Neonatal Intermittent Hypoxia, Reactive Oxygen Species, and Oxygen-Induced Retinopathy
Kay D. Beharry1‒3, Charles L. Cai1, Gloria B. Valencia1, Arwin M. Valencia4, Douglas R. Lazzaro2,3, Fayez Bany-Mohammed5, and Jacob V. Aranda1‒3
1Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA; 2Department of Ophthalmology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA; 3State University of New York Eye Institute, New York, NY 10075, USA; 4Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Summerlin Hospital Medical Center, Valley Healthcare System, Las Vegas, NV 89135, USA; 5Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of California, Irvine, CA 92868, USA
Correspondence: firstname.lastname@example.org (K.D.B.)
Beharry KD et al. Reactive Oxygen Species 3(7):12–25, 2017; ©2017 Cell Med Press
(Received: November 24, 2016; Revised: December 5, 2016; Accepted: December 5, 2016)
ABSTRACT | Most of the major morbidities in the preterm newborn are caused by or are associated with oxygen–induced injuries and are aptly called “oxygen radical diseases in neonatology or ORDIN”. These include bronchopulmonary dysplasia, retinopathy of prematurity, periventricular leukomalacia, intraventricular hemorrhage, necrotizing enterocolitis and others. Relative hyperoxia immediately after birth, immature antioxidant systems, biomolecular events favoring oxidative stress such as iron availability and the role of hydrogen peroxide as a key molecular mediator of these events are reviewed. Potential therapeutic strategies such as caffeine, antioxidants, non-steroidal anti-inflammatory drugs, and others targeted to these critical sites may help prevent oxidative radical diseases in the newborn resulting in improved neonatal outcomes.
KEYWORDS | Intermittent hypoxia oxygen-induced retinopathy; Oxidative stress; Reactive oxygen species
ABBREVIATIONS | AOP, apnea of prematurity; ATP, adenosine triphosphate; ELGAN, extremely low gestational age neonate; EPO, erythropoietin; HIF, hypoxia inducible factor; IGF-1, insulin-like growth factor-1; IH, intermittent hypoxia; IHR, recovery from intermittent hypoxia; NSAID, non-steroidal anti-inflammatory drug; OIR, oxygen-induced retinopathy; ORDIN, oxygen radical diseases in neonatology; OXPHOS, oxidative phosphorylation; pVHL, Von Hippel-Lindau tumor suppressor protein; ROP, retinopathy of prematurity; ROS, reactive oxygen species; SOD, superoxide dismutase; VEGF, vascular endothelial growth factor
2. Apnea of Prematurity and Neonatal Intermittent Hypoxia
3. Mitochondria and ROS
4. ROS and Antioxidants
5. ROS and HIF1α
6. ROS and Retinopathy of Prematurity
Reactive oxygen species (ROS) play a key role in the development of a wide range of neonatal diseases including intraventricular hemorrhage (IVH) , periventricular leukomalacia (PVL) , chronic lung disease/bronchopulmonary dysplasia (CLD/BPD) [3‒6], necrotizing enterocolitis (NEC) , apnea of prematurity (AOP), and retinopathy of prematurity (ROP) [8‒10], thus giving rise to the term “oxygen radical diseases in neonatology (ORDIN)” [11, 12]. Extremely low gestational age neonates (ELGANs) who are born at 23‒27 weeks of gestation, and weighing <1250 grams are particularly vulnerable to oxidative stress and often require oxygen therapy with mechanical ventilation which accentuate their susceptibility to injury. At this gestational age, lung development and respiratory control are extremely immature  and predispose the ELGAN to continuous fluctuations in arterial oxygen saturation (SpO2), or intermittent hypoxia (IH) episodes, many of which are not responsive to an increased inspired oxygen concentration [3, 13]. Unlike IH in adults and older children with sleep apnea, neonatal IH is a developmental disorder. The lungs of ELGANs are in the canalicular stage of development and the respiratory control mechanisms are underdeveloped . Combined immature respiratory control, relatively supraphysiological oxygen, and immature antioxidant defense mechanisms to scavenge damaging oxygen byproducts, contribute to the pathophysiology of many neonatal diseases.
The goal of this review is to summarize the known mechanisms underlying oxygen induced retinopathy (OIR) focusing on IH and ROS, and to highlight recent data emerging from our laboratory that utilizes a unique OIR model that simulates AOP and IH experienced by ELGANs and produces characteristics consistent with severe ROP. Mechanisms learned from the OIR model may be potentially applicable to all neonatal diseases related to oxidative injuries. This review emphasizes the biomolecular vulnerability of the preterm newborn to oxidative injuries and organ damage caused by the interactive actions of relative hyperoxia after birth, immature oxidative stress defenses, biochemical events favorable to oxidative injuries, and the importance of hydrogen peroxide in the pathogenesis of these diseases (Figure 1). Our recent findings point to the importance of curtailing ROS accumulation and oxidative stress during the early postnatal period. Timely use of appropriate pharmacological agents to prevent rather than treat oxidative stress may mitigate severe OIR.
FIGURE 1. Mechanism of reactive oxygen species (ROS) and hydrogen peroxide (H2O2) interaction with iron to form lipid peroxidation in micro preemies. In OXPHOS, electrons are transferred down the redox enzyme complexes located within the mitochondrial inner membrane. The electrons enter at either complex I or II and are transferred through coenzyme Q to complex III, then to cytochrome c, on to complex IV, and finally to oxygen to generate H2O. As a byproduct of OXPHOS, ROS are produced. When mitochondrial ROS production becomes excessive (as in the case of intermittent hypoxia and immature antioxidant systems) they can react with iron to cause lipid peroxidation.
2. APNEA OF PREMATURITY AND NEONATAL INTERMITTENT HYPOXIA
AOP is defined as cessation of breathing lasting longer than 15–20 seconds and/or accompanied by arterial oxygen desaturation and bradycardia in ELGANs. The incidence of AOP varies with the degree of prematurity, from 7% at 34–35 weeks of gestational age to 15% at 32–33 weeks, 54% at 30–31 weeks, and nearly 100% at <28 weeks , and is the most common cause of IH in ELGANs [3, 4, 13, 15]. Apneas of less than 10 seconds in duration can result in a reduction in oxygen saturation of up to 40%  even though these episodes may not be recorded on regular cardiorespiratory monitors currently employed in the neonatal intensive care unit (NICU). IH is defined as brief, repetitive cycles of arterial oxygen desaturations followed by re-oxygenation or IHR (recovery from IH) in normoxia or hyperoxia with supplemental oxygen . An IH event is usually defined as a decline in SaO2 by 5% lasting <3 minutes in duration [13‒18]. Episodes of IH, often called desaturations, frequently occur independent of apnea in preterm babies on mechanical ventilation. IHR that follows IH induces damaging mitochondrial ROS, which not only causes oxidative stress and injury, but also activates signaling mechanisms to counteract those induced by IH. After numerous episodes, occurring within minutes of each other, a “critical” point is achieved where the mechanisms induced by IH become indistinguishable from those induced by IHR .
The merging of the above mechanisms has profound deleterious effects on mitochondrial homeostasis and redox state . IH is inflammatory and can lead to impairment of multiple neonatal systems including the brain , liver , and kidneys [23‒25]; the latter two are major sites of drug metabolism and excretion. This is especially important since ELGANs are exposed to numerous drugs during the first few weeks of life. Due to its relatively high lipid content and ability to produce ROS, the liver is uniquely susceptible to lipid peroxidation (a self-propagating chain reaction that involves hydrogen peroxide reacting with elemental iron to form the hydroxyl radical) and IH injury . Studies have shown that IH impairs drug metabolizing ability of several commonly used drugs in the NICU, including gentamicin, phenobarbital, acetaminophen, and theophylline , which lead to substantial variation in pharmacokinetic profiles and drug responses in ELGANs [27, 28].
3. MITOCHONDRIA AND ROS
Mitochondria are present in each cell’s cytoplasm. The total number per cell varies from less than a hundred up to several thousand, depending on the amount of energy required by the cell . Mitochondria participate in intracellular signaling, apoptosis, and in the metabolism of amino acids, lipids, cholesterol, steroids, and nucleotides. However, the primary role of mitochondria is the generation of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS) and oxygen consumption. Therefore, mitochondria are important oxygen sensors. During normoxia, energy from ATP is produced in the mitochondrial respiratory chain, a group of five enzyme complexes situated on the inner mitochondrial membrane . Reduced cofactors (NADH and FADH2) generated from the metabolism of carbohydrates, proteins, and fats donate electrons to complex I and complex II. These electrons flow between the complexes down an electrochemical gradient shuttled by complexes III and IV and by two mobile electron carriers, ubiquinone (ubiquinol, coenzyme Q10) and cytochrome c. The liberated energy is used by complexes I, III, and IV to pump protons out of the mitochondrial matrix into the intermembrane space. This proton gradient is harnessed by complex V to synthesize ATP from adenosine diphosphate (ADP) and inorganic phosphate [30‒33]. The process of OXPHOS depends critically on the integrity and impermeability of the inner mitochondrial membrane; defects in the complexes, cofactors, or the machinery that transcribes, assembles, and maintains them result in interruptions of mitochondrial ATP supply .
Mitochondrial respiration accounts for about 90% of cellular oxygen uptake, and 1‒2% of the oxygen consumed is converted to ROS [34, 35]. The factors that control ROS production include the oxygen availability to the mitochondria, the redox state of the mitochondrial complexes, and mitochondrial membrane potential . In addition to its role in energy production, mitochondrion is the major producer of ROS , and a prime target for the damaging effect of ROS . The principal ROS is superoxide anion (O2˙ˉ) which is rapidly dismutated to the more stable hydrogen peroxide (H2O2) and O2, generated as byproducts of normal aerobic metabolism . Although complexes I and III are main sites of mitochondrial O2˙ˉ/H2O2 production, complex III is the major source during oxidative stress [40‒42]. Under physiological conditions O2˙ˉ/H2O2 serves to communicate between mitochondria and the rest of the cell  whereas under hypoxic conditions, the ROS are released resulting in the stabilization of hypoxia inducible factors (HIFs) and the induction of genes responsible for metabolic adaptation to low oxygen . It has become increasingly clear that ROS are produced not only during IHR, but also during ischemia [45‒47] and hypoxia. During ischemia O2˙ˉ/H2O2 levels increase, antioxidant defenses are overwhelmed, and other ROS are formed by ROS-induced ROS release [39, 48]. The source of O2˙ˉ/H2O2 generation during cell hypoxia is likely complex III . O2˙ˉ/H2O2 generated at complex III would be released into the inner mitochondrial membrane rather than into the matrix as H2O2 is readily permeable to the inner mitochondrial membrane [50, 51]. This leads to opening of the mitochondrial permeability transition pore  and initiation of apoptosis . Therefore, it is the stable and membrane-permeable H2O2 that is the most abundant reactant that, in excess, likely leads to damage to cell structure and function. Indeed, H2O2 is central to the tissue and organ damage in oxidative stress and injury.
4. ROS AND ANTIOXIDANTS
ROS are scavenged by mitochondrial, cytosolic, and peroxisomal antioxidant systems including superoxide dismutases (SODs). SODs are the primary ROS-detoxifying enzymes , and 3 types exist in the cell: copper- and zinc-containing SOD (Cu,ZnSOD, or SOD1), manganese-containing SOD (MnSOD, or SOD2), and extracellular SOD (ECSOD, or SOD3) . SOD1 is found primarily in the cytoplasm . SOD3 is localized to the extracellular region . SOD2 is found exclusively in the mitochondrial matrix [57, 58]. All 3 forms of SOD catalyze the dismutation of O2˙ˉ into H2O2 and O2. SOD does not prevent the formation of H2O2, and in some cases, can actually enhance H2O2 production. H2O2 is one of the most abundant ROS , and being membrane permeable, it easily and rapidly diffuses through biological membranes by using water channels, or aquaporins [51, 60]. H2O2 is tightly regulated and is the only ROS that requires several enzymes for deactivation and removal. Under physiological conditions it acts as a second messenger and modulator of cell signaling , allowing the mitochondria to act as oxygen sensors .
Although a therapeutic goal may be to reduce ROS, particularly during oxidative stress, too much scavenging or the wrong kind of scavenging may eradicate protective physiological mechanisms. We reported that administration the SOD mimetic, MnTBAP alone actually worsened OIR in rats , suggesting that overexpression of these enzyme systems could lead to excessive H2O2. Because ROS also play a significant physiological role, the effects may be deleterious. For example, SOD activity is dynamically regulated within optimal ranges—the lower limit is sufficient to remove mitochondrial O2˙ˉ production and the upper limit is kept low enough to avoid excess H2O2 production . SOD expression is induced or suppressed to match ROS production, such that more ROS lead to more SOD, more SOD leads to more H2O2. The cell uses multiple enzyme systems to catalyze the decomposition of H2O2 into water and O2. One involves glutathione peroxidase (GPx), two forms of which have been identified in mitochondria [65, 66]. Catalase is another important enzyme used by cells to decompose H2O2 [67, 68]. Catalase converts two molecules of H2O2 into two molecules of H2O and one molecule of O2, and therefore, catalase works best with high concentrations of H2O2 . Catalase is found primarily in peroxisomes, but can also be found in the cytoplasm. Peroxidases are responsible for the detoxification of up to 90% of mitochondrial H2O2 and even more than that of cytosolic H2O2 [69, 70].
Antioxidant systems are compromised in ELGANs who require oxygen therapy . Immature antioxidant systems can lead to H2O2 accumulation in the mitochondria and subsequent accumulation in the cytosol. Many critically ill oxygen-exposed ELGANs require blood transfusion for anemia which gives them a large dose of iron; H2O2 accumulation will likely react with iron to form the highly reactive hydroxyl radical which damages cellular components such as proteins, lipids, and DNA [72, 73] resulting in defects in signaling pathways . Diverting iron to the path of erythropoiesis using recombinant human erythropoietin (EPO) has been shown to decreases oxidant injury in premature rabbits . H2O2 and hydroxyl radicals readily attack the polyunsaturated fatty acids of the fatty acid membrane in the retina, initiating a self-propagating chain reaction, a key mechanism underpinning the development of severe ROP .
5. ROS AND HIF1α
Mitochondria are natural O2 sensors because complex IV is where O2 binding and O2 consumption occur , and O2 sensing by the cell is actually carried out by ROS [78‒80]. Therefore, ROS are not only deleterious, but are essential participants in cell signaling [81‒83]. For example, H2O2 are principal regulators of the HIF family of transcription factors [78‒80, 84‒86]. H2O2 damages DNA, cellular membranes, and organelles resulting in autophagy and HIF activation [87‒89]. H2O2 is a master regulator of oxidative stress-induced endothelial cell dysfunction. It has been referred to as the “fertilizer” of cancer metabolism . If the accumulation of H2O2 is not limited, it can diffuse to the cytosol or participate in a chain of reactions that generate more ROS, and/or activate and stabilize HIF1α [78, 91, 92]. Both HIF1α and HIF2α can be modified by ROS in a direct and indirect manner . Both HIF1α and HIF2α could be prevented from hydroxylation and degradation by increasing ROS generation. Therefore, ROS are important regulators of the HIF system, and the crosstalk between ROS and HIF is an important pathophysiological link [91, 93, 94].
HIF1α is a transcription factor that regulates the cellular response to O2 homeostasis. HIF1α upregulates the expression of many genes including those responsible for angiogenesis, glycolysis, cell growth, cell survival, and metastasis [95, 96]. When O2 is adequate, HIF1α is hydroxylated by prolyl hydroxylase domain-containing proteins (PHDs). Upon hydroxylation, HIF1α binds to the Von Hippel-Lindau tumor suppressor protein (pVHL) which leads to its ubiquitination and subsequent degradation [97‒99]. During hypoxia, the energy for hydroxylation and ubiquitination is inadequate in the cell and HIF1α does not bind to pVHL. Thus, it stabilizes, accumulates, and translocates to the nucleus where it binds to the hypoxia responsive elements (HREs) within about 100‒200 genes including vascular endothelial growth factor (VEGF) and EPO , initiating their expression and activation of glycolysis, angiogenesis, and erythropoiesis [95‒103]. In order to activate gene transcription, HIF recruits a range of gene-specific co-factors that acetylate histones, change chromatin structure, and facilitate epigenetic modifications . Multiple studies have demonstrated that ROS regulate the hypoxia signal transduction pathway that mediates HIF-1α stabilization [105‒107]. During reoxygenation following an IH episode, or IHR a cascade of events occur leading to hemorrhage and cell death. Hemorrhage occurs as a result of restitution of flow through severely injured microvasculature allowing leakage of intravascular fluids and cells into interstitial spaces. We have shown this phenomenon in our oxygen-induced retinopathy model [19, 63, 108, 109], suggesting that IHR accelerates cell injury.
6. ROS AND RETINOPATHY OF PREMATURITY
ROP is a leading cause of childhood blindness worldwide. In the United States, approximately 16,000 preterm infants develop ROP annually, and with improving neonatal care and survival of ELGANs, the incidence is rising in developing countries [110, 111]. ROP is a developmental vascular disorder characterized by abnormal growth of retinal blood vessels in the incompletely vascularized retina of ELGANs [112‒114]. It is especially severe in the sickest, most immature infant requiring long-term mechanical ventilation and oxygen therapy. The incidence of severe ROP varies from 33% to 50% at 23 weeks of gestation, 13% to 23% at 24 weeks of gestation, and 9% to 17% at 25 weeks of gestation . The incidence of detached retinas and blindness has not appreciably declined, and only 20% of infants with threshold ROP achieve normal vision despite early treatment. Early studies by Ashton et al. [116‒118] demonstrated that exposure to oxygen causes vaso-obliteration and vaso-proliferation when room air breathing is resumed. Those early studies led to a two-phase hypothesis of ROP where vaso-obliteration or phase 1 begins at preterm birth with the transition from an intrauterine to extrauterine environment causing a rise in PaO2 of 30‒35 mm Hg to 55‒80 mmHg and loss of placental and maternal growth factors. During this phase, exposure to supplemental oxygen, suppresses retinal growth factors such as VEGF, insulin-like growth factor (IGF)-1 and EPO, which are already compromised due to preterm birth and poor nutrition  leading to arrest and retraction of the developing retinal vessels. This is followed by vaso-proliferation or phase 2 which begins at approximately 32‒34 weeks . As the infant matures, the avascular retina becomes metabolically active, inducing a second phase of retinal neovascularization . This phase of ROP is driven by hypoxia and subsequent upregulation of VEGF and IGF-1 which leads to abnormal vascular overgrowth into the vitreous, retinal hemorrhages, retinal folds, dilated, and tortuous posterior retinal blood vessels, or “Plus” disease, and retinal detachment .
With advancement in neonatal care, not only has ROP been eradicated in those relatively more mature preterm infants (>31 weeks), but survival of ELGANs increased, leading to a “new” form of ROP that involves AOP with IH and IHR. The retina is one of the highest oxygen-consuming tissues of the body, exceeding even that of the brain [123‒125]. This high energy demand requires abundant numbers of mitochondria per cell  and the highest amount of mitochondria are in the photoreceptors. Defects in energy metabolism lead to visual deficits and blindness. The immature retina of ELGANs is hypersensitive to any disturbances or changes in oxygen , and it is now widely accepted that ROP is a disease resulting from oxidative stress [127‒129]. Studies have shown that the vaso-obliterative phase of ROP may not only be caused by the lack of angiogenic factors, but also by endothelial cell damage due to increased levels of ROS [130‒132]. The high susceptibility of the immature retina to ROS is further accentuated by compromised autoregulation of the retinal blood flow , high rate of oxidative metabolism, significant stores of free iron that react with H2O2 by the Fenton reaction to form the highly reactive hydroxyl radicals that lead to lipid peroxidation [134‒137]. Developmental deficiencies in defenses against ROS during neonatal IH also account for neonatal oxidative injuries [71, 138]. Specifically, high levels of H2O2 stabilize HIF1α and activate nuclear factor kappa B (NFkB) which promotes aberrant angiogenesis, neovascularization, and inflammation [57, 68, 77, 79].
Using a new paradigm that encompasses the strengths of the previous paradigm, we established different patterns of IH episodes and the outcome of severe OIR. The data showed that clustered IH episodes produced a more severe form of OIR than regularly dispersed IH episodes . This finding was later corroborated in ELGANs . In this model, grouping desaturations with minimal time for recovery between episodes caused the retina to remain hypoxic for a longer period of time. Timely treatment is difficult and may add to the reduction in therapeutic potential of drugs when administered in IHR. This led us to the question of how many IH episodes (or desaturations) can the immature retina sustain before a “point of no return” is achieved such that the retina is not responsive to treatment, and therefore, not salvageable. We discovered that the maximum number of clustered IH episodes that the rat retina can sustain before irreparable damage is achieved is 6. This was associated with accumulation of H2O2, SOD, and HIF1α accumulation during IHR . Our unique model consistently resulted in severe OIR retinal hemorrhage, enlarged vessels, vascular tufts, vascular tortuosity, and vascular overgrowth [19, 63, 108, 109, 139]. Retinal hemorrhage occurring during IHR may be the result of restitution of blood flow through severely injured microvasculature allowing leakage of intravascular fluids and cells into interstitial spaces . Each preceding episode contributed to limited recovery from the following episode, thus setting the stage for the irreparable damage. In addition to these classic ROP characteristics, this model produced persistence of hyaloid vessels, chronic gliosis, and retinal folds or rosettes, in the photoreceptor layer, and possibly retinal detachment. Using this IH/IHR model, we administered a MnSOD mimetic (MnTBAP) to rats during early postnatal life to determine whether exogenous SOD in IH is protective. We found that high doses of MnTBAP caused severe OIR during IHR . This was associated with modifications of many genes that regulate OXPHOS. These findings suggested that exogenous SOD alone is not protective, but instead may actually induce ROS. As a follow-up, we examined whether co-administration of MnTBAP with catalase would improve H2O2 scavenging and ameliorate oxidative stress in human retinal endothelial cells. Our findings indicate that catalase or MnTBAP alone provided better protection than their co-administration (EUK-134) for HIF1α and VEGF reduction . Collectively, our studies provide evidence that oxidative stress and ROS, particularly H2O2, are important regulators of IH and IHR-induced OIR, and that the molecular links between IH (and IHR), ROS and HIF1α involve regulation of MnSOD.
ROP is a marker of a much more sinister neonatal long term outcome. Motor impairment, cognitive impairment, and severe hearing loss were 3 to 4 times more common in children with severe ROP than those without . The complex and multifactorial etiology of ROP precludes the use of a single therapeutic agent, as no one therapy has proven to be effective without adverse effects. These drugs act through different mechanisms and synergistic approaches should be considered to target oxidative stress and ROS accumulation, as well as the inflammatory mechanisms associated with ROP. Caffeine citrate, which is used worldwide and is standard of care for AOP [143, 144] has been shown to have antioxidant properties , to significantly reduce the incidence of severe ROP , and to normalize aberrant retinal proteomic profiles in OIR . Non-steroidal anti-inflammatory drugs (NSAIDs) have also been shown to reduce the incidence of ROP . Caffeine and NSAID synergism was protective against severe OIR using our IH/IHR model . This novel therapeutic approach to prevent and/or reduce severe ROP should be precisely timed to coincide with the “window” of ROS production. From our data, it is clear that H2O2 overproduction must be curtailed, or be disposed efficiently to prevent the downstream effects that lead to retinal neovascularization. The use of safe and effective pharmacological strategies targeting various biochemical and molecular pathways must be implemented to ultimately prevent severe ROP and avert a lifetime of blindness and severe neurocognitive impairment.
This work was supported by the NIH‒Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA (Grant No.1U54HD071594).
- McCrea HJ, Ment LR. The diagnosis, management, and postnatal prevention of intraventricular hemorrhage in the preterm neonate. Clin Perinatol 2008; 35(4):777‒92, vii. doi: 10.1016/j.clp.2008.07.014.
- Folkerth RD, Trachtenberg FL, Haynes RL. Oxidative injury in the cerebral cortex and subplate neurons in periventricular leukomalacia. J Neuropathol Exp Neurol 2008; 67(7):677‒86. doi: 10.1097/NEN.0b013e31817e5c5e.
- Martin RJ, Wang K, Koroglu O, Di Fiore J, Kc P. Intermittent hypoxic episodes in preterm infants: do they matter? Neonatology 2011; 100(3):303‒10. doi: 10.1159/000329922.
- Martin RJ, Di Fiore JM, Walsh MC. Hypoxic episodes in bronchopulmonary dysplasia. Clin Perinatol 2015; 42(4):825‒38. doi: 10.1016/j.clp.2015.08.009.
- Ahmad A, Cai CL, Kumar D, Cai F, D’Souza A, Fordjour L, et al. Benefits of pre-, pro- and syn-biotics for lung angiogenesis in malnutritional rats exposed to intermittent hypoxia. Am J Transl Res 2014; 6(5):459‒70.
- Chang M, Bany-Mohammed F, Kenney MC, Beharry KD. Effects of a superoxide dismutase mimetic on biomarkers of lung angiogenesis and alveolarization during hyperoxia with intermittent hypoxia. Am J Transl Res 2013; 5(6):594‒607.
- Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011; 364(3):255‒64. doi: 10.1056/NEJMra1005408.
- York JR, Landers S, Kirby RS, Arbogast PG, Penn JS. Arterial oxygen fluctuation and retinopathy of prematurity in very-low-birth-weight infants. J Perinatol 2004; 24(2):82‒7. doi: 10.1038/sj.jp.7211040.
- Di Fiore JM, Bloom JN, Orge F, Schutt A, Schluchter M, Cheruvu VK, et al. A higher incidence of intermittent hypoxemic episodes is associated with severe retinopathy of prematurity. J Pediatr 2010; 157(1):69‒73. doi: 10.1016/j.jpeds.2010.01.046.
- Di Fiore JM, Kaffashi F, Loparo K, Sattar A, Schluchter M, Foglyano R, et al. The relationship between patterns of intermittent hypoxia and retinopathy of prematurity in preterm infants. Pediatr Res 2012; 72(6):606‒12. doi: 10.1038/pr.2012.132.
- Saugstad OD. The oxygen radical disease in neonatology. Indian J Pediatr 1989; 56(5):585‒93.
- Saugstad OD. Update on oxygen radical disease in neonatology. Curr Opin Obstet Gynecol 2001; 13(2):147‒53.
- Di Fiore JM, Martin RJ, Gauda EB. Apnea of prematurity: perfect storm. Respir Physiol Neurobiol 2013; 189(2):213‒22. doi: 10.1016/j.resp.2013.05.026.
- Zhao J, Gonzalez F, Mu D. Apnea of prematurity: from cause to treatment. Eur J Pediatr 2011; 170(9):1097‒105. doi: 10.1007/s00431-011-1409-6.
- Upton CJ, Milner AD, Stokes GM. Apnoea, bradycardia, and oxygen saturation in preterm infants. Arch Dis Child 1991; 66(4 Spec No):381‒5.
- Rhein LM, Dobson NR, Darnall RA, Corwin MJ, Heeren TC, Poets CF, et al. Effects of caffeine on intermittent hypoxia in infants born prematurely: a randomized clinical trial. JAMA Pediatr 2014; 168(3):250‒7. doi: 10.1001/jamapediatrics.2013.4371.
- Stokowski LA. A primer on apnea of prematurity. Adv Neonatal Care 2005; 5(3):155‒70; quiz 71‒4.
- Martin RJ, Di Fiore JM, Macfarlane PM, Wilson CG. Physiologic basis for intermittent hypoxic episodes in preterm infants. Adv Exp Med Biol 2012; 758:351‒8. doi: 10.1007/978-94-007-4584-1_47.
- Beharry KD, Cai CL, Sharma P, Bronshtein V, Valencia GB, Lazzaro DR, et al. Hydrogen peroxide accumulation in the choroid during intermittent hypoxia increases risk of severe oxygen-induced retinopathy in neonatal rats. Invest Ophthalmol Vis Sci 2013; 54(12):7644‒57. doi: 10.1167/iovs.13-13040.
- Gao J, Ding XS, Zhang YM, Dai DZ, Liu M, Zhang C, et al. Hypoxia/oxidative stress alters the pharmacokinetics of CPU86017-RS through mitochondrial dysfunction and NADPH oxidase activation. Acta Pharmacol Sin 2013; 34(12):1575‒84. doi: 10.1038/aps.2013.94.
- Niatsetskaya ZV, Sosunov SA, Matsiukevich D, Utkina-Sosunova IV, Ratner VI, Starkov AA, et al. The oxygen free radicals originating from mitochondrial complex I contribute to oxidative brain injury following hypoxia-ischemia in neonatal mice. J Neurosci 2012; 32(9):3235‒44. doi: 10.1523/JNEUROSCI.6303-11.2012.
- Feng SZ, Tian JL, Zhang Q, Wang H, Sun N, Zhang Y, et al. An experimental research on chronic intermittent hypoxia leading to liver injury. Sleep Breath 2011; 15(3):493‒502. doi: 10.1007/s11325-010-0370-3.
- Jun J, Savransky V, Nanayakkara A, Bevans S, Li J, Smith PL, et al. Intermittent hypoxia has organ-specific effects on oxidative stress. Am J Physiol Regul Integr Comp Physiol 2008; 295(4):R1274‒81. doi: 10.1152/ajpregu.90346.2008.
- Soukhova-O’Hare GK, Roberts AM, Gozal D. Impaired control of renal sympathetic nerve activity following neonatal intermittent hypoxia in rats. Neurosci Lett 2006; 399(3):181‒5. doi: 10.1016/j.neulet.2006.01.054.
- Wu H, Zhou S, Kong L, Chen J, Feng W, Cai J, et al. Metallothionein deletion exacerbates intermittent hypoxia-induced renal injury in mice. Toxicol Lett 2015; 232(2):340‒8. doi: 10.1016/j.toxlet.2014.11.015.
- Chen XY, Zeng YM, Zhang YX, Wang WY, Wu RH. Effect of chronic intermittent hypoxia on theophylline metabolism in mouse liver. Chin Med J (Engl) 2013; 126(1):118‒23.
- Aranda JV, MacLeod SM, Renton KW, Eade NR. Hepatic microsomal drug oxidation and electron transport in newborn infants. J Pediatr 1974; 85(4):534‒42.
- Allegaert K, Rayyan M, Vanhaesebrouck S, Naulaers G. Developmental pharmacokinetics in neonates. Expert Rev Clin Pharmacol 2008; 1(3):415‒28. doi: 10.1586/175124220.127.116.115.
- Chinnery PF, Schon EA. Mitochondria. J Neurol Neurosurg Psychiatry 2003; 74(9):1188‒99.
- Koene S, Smeitink J. Mitochondrial medicine: entering the era of treatment. J Intern Med 2009; 265(2):193‒209. doi: 10.1111/j.1365-2796.2008.02058.x.
- Zeviani M, Di Donato S. Mitochondrial disorders. Brain 2004; 127(Pt 10):2153‒72. doi: 10.1093/brain/awh259.
- Fraser JA, Biousse V, Newman NJ. The neuro-ophthalmology of mitochondrial disease. Surv Ophthalmol 2010; 55(4):299‒334. doi: 10.1016/j.survophthal.2009.10.002.
- Kluge MA, Fetterman JL, Vita JA. Mitochondria and endothelial function. Circ Res 2013; 112(8):1171‒88. doi: 10.1161/CIRCRESAHA.111.300233.
- Papa S. Mitochondrial oxidative phosphorylation changes in the life span: molecular aspects and physiopathological implications. Biochim Biophys Acta 1996; 1276(2):87‒105.
- Boveris A, Oshino N, Chance B. The cellular production of hydrogen peroxide. Biochem J 1972; 128(3):617‒30.
- Murphy MP. How mitochondria produce reactive oxygen species. Biochem J 2009; 417(1):1‒13. doi: 10.1042/BJ20081386.
- Ambrosio G, Zweier JL, Duilio C, Kuppusamy P, Santoro G, Elia PP, et al. Evidence that mitochondrial respiration is a source of potentially toxic oxygen free radicals in intact rabbit hearts subjected to ischemia and reflow. J Biol Chem 1993; 268(25):18532‒41.
- Orrenius S. Reactive oxygen species in mitochondria-mediated cell death. Drug Metab Rev 2007; 39(2‒3):443‒55. doi: 10.1080/03602530701468516.
- Chance B, Sies H, Boveris A. Hydroperoxide metabolism in mammalian organs. Physiol Rev 1979; 59(3):527‒605.
- Muller F. The nature and mechanism of superoxide production by the electron transport chain: its relevance to aging. J Am Aging Assoc 2000; 23(4):227‒53. doi: 10.1007/s11357-000-0022-9.
- Barja G. Mitochondrial oxygen radical generation and leak: sites of production in states 4 and 3, organ specificity, and relation to aging and longevity. J Bioenerg Biomembr 1999; 31(4):347‒66.
- Votyakova TV, Reynolds IJ. DeltaPsi(m)-Dependent and -independent production of reactive oxygen species by rat brain mitochondria. J Neurochem 2001; 79(2):266‒77.
- Chandel NS. Mitochondria as signaling organelles. BMC Biol 2014; 12:34. doi: 10.1186/1741-7007-12-34.
- Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci USA 1998; 95(20):11715‒20.
- Becker LB, vanden Hoek TL, Shao ZH, Li CQ, Schumacker PT. Generation of superoxide in cardiomyocytes during ischemia before reperfusion. Am J Physiol 1999; 277(6 Pt 2):H2240‒6.
- Camara AK, Aldakkak M, Heisner JS, Rhodes SS, Riess ML, An J, et al. ROS scavenging before 27 degrees C ischemia protects hearts and reduces mitochondrial ROS, Ca2+ overload, and changes in redox state. Am J Physiol Cell Physiol 2007; 292(6):C2021‒31. doi: 10.1152/ajpcell.00231.2006.
- Kevin LG, Camara AK, Riess ML, Novalija E, Stowe DF. Ischemic preconditioning alters real-time measure of O2 radicals in intact hearts with ischemia and reperfusion. Am J Physiol Heart Circ Physiol 2003; 284(2):H566‒74. doi: 10.1152/ajpheart.00711.2002.
- Naqui A, Chance B, Cadenas E. Reactive oxygen intermediates in biochemistry. Annu Rev Biochem 1986; 55:137‒66. doi: 10.1146/annurev.bi.55.070186.001033.
- Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev 2014; 94(3):909‒50. doi: 10.1152/physrev.00026.2013.
- Bienert GP, Moller AL, Kristiansen KA, Schulz A, Moller IM, Schjoerring JK, et al. Specific aquaporins facilitate the diffusion of hydrogen peroxide across membranes. J Biol Chem 2007; 282(2):1183‒92. doi: 10.1074/jbc.M603761200.
- Bienert GP, Schjoerring JK, Jahn TP. Membrane transport of hydrogen peroxide. Biochim Biophys Acta 2006; 1758(8):994‒1003. doi: 10.1016/j.bbamem.2006.02.015.
- Zorov DB, Filburn CR, Klotz LO, Zweier JL, Sollott SJ. Reactive oxygen species (ROS)-induced ROS release: a new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. J Exp Med 2000; 192(7):1001‒14.
- Ricci JE, Gottlieb RA, Green DR. Caspase-mediated loss of mitochondrial function and generation of reactive oxygen species during apoptosis. J Cell Biol 2003; 160(1):65‒75. doi: 10.1083/jcb.200208089.
- Holley AK, St Clair DK. Watching the watcher: regulation of p53 by mitochondria. Future Oncol 2009; 5(1):117‒30. doi: 10.2217/14796618.104.22.168.
- Zelko IN, Mariani TJ, Folz RJ. Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med 2002; 33(3):337‒49.
- Hjalmarsson K, Marklund SL, Engstrom A, Edlund T. Isolation and sequence of complementary DNA encoding human extracellular superoxide dismutase. Proc Natl Acad Sci USA 1987; 84(18):6340‒4.
- Okado-Matsumoto A, Fridovich I. Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu,Zn-SOD in mitochondria. J Biol Chem 2001; 276(42):38388‒93. doi: 10.1074/jbc.M105395200.
- Weisiger RA, Fridovich I. Mitochondrial superoxide simutase: site of synthesis and intramitochondrial localization. J Biol Chem 1973; 248(13):4793‒6.
- Bulkley GB. Free radical-mediated reperfusion injury: a selective review. Br J Cancer Suppl 1987; 8:66‒73.
- Bienert GP, Chaumont F. Aquaporin-facilitated transmembrane diffusion of hydrogen peroxide. Biochim Biophys Acta 2014; 1840(5):1596‒604. doi: 10.1016/j.bbagen.2013.09.017.
- Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol 2012; 298:229‒317. doi: 10.1016/B978-0-12-394309-5.00006-7.
- Nemoto S, Takeda K, Yu ZX, Ferrans VJ, Finkel T. Role for mitochondrial oxidants as regulators of cellular metabolism. Mol Cell Biol 2000; 20(19):7311‒8.
- Jivabhai Patel S, Bany-Mohammed F, McNally L, Valencia GB, Lazzaro DR, Aranda JV, et al. Exogenous superoxide dismutase mimetic without scavenging H2O2 causes photoreceptor damage in a rat model for oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 2015; 56(3):1665‒77. doi: 10.1167/iovs.14-15321.
- Archer SL, Gomberg-Maitland M, Maitland ML, Rich S, Garcia JG, Weir EK. Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1alpha-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer. Am J Physiol Heart Circ Physiol 2008; 294(2):H570‒8. doi: 10.1152/ajpheart.01324.2007.
- Esworthy RS, Ho YS, Chu FF. The Gpx1 gene encodes mitochondrial glutathione peroxidase in the mouse liver. Arch Biochem Biophys 1997; 340(1):59‒63. doi: 10.1006/abbi.1997.9901.
- Maiorino M, Scapin M, Ursini F, Biasolo M, Bosello V, Flohe L. Distinct promoters determine alternative transcription of gpx-4 into phospholipid-hydroperoxide glutathione peroxidase variants. J Biol Chem 2003; 278(36):34286‒90. doi: 10.1074/jbc.M305327200.
- Chelikani P, Fita I, Loewen PC. Diversity of structures and properties among catalases. Cell Mol Life Sci 2004; 61(2):192‒208. doi: 10.1007/s00018-003-3206-5.
- Zamocky M, Furtmuller PG, Obinger C. Evolution of catalases from bacteria to humans. Antioxid Redox Signal 2008; 10(9):1527‒48. doi: 10.1089/ars.2008.2046.
- Cox AG, Winterbourn CC, Hampton MB. Measuring the redox state of cellular peroxiredoxins by immunoblotting. Methods Enzymol 2010; 474:51‒66. doi: 10.1016/S0076-6879(10)74004-0.
- Winterbourn CC. Reconciling the chemistry and biology of reactive oxygen species. Nat Chem Biol 2008; 4(5):278‒86. doi: 10.1038/nchembio.85.
- Inayat M, Bany-Mohammed F, Valencia A, Tay C, Jacinto J, Aranda JV, et al. Antioxidants and biomarkers of oxidative stress in preterm infants with symptomatic patent ductus arteriosus. Am J Perinatol 2015; 32(9):895‒904. doi: 10.1055/s-0035-1544948.
- Qutub AA, Popel AS. Reactive oxygen species regulate hypoxia-inducible factor 1alpha differentially in cancer and ischemia. Mol Cell Biol 2008; 28(16):5106‒19. doi: 10.1128/MCB.00060-08.
- Mari M, Morales A, Colell A, Garcia-Ruiz C, Fernandez-Checa JC. Mitochondrial glutathione, a key survival antioxidant. Antioxid Redox Signal 2009; 11(11):2685-700. doi: 10.1089/ARS.2009.2695.
- Vercellotti GM, Severson SP, Duane P, Moldow CF. Hydrogen peroxide alters signal transduction in human endothelial cells. J Lab Clin Med 1991; 117(1):15‒24.
- Bany-Mohammed FM, Slivka S, Hallman M. Recombinant human erythropoietin: possible role as an antioxidant in premature rabbits. Pediatr Res 1996; 40(3):381‒7. doi: 10.1203/00006450-199609000-00003.
- Rivera JC, Sapieha P, Joyal JS, Duhamel F, Shao Z, Sitaras N, et al. Understanding retinopathy of prematurity: update on pathogenesis. Neonatology 2011; 100(4):343‒53. doi: 10.1159/000330174.
- Stowe DF, Camara AK. Mitochondrial reactive oxygen species production in excitable cells: modulators of mitochondrial and cell function. Antioxid Redox Signal 2009; 11(6):1373‒414. doi: 10.1089/ARS.2008.2331.
- Brunelle JK, Bell EL, Quesada NM, Vercauteren K, Tiranti V, Zeviani M, et al. Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. Cell Metab 2005; 1(6):409‒14. doi: 10.1016/j.cmet.2005.05.002.
- Bell EL, Emerling BM, Chandel NS. Mitochondrial regulation of oxygen sensing. Mitochondrion 2005; 5(5):322‒32. doi: 10.1016/j.mito.2005.06.005.
- Mansfield KD, Guzy RD, Pan Y, Young RM, Cash TP, Schumacker PT, et al. Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. Cell Metab 2005; 1(6):393‒9. doi: 10.1016/j.cmet.2005.05.003.
- Droge W. Free radicals in the physiological control of cell function. Physiol Rev 2002; 82(1):47‒95. doi: 10.1152/physrev.00018.2001.
- Fruehauf JP, Meyskens FL, Jr. Reactive oxygen species: a breath of life or death? Clin Cancer Res 2007; 13(3):789‒94. doi: 10.1158/1078-0432.CCR-06-2082.
- Hool LC. Reactive oxygen species in cardiac signalling: from mitochondria to plasma membrane ion channels. Clin Exp Pharmacol Physiol 2006; 33(1‒2):146‒51. doi: 10.1111/j.1440-1681.2006.04341.x.
- Kietzmann T, Gorlach A. Reactive oxygen species in the control of hypoxia-inducible factor-mediated gene expression. Semin Cell Dev Biol 2005; 16(4‒5):474‒86. doi: 10.1016/j.semcdb.2005.03.010.
- Semenza GL. Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1. Biochem J 2007; 405(1):1‒9. doi: 10.1042/BJ20070389.
- Semenza GL. Surviving ischemia: adaptive responses mediated by hypoxia-inducible factor 1. J Clin Invest 2000; 106(7):809‒12. doi: 10.1172/JCI11223.
- Dai DF, Rabinovitch P. Mitochondrial oxidative stress mediates induction of autophagy and hypertrophy in angiotensin-II treated mouse hearts. Autophagy 2011; 7(8):917‒8.
- Roszkowski K, Jozwicki W, Blaszczyk P, Mucha-Malecka A, Siomek A. Oxidative damage DNA: 8-oxoGua and 8-oxodG as molecular markers of cancer. Med Sci Monit 2011; 17(6):CR329‒33.
- Martinez-Outschoorn UE, Trimmer C, Lin Z, Whitaker-Menezes D, Chiavarina B, Zhou J, et al. Autophagy in cancer associated fibroblasts promotes tumor cell survival: role of hypoxia, HIF1 induction and NFkappaB activation in the tumor stromal microenvironment. Cell Cycle 2010; 9(17):3515‒33. doi: 10.4161/cc.9.17.12928.
- Lisanti MP, Martinez-Outschoorn UE, Lin Z, Pavlides S, Whitaker-Menezes D, Pestell RG, et al. Hydrogen peroxide fuels aging, inflammation, cancer metabolism and metastasis: the seed and soil also needs “fertilizer”. Cell Cycle 2011; 10(15):2440‒9. doi: 10.4161/cc.10.15.16870.
- Guzy RD, Hoyos B, Robin E, Chen H, Liu L, Mansfield KD, et al. Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab 2005; 1(6):401‒8. doi: 10.1016/j.cmet.2005.05.001.
- Kaelin WG, Jr. ROS: really involved in oxygen sensing. Cell Metab 2005; 1(6):357‒8. doi: 10.1016/j.cmet.2005.05.006.
- Gorlach A. Regulation of HIF-1alpha at the transcriptional level. Curr Pharm Des 2009; 15(33):3844‒52.
- Paddenberg R, Goldenberg A, Faulhammer P, Braun-Dullaeus RC, Kummer W. Mitochondrial complex II is essential for hypoxia-induced ROS generation and vasoconstriction in the pulmonary vasculature. Adv Exp Med Biol 2003; 536:163‒9.
- Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 1999; 15:551‒78. doi: 10.1146/annurev.cellbio.15.1.551.
- Wenger RH. Mammalian oxygen sensing, signalling and gene regulation. J Exp Biol 2000; 203(Pt 8):1253‒63.
- Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001; 292(5516):468‒72. doi: 10.1126/science.1059796.
- Kallio PJ, Wilson WJ, O’Brien S, Makino Y, Poellinger L. Regulation of the hypoxia-inducible transcription factor 1alpha by the ubiquitin-proteasome pathway. J Biol Chem 1999; 274(10):6519‒25.
- Tanimoto K, Makino Y, Pereira T, Poellinger L. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J 2000; 19(16):4298‒309. doi: 10.1093/emboj/19.16.4298.
- Nilsson I, Shibuya M, Wennstrom S. Differential activation of vascular genes by hypoxia in primary endothelial cells. Exp Cell Res 2004; 299(2):476‒85. doi: 10.1016/j.yexcr.2004.06.005.
- Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992; 359(6398):843‒5. doi: 10.1038/359843a0.
- Mazure NM, Chen EY, Yeh P, Laderoute KR, Giaccia AJ. Oncogenic transformation and hypoxia synergistically act to modulate vascular endothelial growth factor expression. Cancer Res 1996; 56(15):3436‒40.
- Harris AL. Hypoxia: a key regulatory factor in tumour growth. Nat Rev Cancer 2002; 2(1):38‒47. doi: 10.1038/nrc704.
- Perez-Perri JI, Acevedo JM, Wappner P. Epigenetics: new questions on the response to hypoxia. Int J Mol Sci 2011; 12(7):4705‒21. doi: 10.3390/ijms12074705.
- Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem 2000; 275(33):25130‒8. doi: 10.1074/jbc.M001914200.
- Schroedl C, McClintock DS, Budinger GR, Chandel NS. Hypoxic but not anoxic stabilization of HIF-1alpha requires mitochondrial reactive oxygen species. Am J Physiol Lung Cell Mol Physiol 2002; 283(5):L922‒31. doi: 10.1152/ajplung.00014.2002.
- Park JH, Kim TY, Jong HS, Kim TY, Chun YS, Park JW, et al. Gastric epithelial reactive oxygen species prevent normoxic degradation of hypoxia-inducible factor-1alpha in gastric cancer cells. Clin Cancer Res 2003; 9(1):433‒40.
- Coleman RJ, Beharry KD, Brock RS, Abad-Santos P, Abad-Santos M, Modanlou HD. Effects of brief, clustered versus dispersed hypoxic episodes on systemic and ocular growth factors in a rat model of oxygen-induced retinopathy. Pediatr Res 2008; 64(1):50‒5. doi: 10.1203/PDR.0b013e31817307ac.
- Brock RS, Gebrekristos BH, Kuniyoshi KM, Modanlou HD, Falcao MC, Beharry KD. Biomolecular effects of JB1 (an IGF-I peptide analog) in a rat model of oxygen-induced retinopathy. Pediatr Res 2011; 69(2):135‒41. doi: 10.1203/PDR.0b013e318204e6fa.
- Gilbert C, Fielder A, Gordillo L, Quinn G, Semiglia R, Visintin P, et al. Characteristics of infants with severe retinopathy of prematurity in countries with low, moderate, and high levels of development: implications for screening programs. Pediatrics 2005; 115(5):e518‒25. doi: 10.1542/peds.2004-1180.
- Kong L, Fry M, Al-Samarraie M, Gilbert C, Steinkuller PG. An update on progress and the changing epidemiology of causes of childhood blindness worldwide. J AAPOS 2012; 16(6):501‒7. doi: 10.1016/j.jaapos.2012.09.004.
- Chow LC, Wright KW, Sola A, Group COAS. Can changes in clinical practice decrease the incidence of severe retinopathy of prematurity in very low birth weight infants? Pediatrics 2003; 111(2):339‒45.
- Smith LE. Pathogenesis of retinopathy of prematurity. Growth Horm IGF Res 2004; 14 Suppl A:S140‒4. doi: 10.1016/j.ghir.2004.03.030.
- Cringle SJ, Yu DY. Oxygen supply and consumption in the retina: implications for studies of retinopathy of prematurity. Doc Ophthalmol 2010; 120(1):99‒109. doi: 10.1007/s10633-009-9197-2.
- Keith CG, Doyle LW. Retinopathy of prematurity in extremely low birth weight infants. Pediatrics 1995; 95(1):42‒5.
- Ashton N. Pathological basis of retrolental fibroplasia. Br J Ophthalmol 1954; 38(7):385‒96.
- Ashton N, Cook C. Direct observation of the effect of oxygen on developing vessels: preliminary report. Br J Ophthalmol 1954; 38(7):433‒40.
- Ashton N, Ward B, Serpell G. Effect of oxygen on developing retinal vessels with particular reference to the problem of retrolental fibroplasia. Br J Ophthalmol 1954; 38(7):397‒432.
- Raghuveer TS, Bloom BT. A paradigm shift in the prevention of retinopathy of prematurity. Neonatology 2011; 100(2):116‒29. doi: 10.1159/000322848.
- Chen J, Smith LE. Retinopathy of prematurity. Angiogenesis 2007; 10(2):133‒40. doi: 10.1007/s10456-007-9066-0.
- Smith LE. Pathogenesis of retinopathy of prematurity. Semin Neonatol 2003; 8(6):469‒73. doi: 10.1016/S1084-2756(03)00119-2.
- Chan-Ling T, Gock B, Stone J. The effect of oxygen on vasoformative cell division: evidence that ‘physiological hypoxia’ is the stimulus for normal retinal vasculogenesis. Invest Ophthalmol Vis Sci 1995; 36(7):1201‒14.
- Ames A, 3rd, Li YY, Heher EC, Kimble CR. Energy metabolism of rabbit retina as related to function: high cost of Na+ transport. J Neurosci 1992; 12(3):840‒53.
- Anderson B, Jr., Saltzman HA. Retinal oxygen utilization measured by hyperbaric blackout. Arch Ophthalmol 1964; 72:792‒5.
- Yu DY, Cringle SJ. Oxygen distribution and consumption within the retina in vascularised and avascular retinas and in animal models of retinal disease. Prog Retin Eye Res 2001; 20(2):175‒208.
- Brennan LA, Kantorow M. Mitochondrial function and redox control in the aging eye: role of MsrA and other repair systems in cataract and macular degenerations. Exp Eye Res 2009; 88(2):195‒203. doi: 10.1016/j.exer.2008.05.018.
- Hardy P, Beauchamp M, Sennlaub F, Gobeil F, Jr., Tremblay L, Mwaikambo B, et al. New insights into the retinal circulation: inflammatory lipid mediators in ischemic retinopathy. Prostaglandins Leukot Essent Fatty Acids 2005; 72(5):301‒25. doi: 10.1016/j.plefa.2005.02.004.
- Penn JS, Henry MM, Tolman BL. Exposure to alternating hypoxia and hyperoxia causes severe proliferative retinopathy in the newborn rat. Pediatr Res 1994; 36(6):724‒31. doi: 10.1203/00006450-199412000-00007.
- Penn JS, Henry MM, Wall PT, Tolman BL. The range of PaO2 variation determines the severity of oxygen-induced retinopathy in newborn rats. Invest Ophthalmol Vis Sci 1995; 36(10):2063‒70.
- Niesman MR, Johnson KA, Penn JS. Therapeutic effect of liposomal superoxide dismutase in an animal model of retinopathy of prematurity. Neurochem Res 1997; 22(5):597‒605.
- Penn JS, Tolman BL, Bullard LE. Effect of a water-soluble vitamin E analog, trolox C, on retinal vascular development in an animal model of retinopathy of prematurity. Free Radic Biol Med 1997; 22(6):977‒84.
- Raju TN, Langenberg P, Bhutani V, Quinn GE. Vitamin E prophylaxis to reduce retinopathy of prematurity: a reappraisal of published trials. J Pediatr 1997; 131(6):844‒50.
- Hardy P, Abran D, Li DY, Fernandez H, Varma DR, Chemtob S. Free radicals in retinal and choroidal blood flow autoregulation in the piglet: interaction with prostaglandins. Invest Ophthalmol Vis Sci 1994; 35(2):580‒91.
- Yoon JH, Lee MS, Kang JH. Reaction of ferritin with hydrogen peroxide induces lipid peroxidation. BMB Rep 2010; 43(3):219‒24.
- Kobayashi S, Ueda K, Komano T. The effects of metal ions on the DNA damage induced by hydrogen peroxide. Agric Biol Chem 1990; 54(1):69‒76.
- Minotti G, Aust SD. The requirement for iron (III) in the initiation of lipid peroxidation by iron (II) and hydrogen peroxide. J Biol Chem 1987; 262(3):1098‒104.
- Braughler JM, Duncan LA, Chase RL. The involvement of iron in lipid peroxidation: importance of ferric to ferrous ratios in initiation. J Biol Chem 1986; 261(22):10282‒9.
- Abdel Ghany EA, Alsharany W, Ali AA, Younass ER, Hussein JS. Anti-oxidant profiles and markers of oxidative stress in preterm neonates. Paediatr Int Child Health 2016. doi: 10.1080/20469047.2015.1109248.
- Aranda JV, Cai CL, Ahmad T, Bronshtein V, Sadeh J, Valencia GB, et al. Pharmacologic synergism of ocular ketorolac and systemic caffeine citrate in rat oxygen-induced retinopathy. Pediatr Res 2016; 80(4):554‒65. doi: 10.1038/pr.2016.105.
- Fishbein MC. Reperfusion injury. Clin Cardiol 1990; 13(3):213‒7.
- Quan M, Cai CL, Valencia GB, Aranda JV, Beharry KD. MnTBAP or catalase is more protective against oxidative stress in human retinal endothelial cells exposed to intermittent hypoxia than their co-administration (EUK-134). Reactive Oxygen Species 2016; 3(7):xxx‒xxx. doi: 10.20455/ros.2017.801.
- Chiang MF, Arons RR, Flynn JT, Starren JB. Incidence of retinopathy of prematurity from 1996 to 2000: analysis of a comprehensive New York state patient database. Ophthalmology 2004; 111(7):1317‒25. doi: 10.1016/j.ophtha.2003.10.030.
- Aranda JV, Gorman W, Bergsteinsson H, Gunn T. Efficacy of caffeine in treatment of apnea in the low-birth-weight infant. J Pediatr 1977; 90(3):467‒72.
- Aranda JV, Beharry K, Valencia GB, Natarajan G, Davis J. Caffeine impact on neonatal morbidities. J Matern Fetal Neonatal Med 2010; 23 Suppl 3:20‒3. doi: 10.3109/14767058.2010.517704.
- Varma SD, Hegde KR. Prevention of oxidative damage to lens by caffeine. J Ocul Pharmacol Ther 2010; 26(1):73‒7. doi: 10.1089/jop.2009.0097.
- Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al. Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med 2007; 357(19):1893‒902. doi: 10.1056/NEJMoa073679.
- Tu C, Beharry KD, Shen X, Li J, Wang L, Aranda JV, et al. Proteomic profiling of the retinas in a neonatal rat model of oxygen-induced retinopathy with a reproducible ion-current-based MS1 approach. J Proteome Res 2015; 14(5):2109‒20. doi: 10.1021/pr501238m.
- Avila-Vazquez M, Maffrand R, Sosa M, Franco M, De Alvarez BV, Cafferata ML, et al. Treatment of retinopathy of prematurity with topical ketorolac tromethamine: a preliminary study. BMC Pediatr 2004; 4:15. doi: 10.1186/1471-2431-4-15.