28.1Introduction

Oxidative stress has been linked to retinopathy of prematurity (ROP) based on changing oxygen concentrations and needs in the preterm infant and developing retina [1Ð4]. Hypoxia, hyperoxia, and repeated changes in oxygen concentration can occur in the infant in the perinatal period and lead to events that generate reactive oxygen species (ROS) [5]. For example, fetal hypoxia can occur in some complicated deliveries [6], whereas following birth, inspired oxygen causes infant oxygen concentrations to be relatively greater compared to those in utero [7]. A number of events can lead to ßuctuations in blood and tissue oxygen concentrations. The preterm lungs are immature and there can be shunting of blood, which affects oxygen uptake. The afÞnity of oxygen varies based on fetal to adult hemoglobin concentrations, and this is also affected by blood transfusions that are common in preterm infants. Preterm infants also have cardiovascular and hematologic conditions including atrial septal defects, sepsis, and anemia of prematurity, which can affect blood ßow and tissue oxygenation [8]. Compounding these systemic conditions that affect tissue oxygen delivery and ROS generation in the preterm infant, there are developmental changes in the retina that can predispose the preterm infant to the local generation of ROS. The retinal vasculature is immature with areas of avascular and hypoxic retina and creates areas of abutting oxygenated and hypoxic retina [9], both conditions that can predispose to ROS generation. As neuronal circuitry and cells, including photoreceptors, develop, more oxygen is consumed contributing to retinal hypoxia [10, 11]. Further, the preterm infant has reduced ability to scavenge ROS [12]. Finally, the retina is vulnerable to oxidative damage because of an abundance of polyunsaturated fatty acids (PUFA) [1], the high metabolic rate and rapid rate of oxygen consumption of the photoreceptors, and possibly as a result of metabolic changes induced by ambient light and light-induced free radical formation [13Ð15].

ROS, however, also have potential beneÞts to the developing preterm infant. ROS can act as transcription factors and alter gene expression during development and metabolism. ROS are an important Þrst line of defense against bacterial invasion, and the preterm infant has reduced ability to Þght infections. For these reasons, there is concern about broadly inhibiting ROS in the preterm infant. Also, in concordance with the role ROS play in health and disease, antioxidant clinical trials have not always yielded clear-cut results [16].

The goal of this chapter is to address the role of ROS in ROP and to examine both clinical and laboratory evidence.

28.1.1Definition of Retinopathy of Prematurity

ROP occurs only in preterm infants and affects the retina, which lines the back of the eye and is a complex circuitry of neurons, glial cells, and vascular systems that interact in order for phototransduction and visual processes to occur. In humans, the retina is supplied with oxygen and nutrients by blood vessels within the inner neurosensory retina and a vascular layer deep to the retina, called the choroid. Retinal

Fig. 28.1 ROP is characterized by the zone of vascular development and the stage of disease. There are Þve stages. The Þrst four are shown in human preterm infant eyes taken with wide angle imaging. Stage 5 is a total retinal detachment and appears like a white pupil in the infant eye (not shown). In the Þrst four stages of ROP, there is avascular retina peripherally. In Stage 1, there is a line between vascular and avascular retina. In Stage 2, there is a thickened ridge and in Stage 3 there is intravitreous neovascularization. In Stage 4, partial retinal detachment occurs (the dark spots in the avascular retina are from healed laser spots)

vascular development begins at about 16 weeks gestation and is not completed until term birth. During physiologic development of the infant eye, ordered angiogenesis proceeds in the retina extending the retinal vasculature to its furthest extent, called the ora serrata. When an infant is born preterm, there is incomplete retinal vascular development with resultant peripheral avascular retina. In addition, other aspects and stresses lead to persistence of the avascular retina and pathologic disordered angiogenesis that extends outside the plane of the retina into the vitreous as intravitreous neovascularization (IVNV). IVNV (classiÞed as stage 3 ROP, Fig. 28.1) is a form of severe ROP and can lead to blindness from subsequent bleeding and retinal detachment. In ROP, avascular retina is prerequisite to the development of IVNV. Therefore, understanding the causes of avascular retina and IVNV is important, and these features are often outcomes studied in the laboratory setting in experimental models. For clarity in this chapter, the terms physiologic (i.e., intraretinal) or pathologic (i.e., intravitreous) angiogenesis or neovascularization are used.