus, we studied the effects of hyperoxia on the retinal vasculature in a murine model of BPD. The retinal phenotype of this model, which we termed hyperoxia-induced proliferative retinopathy (HIPR), shows severe disruption of retinal vasculature and loss of vascular patterning, disorganized intra-retinal angiogenesis, inflammation and retinal detachment. Neonatal mice were subjected to 75% oxygen exposure from postnatal day (P)0 to P14 to model BPD, then allowed to recover in room air for 1 (P15), 7 (P21), or 14 days (P28). We quantified retinal thickness, protein levels of HIF-1α, NOX2, and VEGF, and examined the cellular locations of these proteins by immunohistochemistry. We examined the retinal blood vessel integrity and inflammatory markers, including macrophages (F4/80) and lymphocytes (CD45R). Compared to controls, normal retinal vascular development was severely disrupted and replaced by a disorganized sheet of intra-retinal angiogenesis in the HIPR mice. At all time-points, HIPR showed persistent hyaloidal vasculature and a significantly thinner central retina compared to controls. HIF-1α protein levels were increased at P15, while VEGF levels continued to increase until P21. Intra-retinal fibrinogen was observed at P21 followed by sub-retinal deposition in at P28. Inflammatory lymphocytes and macrophages were observed at P21 and P28, respectively. This model presents a severe phenotype of disrupted retinal vascular development, intra-retinal angiogenesis inflammation and retinal detachment.
Highlights
Preterm birth, defined as birth at less than 37 weeks gestational age, accounts for about 10% of births in the US [1]
Unlike what has been described as retinal revascularization in the oxygen-induced retinopathy (OIR) mouse model [9, 10], at P28 in the hyperoxiainduced proliferative retinopathy (HIPR) model, there was no evidence of regression of angiogenesis or revascularization of the retina nor evidence of any attempts at vascular organization or branching
We have studied the retinal findings in this mouse hyperoxia-induced bronchopulmonary dysplasia (BPD) model (HIPR), which shows severely disrupted retinal vascular development, disorganized angiogenesis, intra-retinal vascular leakage and exudative and traction retinal detachment (Fig 10)
Summary
Preterm birth, defined as birth at less than 37 weeks gestational age, accounts for about 10% of births in the US [1]. With advancements in neonatal care, the survival of extremely early gestational age (> 23 weeks) and low birth weight infants (< 1000g) has made bronchopulmonary dysplasia (BPD) the most common chronic lung disease and long-term morbidity affecting these preterm infants [2, 3]. With current day improved neonatal care and survival of smaller, more immature infants, the “new” BPD is quite different than in previous eras, and its hallmark is arrested lung and microvasculature development [3, 4]. Since normal retinal vascularization is incomplete until 36–40 weeks gestational age, premature infants are susceptible to retinal vascular compromise [5]. With better control of the oxygen saturation in the neonatal units, the current day ROP is a confined to premature infants of gestational age less than 26 weeks old in the First World. Premature infants who receive supplemental oxygen in the setting of prematurity and lung underdevelopment may be at risk for retinal vascular maldevelopment
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