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Published in final edited form as: Curr Opin Toxicol. 2017 Nov 20;7:102–109. doi: 10.1016/j.cotox.2017.11.008

Oxidative stress in the retina: implications for Retinopathy of Prematurity

Xanthi I Couroucli 1
PMCID: PMC9245835  NIHMSID: NIHMS1812940  PMID: 35784947

Abstract

Oxygen supplementation has been used as a part of respiratory care for preterm and term newborns since the beginning of 19th century. Although oxygen administration can be life-saving, reactive oxygen species (ROS) and reactive nitrogen species (RNS) due to hyperoxia can have detrimental effects in the developing organs of the preterm infants, with both short and long term consequences. Oxygen toxicity on the immature tissues of preterm infants can contribute to the development of several diseases like retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD). The vascular development of human retina is completed at term, whereas the neural retina develops up to 5 years of age. Disruption of the normal retinal neurovascular growth is the pathognomonic feature of ROP, and can lead to vision threatening disease or even blindness. It is estimated that at least 100,000 infants all over the world will be blind every year due to ROP, which is the leading cause of blindness in children. In this review we will discuss the role of ROS and RNS in the development of ROP, and how through historical, epidemiological, and developmental aspects of this devastating disease, we can design future research for its prevention and treatment.

Keywords: ROP, ROS, RNS, preterm infant, retina, hyperoxia, VEGF

1. INTRODUCTION

Supplemental oxygen is frequently used as a lifesaving treatment for preterm infants since 1780 when Chaussier administered oxygen to “near-dead” infants for their revival [1,2]. By the 1930’s more infants were being born in hospitals, and Hess and Chapple administered oxygen to preterm and term infants as part of their respiratory support. In the 1940’s the regular use of supplemental oxygen for the treatment of preterm infants was established, as Wilson et al noticed that their irregular breathing would improve after high inspired oxygen [3]. Nevertheless, in the 1950’s the newborn mortality rate the first 24 hours was much higher in the United States of America compared to Europe, and Virginia Apgar, an American anesthesiologist, recommended administering oxygen to cyanotic newborns in order to reduce this mortality [4].

This widespread practice of unrestricted oxygen supplementation to preterm infants led to the first epidemic of severe retinopathy of prematurity and blindness in the decade of 1940’s and 1950’s. In 1942 Terry described the phenomenon of retrolental fibroblastic overgrowth [5], and in 1950’s Campbell from Australia [6] pointed out the role of oxygen in the development of this new sudden blindness seen in preterm babies, which was called retrolental fibroplasia, now known as Retinopathy of prematurity (ROP). Several studies followed soon, from both UK (Crosse and Evans, and others) and U.S.A. (Ashton et al, Patz et al, and others) [7,8] [9,10] that established the role of hyperoxia to the rising first epidemic of severe ROP in the 1950’s.

In an excellent review by Smith LE et al [9] it was pointed out that ROP is a multifactorial neurovascular retinal disease that can lead to blindness; it occurs only in premature infants, and hyperoxia is a major contributor to its pathogenesis. The human retina vasculature is not fully developed until full term, and the photoreceptors are the last ones to mature even after the small vessels have developed. During that vulnerable developmental retinal stage, the reactive oxygen species (ROS) generated by the hyperoxia or hypoxia in these infants, lead to the destruction and developmental arrest of the neurovascular retina, which is followed by abnormal neovascularization [11,12]. For the last 70 years many clinical studies have been conducted in order to elucidate the optimal oxygen blood levels/saturations of preterm infants receiving oxygen. Between 2005 and 2010 about 5000 extremely preterm infants have been enrolled in 5 major randomized controlled trials [13–17], but still we do not have definite conclusions on the amount of supplemental oxygen that can be given to these infants without severe ROP and/or increased mortality. Therefore, there is a need for prevention of ROP, which is the most frequent preventable blindness in children worldwide. Additionally, since the retina is the extension of the brain, research on treating or preventing the effects of hyperoxia and/or hypoxia on the developing retina could lead to similar therapeutic approaches for neurodevelopmental disorders [18–20].

2. EPIDEMIOLOGY

The incidence of ROP based on population studies can vary depending on the country, the region, survival rates, and gestational age of the infants included in the studies [21]. Over the last 70 years three “epidemics” have been recognized. The first period was between the 1940’ and 1950’s and it was attributed to the administration of high concentration of oxygen to the preterm infants [22]. As the medical treatments improved, more immature infants could survive, and a second “epidemic” of ROP emerged in the 1970’s to 1980’s [23]. The third ROP “epidemic has emerged because more premature infants are saved, but oxygen administration may still not be well controlled in the middle and low income countries. In high income countries ROP could affect 20-50% of infants with birth weight below 1500 grams, with 4-19% having severe ROP and/or blindness [24]. Contrary to this, in the middle and low income countries most studies have found that the mean birth weight of infants developing ROP is above 1250 grams, and the incidence of severe ROP is from 5.0 to 44.9% [25]. In 2008, Gilbert [26] estimated that worldwide about 50,000 children will be blind from ROP. This is simply an underestimation, because in 2010 alone, there were about 32,000 infants blind due to ROP [27]. Recently it has been reported that approximately 100,000 infants will be blind all over the world, every year due to ROP [28]. About 14 million children are blind worldwide, and ROP is now a leading cause for blindness in these children [29]. Unfortunately, the differences between a blind and a non-blind child is more pronounced in the middle and low income countries. It has been found that while 10% of the blind children in UK will die with the first year after the diagnosis of blindness, in lower income countries the equivalent mortality is 60% [30]. Therefore, there is an absolute need to understand, detect, treat and above all make every effort to prevent this lifelong debilitating disease. Knowing the anatomy, physiology and development of the human retina, we can understand the pathophysiology of ROP, and then we can attempt to treat it or, even more important, prevent it [31].

3. ANATOMY AND DEVELOPMENT

The posterior segment of the human eye contains the vitreous humor, retina, choroid, and the optic nerve. The retina is an extension of the central nervous system. It consists of 3 main cellular groups: the vascular group (endothelial cells, pericytes, and smooth muscle cells), the neurons (photoreceptors, bipolar cells, ganglion cells, horizontal cells, and amacrine cells) and microglia (including astrocytes and Müller cells) [32]. There are two types of photoreceptors in the retina: rods and cones. Rods are responsible for vision at low light levels, they do not mediate color vision, and have low acuity. Cones are active at higher light levels, are capable of color vision and are responsible for high acuity. The axons of the ganglion cells form the optic nerves. The macula, especially the central area called fovea, is populated exclusively by cones. At about 34 weeks of gestation the morphology of the photoreceptors becomes more mature. After term birth and about five years of age the retina appears mature, although there is still a population of progenitor cells that remain in the distal retina [33].

There are two blood sources to the retina: the central retinal artery and the choriocapillary vascular plexus at the back of the retina [34]. The central retinal artery travels along with the optic nerve, enters the eye through the optic disk, and branches into capillaries. The layer where the photoreceptors lie is avascular, and therefore it relies on the small vessels of the choroid (choriocapillaris), posteriorly to the retina, for the oxygen supply via diffusion. In the developing retina, astrocytes and blood vessels enter the retina via the optic nerve, and spread to the periphery. Astrocytes migrate first and generate the network on which the developing vessels, will expand by angiogenesis [35,36]. According to several studies, all three retinal ganglion cells, astrocytes and Müller cell-derived Vascular Endothelial Growth Factor (VEGF) contribute to retinal physiologic and pathologic vascularization [35–37]. Additionally, photoreceptors can affect the fate of the retinal vasculature because they produce large amounts of reactive oxygen species. [38–40].

4. PHYSIOLOGY AND DEVELOPMENT

The human fetuses survive and grow in utero under hypoxic environment, with prenatal oxygen tensions (pO2) of 20-30 mmHg that postnatally could increase to 80-100 mmHg [41]. After birth, newborns are exposed to the higher oxygen concentrations of room air (relative hyperoxia). The normal oxygen saturation of fetal blood in the left atrium is about 65%. During labor the human fetus tolerates oxygen saturations as low as 30% without developing acidosis [42]. Postnatally, oxygen supplementation is life saving for the preterm infants with pulmonary insufficiency due to their immature lung development, but this could lead to increased rates of ROP [43].

In humans, the neural retina is generated from multipotent retinal progenitor cells, which form the cones and rods. Rhodopsin (contained in rods) and other opsins (contained in cones) are light sensitive proteins that are involved in visual phototransduction, and their mRNA is produced between the 12th to 15th weeks of gestation [44]. At term birth, photoreceptors are still immature but opsin expression is well established. Once the photoreceptors are produced, they must last for a lifetime, while being subjected to various noxious and stress inducing stimuli, such as light exposure, high metabolic activity, toxins and oxygen administration [45]. During their growth, the photoreceptors can produce very large amount of oxygen radicals and oxidative stress, because the process of phototransduction has high oxygen and metabolic demands, and this could contribute to the generation of ROP [37].

The normal human retinal vascularization can be achieved by two mechanisms: vasculogenesis and angiogenesis. The retinal vasculogenesis is well established by 14 to 15 weeks, before most retina neurons differentiate. Then angiogenesis is responsible for the formation of the inner and outer vascular plexus, and their extension from the central to the peripheral retina. The outer vascular plexus begins around the fovea between the 25th and 26th weeks of gestation, and this coincides with the timing of eye opening and the appearance of photoreceptor functions [32]. The extension of the already excising vessels by angiogenesis begins about the 16th week of gestation in response to the “physiologic hypoxia” that is the result of the growing retina, especially the photoreceptors. The astrocytes that populate the retina before the vessels, secrete angiogenesis factors, such as Hypoxia Inducible Factor1-a (HIF1a) and VEGF, generating a gradient towards which the new vessels are directed [46]. Insulin-like growth factor (IGF-1) also play role in the development of retinal angiogenesis, and its main source is the placenta [9]. The fully developed vessels extend to the full length of retina nasally by 36 weeks and temporally by 40 weeks. Therefore, when a preterm infant is born below 32-35 weeks of gestation, the retinal vessels are not fully developed, and with exposure to both “physiologic” and “iatrogenic” hyperoxia, the generated ROS and RNS halt the development of these vessels.

5. ROLE OF ROS/RNS IN THE DEVELOPMENT OF ROP

Retinopathy of prematurity develops because of the arrest of normal retinal neurovascular development in the preterm infant, due to prematurity, effects of high oxygen exposures, poor growth, inflammatory and infectious pre and post-natal events, as well as deficiencies of factors normally provided in utero. Especially the ROS generated from oxygen play a major role in the generation of oxidative stress, and they include superoxide anion (•O2−) and hydroxyl radical (OH). Superoxide anion is formed by the reduction of oxygen by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and it is converted to hydrogen peroxide (H2O2) and singlet oxygen [47]. Nitric oxide (•NO) can react with superoxide (•O2−) to generate peroxynitrite (ON−), which is one of the reactive nitrogen species (RNS). As Murad’s team showed in 1980s, nitric oxide apart from reacting with other free radicals is also one of the smallest known signaling molecules [48,49]. Both ROS and RNS can cause lipid, protein and DNA oxidation and nitrosylation as well as mitochondrial and cellular membrane damage. Chemtob’s team demonstrated that trans-arachidonic acids generated during nitrative stress can lead to retinal vascular degeneration in newborn rats exposed to hyperoxia [50].

In the newborn the antioxidant enzymes are regulated by the antioxidant response element (ARE), which in turn is modulated by an ARE-binding transcription factor called NF-E2-related factor 2 (Nrf2) and its active complex Nrf2-Keap1[51]. It has been shown by Lutty’s team that Nrf2 was beneficial to the endothelial survival in an ROP mouse model [52]. The process of vascular development and phototransduction generates oxidative stress in the retina, and with the addition of supplemental oxygen the balance of oxidant stresses and antioxidant cellular mechanisms results in increased oxidative stress.

It is hypothesized that ROP consists of two distinct phases. The first phase starts immediately after preterm birth, when exposure to supplemental oxygen, required for the treatment of respiratory failure, further suppresses retinal growth factors and leads to the halt of the retinal neurovascular development as well as the vaso-obliteration of existing small vascular beds. With the addition of inspired oxygen, more reactive oxygen species (ROS) and nitrogen species (RNS) can be produced than neutralized, which lead to more structural and functional modifications to different molecules. Since the phospholipid enriched retina is particularly sensitive to the ROS that are generated in high or low oxygen, exposure to hyperoxia can lead to the initial stages of ROP.

At the molecular level, as Hartnett and Penn have elegantly described, persistent or intermittent hyperoxia, active inflammation and poor growth modulate angiogenic and neurogenic transcription factors, pathways and genes like HIF1-a, Janus associated kinase-signal transducers and activators of transcription (JAC-STATs), VEGF, Vascular Endothelial Growth Factor Receptor 1/2/3/4 (VEGFR1/2/3/4) [53,54], Erythropoietin (EPO), Insulin-like growth factor-1 (IGF-1), Nitric oxide synthases (NOS) and others [2,55] . With the destabilization of HIF1-a under hyperoxia, there is no induction of the oxygen response elements in the promoters of angiogenic genes including the VEGF. The modulation of antioxidant enzymes by Nrf2 at this stage could be inadequate due to overwhelming production of ROS/RNS during hyperoxia.

Additionally, the ROS apart from exerting their effects directly on the cells, they can also affect the expression of various angiogenic genes. In preterm infants, since their immune system is not fully developed, NADPH oxidase can produce more ROS to protect from invading bacteria [55]. Nevertheless, these ROS and RNS can also have deleterious effects on the endothelial and neural cells of the developing retina. The collective effects of the initial administration of needed supplemental oxygen to the preterm infants, could lead to the arrest of development and destruction of their retina vascular and neural tissues.

Postnatally, the second phase begins at approximately 30–32 weeks of postnatal age (PNA). As the infant grows, the avascular retina (especially the photoreceptors) becomes metabolically active and hypoxic, which leads to upregulation of angiogenic and inflammatory factors and pathways [12] and abnormal vision threatening retinal vascular overgrowth, which is the hallmark of severe ROP. Additionally, the growth and function of photoreceptors and neural retina is altered even years after the diagnosis of active ROP, as seen by Electroretinograms (ERG’s) performed in human studies [56]. The hypothesis of the two phases for the development of human ROP was proposed about 30 years before the classification of ROP according to the extension in the retina zones and stages of the disease. Additionally, very low birth weight infants with BPD already receiving oxygen, could have frequent episodes of intermittent hypoxia, and this could lead to more severe developmental arrest of the neurovascular retina. Infants who have the greatest fluctuations in their oxygenation seem to develop more severe ROP.

During the second phase of active ROP, there is marked upregulation of angiogenic factors and pathways due to the hypoxic areas of the developing retina. The induction of VEGF and its receptor 2 (VEGFR2) play a major role in the abnormal neovascularization, especially the VEGF165 isoform [57]. Recent studies have shown that both the retinal and choroidal abnormal neovascularization contribute to the development of ROP, since the photoreceptor layer gets oxygenated from both the retina and choroid vessels [12,58]. In a newborn rat model of ROP it was found by next generation sequencing that additional pathways involved in inflammation, neural signaling and cell death are highly modulated in ROP rats [59].

The human retina is the only organ where observation of its vessels can be achieved by direct visualization (Fig. 1, A–D). The first clinical examination for the classification of ROP takes place about 31-32 weeks of postnatal age, there are 5 stages referring to the severity of the disease (Fig. 1, E–I), and 3 Zones referring to the extension of retinal vascularization (Fig. 1, Da and Db). When the vascular abnormalities are confined within the area of the optic nerve or macula (Zone one), there is higher possibility for retinal detachment and blindness. The Stage 1 and 2 refer to mild ROP (Fig. 1, E, and F), stage 3 moderate to severe ROP (Fig. 1, G), stage 4 severe ROP with partial retinal detachment (Fig. 1, H) and stage 5 severe ROP with complete retinal detachment (Fig. 1, I). The more severe the vascular arrest and vaso-obliteration during the first phase, the more profound abnormal neovascularization and photoreceptor dysfunction can be seen in the second phase of ROP (Fig. 1, J–L).

FIGURE 1. Artist’s drawings, Baylor College of Medicine.

FIGURE 1.

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A-C: Retinal vessels of a term (A) and preterm infant on room air or oxygen (B, C).

The retinal vessels of a newborn term infant extend from the optic nerve to the edges of the peripheral retina. The retinal vessels of a preterm infant on room air are not fully developed.

Da and Db: Zones of retina of a preterm infant on oxygen (Da) and a term infant on room air or oxygen (Db).

The retinal vessels of a preterm infant on oxygen could extend only up to the borders of Zone one because of the effects of ROS/RNS on the developing retina. The retinal vessels of an infant born at term, are fully developed, extending from the optic nerve area to the edges of the peripheral retina.

E-I: Stages of ROP.

The stages of ROP ensue after the preterm infant is exposed to oxygen, which leads to retinal vaso-obliteration and developmental vascular arrest. The retina grows with reduced vascularity that causes hypoxia and subsequent abnormal neovascularization (E-G). This abnormal angiogenesis extends into the vitreous, and if extensive can cause partial (H) or complete retinal detachment (I).

ROLE OF ROS/RNS IN THE DEVELOPMENT OF ROP.

J: Retinal vessels of a newborn preterm infant on room air.

In a newborn preterm infant on room air, the retinal vessels are not fully developed.

K: During phase 1 of ROP the preterm infant is on oxygen.

ROS and RNS that develop due to hyperoxia, can cause arrest of retinal angiogenesis and neurogenesis.

L: During phase 2 of ROP there is abnormal neovascularization.

ROS/RNS lead to the arrest of angiogenesis and vaso-obliteration, the retina becomes hypoxic and abnormal vision threatening vascularization ensues.

6. ANIMAL MODELS OF ROP

There are three major newborn animal models for experimental ROP. None of the models is considered to exactly simulate the human ROP, but each of these models has some characteristics of the human ROP. The first experimental ROP model was the canine, and was described by Arnall Patz [60] and was modified by Flower et al [61]. Both the canine experimental ROP model and the human preterm newborns have similar retinal vascular development, and advanced stages of ROP can be seen in newborn dogs exposed to 100% hyperoxia for 4 days that are subsequently maintained in room air [62]. Therefore, this model addresses the high oxygen exposures of the preterm newborns and both the retinal vaso-obliteration and vascular arrest that can be seen in these infants in hyperoxia and after removal from hyperoxia.

The newborn mouse model had several stages of development. When the field of angiogenesis was established in the early 1970’s by Folkman et al [63], ocular neovascularization was caused by tumor corneal implants producing angiogenic factors. The present mouse model was developed by Smith et al [64], and involves exposure to 75% oxygen of newborn C57BL/6 mice from postnatal day 7 to 12. This causes retinal vaso-obliteration representing the first phase of experimental ROP. The second phase of retinal neovascularization is seen after the 12th postnatal day when the mice are returned to room air. The newborn mouse model of oxygen induced retinopathy represents the hypothesis that human ROP happens in two phases. The first phase of retinal vaso-obliteration is due to hyperoxia, and the second phase due to the hypoxia the growing avascular retina senses. Although the mouse model is helpful for studying genetically different mice, there are differences in the retinal vascular development between a preterm human infant and a term newborn mouse.

The newborn rat model of oxygen induced retinopathy developed by Penn et al [65], can mimic certain characteristics to the human ROP. Both in human preterm newborns and rat pups the retinal vascular development has the same pattern. Preterm infants on supplemental oxygen have frequent desaturations due to their respiratory insufficiency, and therefore are likely to develop severe retinopathy with preretinal neovascularization. To resemble this clinical set up, Penn exposed the newborn rat pups to variable ambient oxygen (50% for 24 hours and 10% for the next 24 hours up to 14 days) and found the same pathological changes with the human ROP. Therefore, this rat model of ROP addresses both the effects of alternating hyperoxic and hypoxic stress on the developing retina, and it could be a model for studying therapeutic agents of abnormal retinal vascularization [66].

7. ROP: THEN AND NEXT

Based on our knowledge of the effects of ROS/RNS on the developing retina, studies on the use of anti-oxidants (vitamin E [67,68], C [69], A [24], lutein [70],) for the prevention or treatment of ROP had been conducted with variable results. Clinical studies on the administration of IGF-1 [71] and omega-3 [72] for the prevention of ROP are on the way. Investigations on the amount of supplemental oxygen given to preterm infants without major side effects (including ROP and death) are still being analyzed. Our knowledge on the role of pathologic angiogenesis of the retina has opened the way for the treatment of the severe late ROP with laser photocoagulation and intravitreal injections of anti-VEGF antibodies [73]. Nevertheless, laser treatment of the retina can destroy parts of the retina, and the anti-VEGF antibodies can leak into the systemic circulation, having possible effects in the developing organs. More recently, the advanced high throughput mRNA sequencing method (RNA-seq) and stem cell research has provided broad widening information for research in potential targets for prevention and treatments in several retinal diseases [28,74]. Stem cell therapies may be a future treatment consideration for severe ROP [74,75].

To date there are therapeutic modalities for ROP, but there is no prevention. Therefore, beyond all, there is an absolute need for the prevention of ROP, which is a life-long disease [31,76]. Long-term complications of ROP such as refractory errors, glaucoma and risk of retinal detachment could persist through adolescence and adulthood. Since one of the major causes of preventable blindness in children is ROP, we need to collectively increase our efforts for its prevention.

HIGHLIGHTS:

  • Supplemental oxygen is needed for the treatment of pulmonary insufficiency of preterm infants.

  • ROS and RNS generated due to hyperoxia can cause arrest of the developing neurovascular retina and vaso-obliteration.

  • ROP is due to abnormal increased retinal neovascularization that follows the hyperoxic retinal injury, and is the leading cause of blindness in children today.

  • It is estimated that at least 100,000 infants worldwide will be blind every year due to this devastating disease.

  • A blind child is more likely to live in poverty, be more frequently hospitalized and to die in Childhood than a child who is not blind.

  • There are several treatments with various side effects, and preventative measures in the form of controlling the oxygen administration to preterm infants maybe difficult to achieve.

  • Antioxidants may play a role in the prevention of ROP, but further research is urgent and very much warranted.

ACKNOWLEDGMENTS:

We are grateful to the Knights Templar Eye Research Foundation for their grant support from 7/1/2008 to 6/30/2010, which gave us the opportunity to study the experimental ROP.

Abbreviations:

ROP

Retinopathy of prematurity

ROS

Reactive Oxygen Species

RNS

Reactive Nitrogen species

•NO

Nitric oxide

•O2−

superoxide anion

ONOO−

peroxynitrite

HIF1-a

Hypoxia Inducible Factor1-a

VEGF

Vascular Endothelial Growth Factor

VEGFR 2

Vascular Endothelial Growth Factor Receptor 2

Nrf2

NF-E2-related factor 2

JAC-STATs

Janus associated kinase-signal transducers and activators of transcription

IGF-1

Insulin-like growth factor-1

EPO

Erythropoietin

Footnotes

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