ABSTRACT
BACKGROUND: Preterm infants receiving supplemental oxygen therapy experience frequent fluctuations in their blood oxygen levels, the magnitude of which has been associated with the incidence and severity of retinopathy of prematurity in such infants. OBJECTIVE: Our objective was to investigate in a relevant animal model whether the immature brain with its poorly vascularised white matter might also be susceptible to injury when exposed to such fluctuations in blood oxygen. METHODS: Newborn rats were reared in an atmosphere in which a computer reproduced the oxygen fluctuations derived from the transcutaneous oxygen levels of a 24-week preterm infant who had developed severe retinopathy. Following 14 days of exposure, we measured the expression of active caspase-3, myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) in the brains comparing with rat pups raised in room air. RESULTS: Compared to room air controls, at day 14, the expression of active caspase-3 was increased by up to 162% (significant increase in 7 of 9 regions), MBP decreased by up to 70% (significant in the hypothalamus only) and GFAP increased by up to 103% (significant in 6 of 7 regions. On day 21, following 7 days of reparative recovery, GFAP levels in most areas of oxygen-exposed brains had returned to near control levels. There were no longer significant differences in caspase-3 levels apart from the cerebral cortex, cerebellum and striatum. In contrast, MBP expression was now much higher in most regions of the treated brains compared to controls. CONCLUSION: We conclude that fluctuations in blood oxygen, observed in preterm survivors, may constitute a source of injury to the white matter and corpus striatum of the developing brain and contribute to the neurological sequelae in extremely premature infants.
Subject(s)
Brain/drug effects , Hyperoxia/metabolism , Myelin Basic Protein/metabolism , Oxygen/pharmacology , Animals , Animals, Newborn , Apoptosis/drug effects , Brain/metabolism , Brain/pathology , Caspase 3/metabolism , Cell Count , Disease Models, Animal , Fluorescent Antibody Technique, Direct , Glial Fibrillary Acidic Protein/metabolism , Hyperoxia/chemically induced , Hyperoxia/pathology , Immunoenzyme Techniques , Nerve Fibers, Myelinated/drug effects , Nerve Fibers, Myelinated/metabolism , Nerve Fibers, Myelinated/pathology , Oxygen/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
The aim of this study was to investigate whether the mean around which arterial oxygen fluctuations take place was important in a unique animal model of oxygen-induced retinopathy. Retinopathy of prematurity (ROP) is associated with fluctuating arterial oxygen. A recent retrospective study suggested that management of high-risk preterm infants at lower oxygen saturations was associated with less severe ROP. Rat pups were raised in a variable oxygen environment around a high (24%), normal (21%) or low (17%) mean inspired oxygen for 14 d. Rat pups raised in the high (24%) mean variable oxygen environment had more retarded retinal vascular development than did rats raised in an environment that fluctuated around 21% mean oxygen. In contrast, rats raised in a lower mean (17%) but still variable oxygen environment had no discernible retinal differences from controls raised in constant room air. Rats raised in a relatively hypoxic but variable oxygen environment develop less severe retinal vascular abnormalities than those raised in variable oxygen around higher oxygen means.
