Signaling pathways triggered by oxidative stress that mediate features of severe retinopathy of prematurity

Jama Ophthalmology (Impact Factor: 3.83). 01/2013; 131(1):80-5. DOI: 10.1001/jamaophthalmol.2013.986
Source: PubMed

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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    ABSTRACT: Purpose. To study the effect of systemic hypoxia inducible factor prolyl hydroxylase inhibition (HIF PHDi) in the rat 50/10 oxygen-induced retinopathy (OIR) model. Methods. Oxygen induced retinopathy was created with the rat 50/10 OIR model. OIR animals received intraperitoneal injections of dimethyloxalylglycine (DMOG, 200μg/g), an antagonist of α-ketoglutarate cofactor and inhibitor for HIF PHD, on P3, P5, and P7. Control animals received intraperitoneal injections of PBS. On P14 and P21, animals were sacrificed and the effect on vascular obliteration, tortuosity, and neovascularization quantified. To analyze HIF and erythropoietin, rats at P5 were injected with DMOG (200 μg/g). Western blot or ELISA measured the levels of HIF-1 and Epo protein. Epo mRNA was measured by quantitative PCR. Results. Alternating hyperoxia/hypoxia in untreated rats led to peripheral vascular obliteration on day P14 and P21. Rats that were treated with systemic DMOG by intraperitoneal injections had 3 times less ischemia and greater peripheral vascularity (p=0.001) than control animals treated with PBS injections. Neovascularization similarly decreased by a factor of 3 (p=0.0002). Intraperitoneal DMOG administration increased the levels of HIF and Epo in the liver and brain. Serum Epo also increased 6-fold (p=0.0016). Systemic DMOG had no adverse effect on growth of rats treated with oxygen. Conclusion. One of the many controversies in the study of ROP is whether hyperoxia or alternating hyperoxia/hypoxia creates the disease phenotype in humans. We have previously demonstrated that PHDi prevents OIR in mice exposed to 5 days of sustained 75% oxygen followed by 5 days of 21% oxygen. The 50/10 rat experiments demonstrate that PHDi is also effective in a 24-h alternating hyperoxia/hypoxia model. The rat OIR model further validates the therapeutic value of HIF PHDi to prevent retinopathy of prematurity, because it reduces oxygen-induced vascular obliteration and retinovascular growth attenuation in prolonged and/or alternating hyperoxia.
    Investigative ophthalmology & visual science 06/2013; 54(7). DOI:10.1167/iovs.13-12171 · 3.66 Impact Factor
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    ABSTRACT: Retinopathy of prematurity (ROP) is a potentially blinding disorder in premature infants. The underlying pathophysiology is incompletely understood, limiting the prevention and treatment of this devastating condition. Current therapies are directed toward management of aberrant neovascularization thought to result from retinal ischemia in the developing preterm retina. The molecular mediators important for development of retinal ischemia and subsequent neovascular pathology are not fully understood. However, oxygen has been shown to be a key mediator of disease and the oxygen environment for preterm infants has been extensively studied. Despite this, the optimal oxygen environment for preterm infants remains unclear and recent works seeking to clarify this relationship demonstrate somewhat disparate findings. These data further substantiate that ROP is a complex disease with multifactorial etiology including genetic and environmental factors. Therefore, while environmental factors such as oxygen are important to our understanding of the disease process and care of preterm infants, identification of the molecular mediators downstream of oxygen which are necessary for development of ROP pathology will be critical to improve prevention, diagnosis and treatment strategies.
    Journal of Ophthalmic & Vision Research 01/2014; 9(1):94-100.
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    ABSTRACT: Purpose Resuscitation of newborns is one of the most frequent procedures in neonatal medicine. The use of supplementary oxygen during resuscitation of the asphyxiated newborn has been shown to be detrimental to vulnerable tissues. We wanted to assess transcriptional changes in ocular tissue after the acute use of oxygen in the delivery room in a hypoxia-reoxygenation model of the newborn mouse. Methods C57BL/6 mice (n = 57) postnatal day seven were randomized to either 120-minutes of hypoxia 8 % O2 followed by 30-minutes of reoxygenation with 21, 40, 60 or 100 % O2, or to normoxia followed by 30-minutes of 21 or 100 % O2. Whole ocular homogenates were analyzed by Affymetrix 750k expression array, and RT-PCR was performed for validation. Bayesian analysis of variance for microarray data (BAMarray) was used to identify single significant genes and Gene Set Enrichment Analysis (GSEA) to reveal significant pathway systems. Results In total, ~ 92% of the gene expression changes were altered in response to reoxygenation with 60 or 100% O2 compared to when lower percentages, 21 and 40% were applied. After 100% O2-treatment genes involved in inflammation (Ccl12), angiogenesis (Igfr1, Stat3) and metabolism (Hk2) were upregulated. Pathway analyses after hypoxia-reoxygenation revealed significant alterations of six pathways which included Apoptosis, TGF-beta signaling, Oxidative phosphorylation, Voltage-gated calcium channel complex, Mitochondrion, and Regulation of RAS protein signal transduction. Conclusions Hypoxia-reoxygenation can induce immediate transcriptional responses in ocular tissue involving inflammation, angiogenesis, energy failure, and Ras-signaling.
    Investigative ophthalmology & visual science 01/2014; 55(3). DOI:10.1167/iovs.13-13159 · 3.66 Impact Factor
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