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Cung T, Wang H, Hartnett ME. The Effects of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Erythropoietin, and Their Interactions in Angiogenesis: Implications in Retinopathy of Prematurity. Cells 2022; 11:cells11121951. [PMID: 35741081 PMCID: PMC9222209 DOI: 10.3390/cells11121951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 06/07/2022] [Accepted: 06/10/2022] [Indexed: 01/27/2023] Open
Abstract
Retinopathy of prematurity (ROP) is a leading cause of vision impairment and blindness in premature infants. Oxidative stress is implicated in its pathophysiology. NADPH oxidase (NOX), a major enzyme responsible for reactive oxygen species (ROS) generation in endothelial cells, has been studied for its involvement in physiologic and pathologic angiogenesis. Erythropoietin (EPO) has gained interest recently due to its tissue protective and angiogenic effects, and it has been shown to act as an antioxidant. In this review, we summarize studies performed over the last five years regarding the role of various NOXs in physiologic and pathologic angiogenesis. We also discuss the effect of EPO in tissue and vasoprotection, and the intersection of EPO and NOX-mediated oxidative stress in angiogenesis and the pathophysiology of ROP.
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Romero-Maldonado S, Montoya-Estrada A, Reyes-Muñoz E, Guzmán-Grenfell AM, Torres-Ramos YD, Sánchez-Mendez MD, Tolentino-Dolores M, Salgado-Valladares MB, Belmont-Gómez A, Najéra N, Ceballos G, Cardona-Pérez JA, Hicks JJ, Mancilla-Ramírez J. Efficacy of water-based vitamin E solution versus placebo in the prevention of retinopathy of prematurity in very low birth weight infants: A randomized clinical trial. Medicine (Baltimore) 2021; 100:e26765. [PMID: 34397821 PMCID: PMC8341298 DOI: 10.1097/md.0000000000026765] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 06/02/2021] [Accepted: 07/06/2021] [Indexed: 01/04/2023] Open
Abstract
Background: Vitamin E has antioxidant properties, which help in scavenging free radicals, thereby reducing oxidation of lipids and proteins. This study aims to evaluate the efficacy of oral vitamin E supplementation in preventing retinopathy of prematurity (ROP) in very low birth weight (VLBW) infants with respiratory distress syndrome (RDS) and decreasing oxidative stress 15 and 28 days post-intervention. Methods: Ninety VLBW infants were randomly assigned to two groups: Each group received 25 IU of vitamin E (T) or placebo (C). Results: The incidence of ROP in groups T and C was 12.5% (n=6) and 31% (n = 13), respectively (RR: 0.40; 95% CI: 0.10–0.96). There were no differences in mortality between groups. As expected, the vitamin E concentration was significantly increased 28 days post-intervention in group T. Conclusion: Oral supplementation with vitamin E may effectively prevent ROP development in VLBW infants with RDS. Oxidative damage markers were significantly lower, whereas total antioxidant capacity was increased in group T. However, levels of other antioxidants as vitamin A and C were not measured in two groups.
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Affiliation(s)
- Silvia Romero-Maldonado
- Unidad de Cuidados Intermedios al Recién Nacido (UCIREN), Instituto Nacional de Perinatología, Isidro Espinosa de los Reyes (INPerIER), Mexico City, Mexico
- Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
| | | | - Enrique Reyes-Muñoz
- Departamento de Endocrinología Ginecológica y Perinatal, Mexico City, Mexico
| | | | | | - Mario David Sánchez-Mendez
- Unidad de Cuidados Intermedios al Recién Nacido (UCIREN), Instituto Nacional de Perinatología, Isidro Espinosa de los Reyes (INPerIER), Mexico City, Mexico
| | | | | | - Aurora Belmont-Gómez
- Coordinación de Farmacología Clínica, Instituto Nacional de Perinatología Isidro Espinosa de los Reyes (INPerIER), Mexico City, Mexico
| | - Nayelli Najéra
- Departamento de Posgrado e investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Guillermo Ceballos
- Departamento de Posgrado e investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Jorge Arturo Cardona-Pérez
- Dirección General, Instituto Nacional de Perinatología, Isidro Espinosa de los Reyes (INPerIER), Mexico City, Mexico
| | - Juan José Hicks
- Dirección General de Políticas de Investigación en Salud, Comisión Coordinadora de Institutos Nacionales de Salud y Hospitales de Alta Especialidad, Secretaria de Salud, Mexico City, Mexico
| | - Javier Mancilla-Ramírez
- Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
- Jefatura de Investigación, Hospital de la Mujer, Secretaria de Salud, Mexico City, Mexico
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Bumetanide Suppression of Angiogenesis in a Rat Model of Oxygen-Induced Retinopathy. Int J Mol Sci 2020; 21:ijms21030987. [PMID: 32024231 PMCID: PMC7037744 DOI: 10.3390/ijms21030987] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 01/24/2020] [Accepted: 01/29/2020] [Indexed: 12/18/2022] Open
Abstract
Aquaporins (AQPs) are involved in hypoxia-induced angiogenesis and retinal damage. Bumetanide is a diuretic agent, Na+/K+/Cl− cotransporter (NKCC1), and AQP 1–4 inhibitor. We tested the hypothesis that early postnatal treatment with bumetanide suppresses biomarkers of angiogenesis and decreases severe retinopathy oxygen-induced retinopathy (OIR). Neonatal rats were exposed at birth (P0) to either (1) room air (RA); (2) hyperoxia (50% O2); or (3) intermittent hypoxia (IH) consisting of 50% O2 with brief, clustered episodes of 12% O2 from P0 to postnatal day 14 (P14), during which they were treated intraperitoneally (IP) with bumetanide (0.1 mg/kg/day) or an equivalent volume of saline, on P0–P2. Pups were examined at P14 or allowed to recover in RA from P14–P21. Retinal angiogenesis, morphometry, pathology, AQPs, and angiogenesis biomarkers were determined at P14 and P21. Bumetanide reduced vascular abnormalities associated with severe OIR. This was associated with reductions in AQP-4 and VEGF. Bumetanide suppressed sVEGFR-1 in the serum and vitreous fluid, but levels were increased in the ocular tissues during recovery. Similar responses were noted for IGF-I. In this model, early systemic bumetanide administration reduces severe OIR, the benefits of which appear to be mediated via suppression of AQP-4 and VEGF. Further studies are needed to determine whether bumetanide at the right doses may be considered a potential pharmacologic agent to treat retinal neovascularization.
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Zhang HB, Wang XD, Xu K, Li XG. The progress of prophylactic treatment in retinopathy of prematurity. Int J Ophthalmol 2018; 11:858-873. [PMID: 29862189 DOI: 10.18240/ijo.2018.05.24] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 09/28/2017] [Indexed: 12/19/2022] Open
Abstract
Retinopathy of prematurity (ROP) is a retinal vascular disorder frequently found in premature infants. Different therapeutic strategies have been developed to treat ROP. However, there are still many children with ROP suffering by severe limitations in vision or even blindness. Recently, ROP has been suggested to be caused by abnormal development of the retinal vasculature, but not simply resulted by retinal neovascularization which takes about 4 to 6wk after birth in premature infants. Thus, instead of focusing on how to reduce retinal neovascularization, understanding the pathological changes and mechanisms that occur prior to retinal neovascularization is meaningful, which may lead to identify novel target(s) for the development of novel strategy to promote the healthy growth of retinal blood vessels rather than passively waiting for the appearance of retinal neovascularization and removing it by force. In this review, we discussed recent studies about, 1) the pathogenesis prior to retinal neovascularization in oxygen-induced retinopathy (OIR; a ROP in animal model) and in premature infants with ROP; 2) the preclinical and clinical research on preventive treatment of early OIR and ROP. We will not only highlight the importance of the mechanisms and signalling pathways in regulating early stage of ROP but also will provide guidance for actively exploring novel mechanisms and discovering novel treatments for early phase OIR and ROP prior to retinal neovascularization in the future.
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Affiliation(s)
- Hong-Bing Zhang
- Eye Institute of Shaanxi Province; Xi'an First Hospital, Xi'an 710002, Shaanxi Province, China
| | - Xiao-Dong Wang
- Eye Institute of Shaanxi Province; Xi'an First Hospital, Xi'an 710002, Shaanxi Province, China
| | - Kun Xu
- Eye Institute of Shaanxi Province; Xi'an First Hospital, Xi'an 710002, Shaanxi Province, China
| | - Xiao-Gang Li
- Department of Internal Medicine; Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
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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 (APEX, N.C.) 2017; 3:47-65. [PMID: 29806034 PMCID: PMC5967656 DOI: 10.20455/ros.2017.801] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Retinopathy of prematurity is a blinding disease that affects extremely low gestational age neonates. Its etiology is due to extrauterinehyperoxia in an immature antioxidant system culminating as oxidative stress on the retina. Our aim is to elucidate the role of pharmacological antioxidants in modulating the biochemical and molecular response of human retinal microvascular endothelial cells (HRECs) exposed to oxidative stress. HRECs were treated with MnTBAP [a superoxide dismutase (SOD) mimetic], catalase, EUK-134 (SOD + catalase), or saline prior to exposure to normoxia (Nx), hyperoxia (Hx), or intermittent hypoxia (IH). Media levels of SOD, catalase, glutathione peroxidase (GPx), 8-isoPGF2α, and H2O2; cellular SOD and catalase; cellular function (migration and tube formation); and antioxidant gene expression were assessed. Pharmacological antioxidants had delayed suppressive effect on 8-isoPGF2α. MnTBAP and catalase were more effective for H2O2 scavenging in the media than co-administration in the form of EUK-134. A delayed response was noted in SOD and catalase media activity in MnTBAP- and catalase-treated cells, respectively in 50% and IH. MnTBAP had progressively increased media GPx in all oxygen conditions. Antioxidants resulted in normal, but more abundant tubulogenesis in IH and Hx. The distinct temporal response to oxidative stress reflected the respective antioxidant's potency and catalytic properties. The cell permeability of the antioxidants limited the ability to scavenge intracellular free radicals. The results support that MnTBAP or catalase may be more effective for the prevention of oxidative stress in oxygen-induced retinopathy.
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Affiliation(s)
- Michelle Quan
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
| | - Charles L Cai
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
| | - Gloria B Valencia
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
| | - Jacob V Aranda
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
- Department of Ophthalmology, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
- SUNY Eye Institute, New York, NY, USA
| | - Kay D Beharry
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
- Department of Ophthalmology, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
- SUNY Eye Institute, New York, NY, USA
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Hartnett ME. Vascular endothelial growth factor antagonist therapy for retinopathy of prematurity. Clin Perinatol 2014; 41:925-43. [PMID: 25459781 PMCID: PMC4254506 DOI: 10.1016/j.clp.2014.08.011] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
In this article, the growing problem of retinopathy of prematurity (ROP) worldwide, treatments for severe ROP including standard-of-care laser treatment, and the need for new treatments are discussed. Also discussed are the reasons to consider inhibiting the vascular endothelial growth factor (VEGF) signaling pathway in severe ROP and the concerns about broad VEGF inhibition. Finally, the potential role of VEGF in ROP based on studies in animal models of oxygen-induced retinopathy, the effects of anti-VEGF based on basic research data, and the clinical relevance of these data are covered.
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Affiliation(s)
- M. Elizabeth Hartnett
- Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, 65 Mario Capecchi Dr., SLC, Ut, 84108, 801-213-4152
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Temporal quantification of oxygen saturation ranges: an effort to reduce hyperoxia in the neonatal intensive care unit. J Perinatol 2014; 34:33-8. [PMID: 24071904 DOI: 10.1038/jp.2013.122] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Revised: 07/29/2013] [Accepted: 08/26/2013] [Indexed: 11/09/2022]
Abstract
OBJECTIVE To reduce exposure to hyperoxia and its associated morbidities in preterm neonates. STUDY DESIGN A multidisciplinary group was established to evaluate oxygen exposure in our neonatal intensive care unit. Infants were assigned target saturation ranges and signal extraction technology implemented to temporally quantify achievement of these ranges. The outcomes bronchopulmonary dysplasia/death, retinopathy of prematurity (ROP)/death, severe ROP and ROP requiring surgery were compared in a pre- versus post-intervention evaluation using multivariate analyses. RESULT A total of 304 very low birth weight pre-initiative infants were compared with 396 post-initiative infants. Multivariate analyses revealed decreased odds of severe ROP (adjusted odds ratio (OR): 0.41; 95% confidence interval (CI): 0.24-0.72) and ROP requiring surgery (adjusted OR 0.31; 95% CI: 0.17-0.59) post-initiative. No differences in death were observed. CONCLUSION Significant reductions in severe ROP and ROP requiring surgery were observed after staff education and implementation of new technology to quantify success in achieving targeted saturations and reinforce principles and practices.
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Mutinati M, Pantaleo M, Roncetti M, Piccinno M, Rizzo A, Sciorsci RL. Oxidative stress in neonatology: a review. Reprod Domest Anim 2013; 49:7-16. [PMID: 24112309 DOI: 10.1111/rda.12230] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Accepted: 07/30/2013] [Indexed: 11/30/2022]
Abstract
Free radicals are highly reactive oxidizing agents containing one or more unpaired electrons. Both in human and veterinary neonathology, it is generally accepted that oxidative stress functions as an important catalysator of neonatal disease. Soon after birth, many sudden physiological and environmental conditions make the newborn vulnerable for the negative effects of oxidative stress, which potentially can impair neonatal vitality. As a clinician, it is important to have in depth knowledge about factors affecting maternal/neonatal oxidative status and the cascades of events that enrol when the neonate is subjected to oxidative stress. This report aims at providing clinicians with an up-to-date review about oxidative stress in neonates across animal species. It will be emphasized which handlings and treatments that are applied during neonatal care or resuscitation can actually impose oxidative stress upon the neonate. Views and opinions about maternal and/or neonatal antioxydative therapy will be shared.
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Affiliation(s)
- M Mutinati
- Department of Emergency and Organ Transplantation (D.E.T.O.), University of Bari "Aldo Moro", Valenzano (BA), Italy
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Abstract
Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are the leading causes of blindness in adults. The impact of these conditions on the quality of life is increasing in significance with a rise in life expectancy. The role of hyperglycemia, oxidative stress and inflammatory responses in the development and/or progression of DR and AMD, and several other sight threatening ocular diseases, is well established. In proliferative retinopathy, signals sent by the retina for nourishment, triggers the growth of fragile and abnormal blood vessels. Changes in ocular pressure may lead to rupture of these blood vessels causing severe vision problems. Recent in vitro and preclinical studies demonstrate that certain phytochemicals possessing potent antioxidant and anti-inflammatory activity and ocular blood flow enhancing properties may be very useful in the treatment of, or as a prophylactic measure for, DR and AMD. Apart from these properties they have also been investigated for their anti-bacterial, hormonal, enzyme stimulation, and anti-angiogenic activities. The attractive aspect of these potential therapeutic candidates is that they can act on multiple pathways identified in the etiology of DR, AMD, cataract and other ocular diseases. However, results from clinical trials have been somewhat ambiguous, raising questions about the concentrations of these bioflavonoids achieved in the neural retina following oral administration. Unfortunately, as of date, an efficient noninvasive means to deliver therapeutic agents/candidates to the back-of-the eye is still not available. This review examines some of these promising natural agents and discusses the challenges encountered in delivering them to the posterior segment ocular tissues through the oral route.
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Wang H, Zhang SX, Hartnett ME. Signaling pathways triggered by oxidative stress that mediate features of severe retinopathy of prematurity. JAMA Ophthalmol 2013; 131:80-5. [PMID: 23307212 PMCID: PMC3703446 DOI: 10.1001/jamaophthalmol.2013.986] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Oxidative stress has been implicated in the pathogenesis of retinopathy of prematurity for decades. It is becoming increasingly understood that reactive oxygen species can trigger signaling pathways that have beneficial or pathologic outcomes. Broad inhibition of reactive oxygen species in the preterm infant may lead to unwanted consequences, as has been experienced with vitamin E studies in the past. In this study, we provide a current understanding of the role of oxidative stress in activating signaling pathways that cause pathologic features in severe retinopathy of prematurity as it manifests in the era of oxygen regulation.
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Affiliation(s)
- Haibo Wang
- John A. Moran Eye Center, The University of Utah, 65 N. Mario Capecchi Drive, Salt Lake City, UT
| | - Sarah X Zhang
- Harold Hamm Oklahoma Diabetes and Section of Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Mary Elizabeth Hartnett
- John A. Moran Eye Center, The University of Utah, 65 N. Mario Capecchi Drive, Salt Lake City, UT
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Sandal G, Uras N, Gokmen T, Oguz SS, Erdeve O, Dilmen U. Assessment of oxidant/antioxidant system in newborns and their breast milks. J Matern Fetal Neonatal Med 2012; 26:540-3. [PMID: 23211119 DOI: 10.3109/14767058.2012.717998] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
AIM In this study, it is aimed to investigate total oxidant and antioxidant status of newborns and their breast milks. METHODS Totally, 184 infants who were born in our hospital were included in the study. Study group was divided into two main study groups, including term and preterm groups; main study groups were also divided into two sub-groups, AGA and SGA. TOS and TAC levels were measured in cord blood of all newborns and in mother milks. Groups were statistically compared with each other in terms of TOS, TAC and OSI levels. RESULTS The study included 92 preterm newborns (Group I) and 92 term newborns (Group II). TOS, TAC and OSI levels were found significantly higher in Group I than Group II (p < 0.0001, p = 0.17, p < 0.0001, respectively). When sub-groups of Group I and Group II, namely TAGA, TSGA and PAGA and PSGA, were compared with each other. TOS and OSI levels were significantly higher and TAC levels were significantly lower in TSGA group relative to TAGA group (p < 0.0001; p = 0.001; p < 0.0001, respectively). No statistically significant difference was found between Group I and Group II and between sub-groups of Group I and II with regards the TOC, TAC and OSI levels of mother milk. CONCLUSION In preterm newborns and term SGA infants, total oxidant stress is increased and antioxidant capacity is low. No significant difference was found between mother milks of preterm and term AGA and SGA infants.
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Affiliation(s)
- Gonca Sandal
- Neonatology Department, Zekai Tahir Burak Maternity Teaching Hospital, Altindag, Ankara, Turkey.
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Hypoxia-induced oxidative stress in ischemic retinopathy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2012; 2012:426769. [PMID: 23125893 PMCID: PMC3483772 DOI: 10.1155/2012/426769] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/02/2012] [Revised: 08/24/2012] [Accepted: 09/17/2012] [Indexed: 12/28/2022]
Abstract
Oxidative stress plays a crucial role in the pathogenesis of retinal ischemia/hypoxia, a complication of ocular diseases such as diabetic retinopathy (DR) and retinopathy of prematurity (ROP). Oxidative stress refers to the imbalance between the production of reactive oxygen species (ROS) and the ability to scavenge these ROS by endogenous antioxidative systems. Free radicals and ROS are implicated in the irreversible damage to cell membrane, DNA, and other cellular structures by oxidizing lipids, proteins, and nucleic acids. Anti-oxidants that can inhibit the oxidative processes can protect retinal cells from ischemic/hypoxic insults. In particular, treatment using anti-oxidants such as vitamin E and lutein, inhibition of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) or related signaling pathways, and administration of catalase and superoxide dismutase (SOD) are possible therapeutic regimens for DR, ROP, and other retinal ischemic diseases. The role of oxidative stress in the pathogenesis of DR and ROP as well as the underlying mechanisms involved in the hypoxia/ischemia-induced oxidative damage is discussed. The information provided will be beneficial in understanding the underlying mechanisms involved in the pathogenesis of the diseases as well as in developing effective therapeutic interventions to treat oxidative stress-induced damages.
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Siatkowski RM, Yanovitch TL, Ash JD, Moreau A. The effects of D-penicillamine on a murine model of oxygen-induced retinopathy. J AAPOS 2011; 15:370-3. [PMID: 21907121 PMCID: PMC3644968 DOI: 10.1016/j.jaapos.2011.04.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2010] [Revised: 04/15/2011] [Accepted: 04/20/2011] [Indexed: 01/25/2023]
Abstract
PURPOSE To determine the effect of intraperitoneal and intravitreal D-penicillamine (DPA) on retinal neovascularization in a murine model of oxygen-induced retinopathy. METHODS On postnatal day 7, 16 mice were injected intraperitoneally with 300 mg/kg/day DPA for 3 days followed by 50 mg/kg/day for 7 days. A different group of 7 mice were injected intraperitoneally with 600 mg/kg/day DPA for 3 days followed by 100 mg/kg/day for 7 days. A third group of 14 mice were injected with 1,500 mg/kg/day DPA for 2 days; a control cohort of 17 mice received intraperitoneal phosphate-buffered saline (PBS). An additional 15 mice underwent intravitreal injection of 1 μL of 100 mg/mL DPA in the right eye and 1 μL PBS intravitreally in the left eye as a control. All groups were placed in a 75% oxygen chamber for 7 days then room air for 3 days before being sacrificed and enucleated. The retinas were stained and flat-mounted to determine the severity of retinal neovascularization by quantifying neovascular buds. RESULTS After intraperitoneal injection, the mean number of glomeruli and tubules was similar in the DPA and PBS groups (P = 1.0), regardless of DPA dosage. The dosage of 1,500 mg/kg/day proved to be uniformly lethal. After intravitreal injections, the mean number of glomeruli (P = 0.16) and tubules (P = 0.7) were similar in the DPA and PBS groups. CONCLUSIONS Neither intraperitoneal nor intravitreal injection of DPA inhibits retinal neovascularization in a murine model of oxygen-induced retinopathy.
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Granulocyte colony-stimulating factor attenuates oxidative stress-induced apoptosis in vascular endothelial cells and exhibits functional and morphologic protective effect in oxygen-induced retinopathy. Blood 2010; 117:1091-100. [PMID: 21059898 DOI: 10.1182/blood-2010-05-286963] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Granulocyte colony-stimulating factor (G-CSF) is a known hematopoietic glycoprotein, and recent studies have revealed that G-CSF possesses other interesting properties. Oxidative stress is involved in many diseases, such as atherosclerosis, heart failure, myocardial infarction, Alzheimer disease, and diabetic retinopathy. This study was designed to examine whether G-CSF has a protective effect on endothelial cells against oxidative stress and to investigate whether G-CSF has a therapeutic role in ischemic vascular diseases. Expression of G-CSF (P < .01) and G-CSF receptor (P < .05) mRNA in human retinal endothelial cells (HRECs) was significantly up-regulated by oxidative stress. Treatment with 100 ng/mL G-CSF significantly reduced H(2)O(2)-induced apoptosis in HRECs from 61.7% to 41.4% (P < .05). Akt was phosphorylated in HRECs by G-CSF addition, and LY294002, a PI3K inhibitor, significantly attenuated the antiapoptotic effect of G-CSF (by 44.1%, P < .05). The rescue effect was also observed in human umbilical vein endothelial cells. In mouse oxygen-induced retinopathy model, G-CSF significantly reduced vascular obliteration (P < .01) and neovascular tuft formation (P < .01). G-CSF treatment also clearly rescued the functional and morphologic deterioration of the neural retina. A possibility of a novel therapeutic strategy for ischemic diseases through attenuating vascular regression using G-CSF was proposed.
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Yanni SE, Clark ML, Yang R, Bingaman DP, Penn JS. The effects of nepafenac and amfenac on retinal angiogenesis. Brain Res Bull 2010; 81:310-9. [PMID: 19897019 PMCID: PMC2815002 DOI: 10.1016/j.brainresbull.2009.10.018] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2009] [Revised: 10/11/2009] [Accepted: 10/26/2009] [Indexed: 01/22/2023]
Abstract
PURPOSE Nepafenac is a potent NSAID that rapidly penetrates the eye following topical ocular administration. In the eye, nepafenac is converted to amfenac, which has unique time-dependent inhibitory properties for COX-1 and COX-2. The purpose of the present study was to investigate the capacity of amfenac to inhibit discrete aspects of the angiogenic cascade in vitro, and to test the efficacy of amfenac and nepafenac in vivo, using the rat OIR model. METHODS Müller cells were treated with amfenac, celecoxib (COX-2), or SC-560 (COX-1), and hypoxia-induced VEGF and PGE(2) assessed. Endothelial cells were treated with amfenac, celecoxib, or SC-560, and VEGF-induced proliferation and tube formation assessed. Rat pups were subjected to OIR, received intravitreal injections of amfenac, celecoxib, or SC-560, and neovascularization (NV), prostanoid production, and VEGF assessed. Other OIR-exposed pups were treated with topical nepafenac, ketorolac, or diclofenac, and inhibition of NV assessed. RESULTS Amfenac treatment failed to inhibit hypoxia-induced VEGF production. Amfenac treatment significantly inhibited VEGF-induced tube formation and proliferation by EC. Amfenac treatment significantly reduced retinal prostanoid production and NV in OIR. Nepafenac treatment significantly reduced retinal NV in OIR; ketorolac and diclofenac had no effect. CONCLUSIONS Nepafenac and amfenac inhibit OIR more effectively than the commercially available topical and injectable NSAIDs used in this study. Our data suggests there are COX-dependent and COX-independent mechanisms by which amfenac inhibits OIR. Because it is bioavailable to the posterior segment following topical delivery, nepafenac appears to be a promising advancement in the development of therapies for neovascular eye diseases.
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Affiliation(s)
- Susan E. Yanni
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Monika L. Clark
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Rong Yang
- Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - David P. Bingaman
- Retina Pharmaceutical Research, Alcon Research Ltd., Fort Worth, Texas
| | - John S. Penn
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
- Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee
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16
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Hartnett ME. The effects of oxygen stresses on the development of features of severe retinopathy of prematurity: knowledge from the 50/10 OIR model. Doc Ophthalmol 2010; 120:25-39. [PMID: 19639355 PMCID: PMC3708708 DOI: 10.1007/s10633-009-9181-x] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2009] [Accepted: 06/15/2009] [Indexed: 12/17/2022]
Abstract
The objective of this study is to determine growth factor expression and activation of signaling pathways associated with intravitreous neovascularization and peripheral avascular retina using a model of retinopathy of prematurity (ROP) relevant to today with oxygen monitoring in neonatal units. Studies using 50/10 oxygen-induced retinopathy (OIR) and 50/10 OIR+SO models were reviewed. Repeated fluctuations in oxygen increased retinal vascular endothelial growth factor (VEGF) even while peripheral avascular retina persisted and prior to the development of intravitreous neovascularization. Repeated fluctuations in oxygen increased VEGF(164) expression but not VEGF(120). Neutralizing VEGF bioactivity significantly reduced intravitreous neovascularization and arteriolar tortuosity without interfering with ongoing retinal vascularization. Repeated oxygen fluctuations led to retinal hypoxia and increased reactive oxygen species (ROS). Inhibiting ROS with NADPH oxidase inhibitor, apocynin, reduced avascular retina by interfering with apoptosis. Supplemental oxygen reduced retinal VEGF concentration and exacerbated NADPH oxidase activation to contribute to intravitreous neovascularization through activation of the JAK/STAT pathway. Oxygen stresses relevant to those experienced by preterm infants today trigger signaling of different pathways to cause avascular retina and intravitreous neovascularization. Increased signaling of VEGF appears important to the development of both avascular retina and intravitreous neovascularization.
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Affiliation(s)
- M Elizabeth Hartnett
- Department of Ophthalmology, University of North Carolina, 130 Mason Farm Road, Chapel Hill, NC 27599-7040, USA.
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17
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Byfield G, Budd S, Hartnett ME. The role of supplemental oxygen and JAK/STAT signaling in intravitreous neovascularization in a ROP rat model. Invest Ophthalmol Vis Sci 2009; 50:3360-5. [PMID: 19264880 DOI: 10.1167/iovs.08-3256] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
PURPOSE To investigate whether oxygen stresses experienced in retinopathy of prematurity (ROP) trigger signaling through reactive oxygen species (ROS) and whether the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway lead to intravitreous neovascularization (IVNV) in an oxygen-induced retinopathy (OIR) rat model. METHODS Newborn rat pups exposed to repeated fluctuations in oxygen and rescued in supplemental oxygen (28% O(2), 50/10 OIR+SO) were treated with apocynin, an NADPH oxidase and ROS inhibitor (10 mg/kg/d), AG490, a JAK2 inhibitor (5 mg/kg/d), or phosphate-buffered saline. Intraperitoneal injections were given from postnatal day (P)12 to P17 (apocynin), or from P3 to P17 (AG490). Outcomes were intravitreous neovascularization and avascular/total retinal areas, vascular endothelial growth factor, phosphorylated JAK2, and phosphorylated STAT3. RESULTS Apocynin significantly reduced phosphorylated STAT3 in 50/10 OIR+SO (P = 0.04), in association with previously reported inhibition of the IVNV area. Inhibition of JAK with AG490 significantly reduced phosphorylated JAK2 (P < 0.001), phosphorylated STAT3 (P = 0.002), and IVNV area (P = 0.033) in the 50/10 OIR+SO model compared with control. CONCLUSIONS Activation of NADPH oxidase from supplemental oxygen works through activated STAT3 to lead to IVNV. In addition, inhibition of the JAK/STAT pathway reduces IVNV. Further studies are needed to determine the effects and relationships of oxygen stresses on JAK/STAT and NAPDH oxidase signaling.
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Affiliation(s)
- Grace Byfield
- Department of Ophthalmology, University of North Carolina, Chapel Hill, North Carolina 27599-7041, USA
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18
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The effect of oxygen and light on the structure and function of the neonatal rat retina. Doc Ophthalmol 2008; 118:37-54. [DOI: 10.1007/s10633-008-9128-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2008] [Accepted: 04/07/2008] [Indexed: 10/22/2022]
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19
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Al-Shabrawey M, Bartoli M, El-Remessy AB, Platt DH, Matragoon S, Behzadian MA, Caldwell RW, Caldwell RB. Inhibition of NAD(P)H oxidase activity blocks vascular endothelial growth factor overexpression and neovascularization during ischemic retinopathy. THE AMERICAN JOURNAL OF PATHOLOGY 2005; 167:599-607. [PMID: 16049343 PMCID: PMC1603550 DOI: 10.1016/s0002-9440(10)63001-5] [Citation(s) in RCA: 148] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Because oxidative stress has been strongly implicated in up-regulation of vascular endothelial growth factor (VEGF) expression in ischemic retinopathy, we evaluated the role of NAD(P)H oxidase in causing VEGF overexpression and retinal neovascularization. Dihydroethidium imaging analyses showed increased superoxide formation in areas of retinal neovascularization associated with relative retinal hypoxia in a mouse model for oxygen-induced retinopathy. The effect of hypoxia in stimulating superoxide formation in retinal vascular endothelial cells was confirmed by in vitro chemiluminescence assays. The superoxide formation was blocked by specific inhibitors of NAD(P)H oxidase activity (apocynin, gp91ds-tat) indicating that NAD(P)H oxidase is a major source of superoxide formation. Western blot and immunolocalization analyses showed that retinal ischemia increased expression of the NAD(P)H oxidase catalytic subunit gp91phox, which localized primarily within vascular endothelial cells. Treatment of mice with apocynin blocked ischemia-induced increases in oxidative stress, normalized VEGF expression, and prevented retinal neovascularization. Apocynin and gp91ds-tat also blocked the action of hypoxia in causing increased VEGF expression in vitro, confirming the specific role of NAD(P)H oxidase in hypoxia-induced increases in VEGF expression. In conclusion, NAD(P)H oxidase activity is required for hypoxia-stimulated increases in VEGF expression and retinal neovascularization. Inhibition of NAD(P)H oxidase offers a new therapeutic target for the treatment of retinopathy.
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Affiliation(s)
- Mohamed Al-Shabrawey
- Vascular Biology Center, Medical College of Georgia, 1120 15th St., Augusta, GA 30912-2500, USA
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20
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Beauchamp MH, Sennlaub F, Speranza G, Gobeil F, Checchin D, Kermorvant-Duchemin E, Abran D, Hardy P, Lachapelle P, Varma DR, Chemtob S. Redox-dependent effects of nitric oxide on microvascular integrity in oxygen-induced retinopathy. Free Radic Biol Med 2004; 37:1885-94. [PMID: 15528047 DOI: 10.1016/j.freeradbiomed.2004.09.008] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2004] [Revised: 08/10/2004] [Accepted: 09/02/2004] [Indexed: 11/19/2022]
Abstract
Opposing effects have been ascribed to nitric oxide (NO) on retinal microvascular survival. We investigated whether changes in the redox state may contribute to explain apparent conflicting actions of NO in a model of oxygen-induced retinal vasoobliteration. Retinal microvascular obliteration was induced by exposing 7-day-old rat pups (P7) for 2 or 5 days to 80% O(2). The redox state of the retina was assessed by measuring reduced glutathione and oxidative and nitrosative products malondialdehyde and nitrotyrosine. The role of NO on vasoobliteration was evaluated by treating animals with nitric oxide synthase (NOS) inhibitors (N-nitro-l-arginine; L-NA) and by determining NOS isoform expression and activity; the contribution of nitrosative stress was also determined in animals treated with the degradation catalyst of peroxynitrite FeTPPS or with the superoxide dismutase mimetic CuDIPS. eNOS, but not nNOS or iNOS, expression and activity were increased throughout the exposure to hyperoxia. These changes were associated with an early (2 days hyperoxia) decrease in reduced glutathione and increases in malondialdehyde and nitrotyrosine. CuDIPS, FeTPPS, and L-NA treatments for these 2 days of hyperoxia nearly abolished the vasoobliteration. In contrast, during 5 days exposure to hyperoxia when the redox state rebalanced, L-NA treatment aggravated the vasoobliteration. Interestingly, VEGFR-2 expression was respectively increased by NOS inhibition after short-term (2 days) exposure to hyperoxia and decreased during the longer hyperoxia exposure. Data disclose that the dual effects of NO on newborn retinal microvascular integrity in response to hyperoxia in vivo depend on the redox state and seem mediated at least in part by VEGFR-2.
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Affiliation(s)
- Martin H Beauchamp
- Department of Pediatrics, Ophthalmology, and Pharmacology, Research Center of Hôpital Ste-Justine, Montréal, Québec H3T 1C5, Canada
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Abstract
Free radicals have been implicated in the pathogenesis of a wide spectrum of human diseases. Premature infants are probably developmentally unprepared for extrauterine life in an oxygen-rich environment and exhibit a unique sensitivity to oxidant injury. Diseases associated with premature infants, including bronchopulmonary dysplasia, periventricular leukomalacia, intraventricular hemorrhage, retinopathy of prematurity, and necrotizing enterocolitis, have been linked to free radical-mediated cell and tissue injury. With the advent of therapies designed to combat the injurious effects of free radicals, the role of these highly reactive chemical molecules in the pathogenesis of neonatal diseases needs to be fully determined.
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Affiliation(s)
- Donough J O'Donovan
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
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22
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Siu AW, Reiter RJ, To CH. The efficacy of vitamin E and melatonin as antioxidants against lipid peroxidation in rat retinal homogenates. J Pineal Res 1998; 24:239-44. [PMID: 9572534 DOI: 10.1111/j.1600-079x.1998.tb00539.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Free radical-induced oxidation can cause severe cell damage in biological systems. Melatonin, a pineal secretory product, is a recently identified antioxidant that protects cells from the damaging effects of free radicals. We compared the effect of melatonin and vitamin E, another antioxidant, against lipid peroxidation (LPO) in rat retinal homogenates. The aim was to characterize the antioxidative efficacy of melatonin in retina, a tissue highly susceptible to oxidative damage. The LPO product, malondialdehyde (MDA), was determined to provide an index of cell damage in vitro. After the incubation with iron(II) ions, the free radical scavenging effectiveness of four different concentrations (i.e., 0.5, 1.0, 2.0, and 4.0 mM) of vitamin E and melatonin were determined by comparing the final levels of MDA. Lipid peroxidation product levels were significantly reduced in a dose-response manner by all concentrations of vitamin E. Melatonin, in concentrations of either 2.0 or 4.0 mM, also significantly reduced LPO. Statistical analysis of the data showed that vitamin E treatment always yielded a lower level of LPO products than did the same concentration of melatonin. The concentrations of each agent required to inhibit 50% of the lipid damage (IC50) were 0.69 mM and 4.98 mM for vitamin E and melatonin, respectively. Both vitamin E and melatonin protect the retina against LPO in a dose-dependent manner. Although the IC50 value for melatonin is about 7.2 times higher than that of vitamin E, melatonin's pharmacological and physiological role in the treatment and/or prevention of certain retinal diseases in vivo should be further investigated.
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Affiliation(s)
- A W Siu
- Department of Optometry and Radiography, The Hong Kong Polytechnic University, Hung Hom, Kowloon
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23
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Niesman MR, Johnson KA, Penn JS. Therapeutic effect of liposomal superoxide dismutase in an animal model of retinopathy of prematurity. Neurochem Res 1997. [PMID: 9131639 DOI: 10.1023/a: 1022474120512] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
A newborn rat model of retinopathy of prematurity was used to test the hypothesis that a lack of superoxide dismutase contributes to the retinal vaso-attenuation seen during exposure of the animals to hyperoxic conditions. To determine the endogenous superoxide dismutase activity of the retina under hyperoxic conditions, litters of albino rats were placed in either constant 80% ambient oxygen (constant hyperoxia), or placed in 21% oxygen (room air) immediately after birth. Every other day, for 14 days, several rat pups were sacrificed and their retinas removed for the determination of total superoxide dismutase (SOD) activity and manganese-associated SOD activity. An attempt was made to increase retinal SOD activity by intraperitoneal administration of exogenous SOD encapsulated in polyethylene glycol-modified liposomes. Additional litters were exposed to the same oxygen treatments and supplemented twice daily with either liposome-encapsulated superoxide dismutase in saline or liposomes containing saline without SOD. Animals were sacrificed at various time points for the determination of total superoxide dismutase activity and computer-assisted analysis of vessel density and avascular area. Animals raised in an atmosphere of constant 80% oxygen had significantly reduced levels of retinal superoxide dismutase activity through 6 days of life when compared to their room air-raised littermates. At 6 days of age, daily supplementation with liposome-encapsulated SOD had significantly increased retinal superoxide dismutase activity and reduced oxygen-induced vaso-attenuation as evidenced by increased vessel density and decreased avascular area, when compared to littermates exposed to constant hyperoxia that received control liposomes. Superoxide dismutase had no adverse effects on any of the animals regardless of treatment. Tracing experiments demonstrated that liposomes entered the retina and were found in cells morphologically resembling microglia. Delivery of SOD to the retina via long-circulating liposomes proved beneficial, suggesting that restoration and/or supplementation of endogenous antioxidants in oxygen-damaged retinal tissue is a potentially valuable therapeutic strategy.
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Affiliation(s)
- M R Niesman
- Arkansas Center for Eye Research, University of Arkansas for Medical Sciences, Little Rock 72205, USA
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24
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Niesman MR, Johnson KA, Penn JS. Therapeutic effect of liposomal superoxide dismutase in an animal model of retinopathy of prematurity. Neurochem Res 1997; 22:597-605. [PMID: 9131639 DOI: 10.1023/a:1022474120512] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
A newborn rat model of retinopathy of prematurity was used to test the hypothesis that a lack of superoxide dismutase contributes to the retinal vaso-attenuation seen during exposure of the animals to hyperoxic conditions. To determine the endogenous superoxide dismutase activity of the retina under hyperoxic conditions, litters of albino rats were placed in either constant 80% ambient oxygen (constant hyperoxia), or placed in 21% oxygen (room air) immediately after birth. Every other day, for 14 days, several rat pups were sacrificed and their retinas removed for the determination of total superoxide dismutase (SOD) activity and manganese-associated SOD activity. An attempt was made to increase retinal SOD activity by intraperitoneal administration of exogenous SOD encapsulated in polyethylene glycol-modified liposomes. Additional litters were exposed to the same oxygen treatments and supplemented twice daily with either liposome-encapsulated superoxide dismutase in saline or liposomes containing saline without SOD. Animals were sacrificed at various time points for the determination of total superoxide dismutase activity and computer-assisted analysis of vessel density and avascular area. Animals raised in an atmosphere of constant 80% oxygen had significantly reduced levels of retinal superoxide dismutase activity through 6 days of life when compared to their room air-raised littermates. At 6 days of age, daily supplementation with liposome-encapsulated SOD had significantly increased retinal superoxide dismutase activity and reduced oxygen-induced vaso-attenuation as evidenced by increased vessel density and decreased avascular area, when compared to littermates exposed to constant hyperoxia that received control liposomes. Superoxide dismutase had no adverse effects on any of the animals regardless of treatment. Tracing experiments demonstrated that liposomes entered the retina and were found in cells morphologically resembling microglia. Delivery of SOD to the retina via long-circulating liposomes proved beneficial, suggesting that restoration and/or supplementation of endogenous antioxidants in oxygen-damaged retinal tissue is a potentially valuable therapeutic strategy.
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Affiliation(s)
- M R Niesman
- Arkansas Center for Eye Research, University of Arkansas for Medical Sciences, Little Rock 72205, USA
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25
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Tunçel N, Başmak H, Uzuner K, Tunçel M, Altiokka G, Zaimoğlu V, Ozer A, Gürer F. Protection of rat retina from ischemia-reperfusion injury by vasoactive intestinal peptide (VIP): the effect of VIP on lipid peroxidation and antioxidant enzyme activity of retina and choroid. Ann N Y Acad Sci 1996; 805:489-98. [PMID: 8993429 DOI: 10.1111/j.1749-6632.1996.tb17509.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- N Tunçel
- Department of Physiology, Faculty of Medicine, University of Osmangazi, Eskişehir, Turkey
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26
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Chan-Ling T, Stone J. Chapter 7 Retinopathy of prematurity: Origins in the architecture of the retina. ACTA ACUST UNITED AC 1993. [DOI: 10.1016/0278-4327(93)90008-h] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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