Hypoxia–Reoxygenation Affects Whole-Genome Expression in the Newborn Eye

Wollen, Embjørg J.; Kwinta, Przemko; Bik-Multanowski, Mirosław; Madetko‐Talowska, Anna; Sejersted, Yngve; Wright, Marianne; Günther, Clara‐Cecilie; Nygård, Ståle; Saugstad, Ola Didrik; Pietrzyk, Jacek J

doi:10.1167/iovs.13-13159

Cited by 6 publications

(4 citation statements)

References 44 publications

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“…Perez-Polo and coworkers found a stronger inflammatory response after hyperoxic reoxygenation following HI in rats (24,25). We also found increased protein concentration of CCL12, a proinflammatory chemokine, after hyperoxic reoxygenation, consistent with our recent reports of increased Ccl12 expression in the eye and brain of neonatal mice after hyperoxic reoxygenation (17,26). Mojsilovic-Petrovic et al (27) found increased expression of Ccl12 in astrocyte cultures from P7 mice after hypoxia alone.…”

Section: Igf1rsupporting

confidence: 90%

Increased expression of inflammatory genes in the neonatal mouse brain after hyperoxic reoxygenation

et al. 2014

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Background: Hyperoxic reoxygenation following hypoxia increases the expression of inflammatory genes in the neonatal mouse brain. We have therefore compared the temporal profile of 44 a priori selected genes after hypoxia and hyperoxic or normoxic reoxygenation. Methods: Postnatal day 7 mice were subjected to 2 h of hypoxia (8% O 2 ) and 30 min reoxygenation with 60% or 21% O 2 . After 0 to 72 h observation, mRNA and protein were examined in the hippocampus and striatum. results: There were significantly higher gene expression changes in six genes after hyperoxic compared to normoxic reoxygenation. Three genes had a generally higher expression throughout the observation period: the inflammatory genes Hmox1 (mean difference: 0.52, 95% confidence interval (CI): 0.15-1.01) and Tgfb1 (mean difference: 0.099, CI: 0.003-0.194), and the transcription factor Nfkb1 (mean difference: 0.049, CI: 0.011-0.087). The inflammatory genes Cxcl10 and Il1b, and the DNA repair gene Neil3, had a higher gene expression change after hyperoxic reoxygenation at one time point only. Nineteen genes involved in inflammation, transcription regulation, apoptosis, angiogenesis, and glucose transport had significantly different gene expression changes with time in all intervention animals. conclusion: We confirm that hyperoxic reoxygenation induces a stronger inflammatory gene response than reoxygenation with air.

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Section: Igf1rsupporting

confidence: 90%

Increased expression of inflammatory genes in the neonatal mouse brain after hyperoxic reoxygenation

et al. 2014

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“…A growing body of evidence supports the hypothesis that Ras activation is crucial for retinal neovascularization and targeting Ras kinases directly or indirectly has proven efficacious in animal models of oxygen-induced retinopathy. 21 – 24 Erk and Akt, the principal downstream kinases that mediate Ras signaling, are activated in retinal and nonretinal EC in response to VEGF and their activation is essential for VEGF-induced EC proliferation, migration, and vessel-like network formation. 25 – 28 Further, phosphorylated Erk colocalizes with VEGFR2 in sprouting endothelial cells during retinal neovascularization and pharmacologic inhibition of Erk kinase and the Akt-mTOR pathway suppresses retinal neovascularization during oxygen-induced retinopathy.…”

Section: Discussionmentioning

confidence: 99%

Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization

Zhang

Hudson

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeNeurofibromatosis type 1 (NF1) is the result of inherited mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. Eye manifestations are common in NF1 with recent reports describing a vascular dysplasia in the retina and choroid. Common features of NF1 retinopathy include tortuous and dilated feeder vessels that terminate in capillary tufts, increased endothelial permeability, and neovascularization. Given the retinal vascular phenotype observed in persons with NF1, we hypothesize that preserving neurofibromin may be a novel strategy to control pathologic retinal neovascularization.MethodsNf1 expression in human endothelial cells (EC) was reduced using small hairpin (sh) RNA and EC proliferation, migration, and capacity to form vessel-like networks were assessed in response to VEGF and hypoxia. Wild-type (WT), Nf1 heterozygous (Nf1+/−), and Nf1flox/+;Tie2cre pups were subjected to hyperoxia/hypoxia using the oxygen-induced retinopathy model. Retinas were analyzed quantitatively for extent of retinal vessel dropout, neovascularization, and capillary branching.ResultsNeurofibromin expression was suppressed in response to VEGF, which corresponded with activation of Mek-Erk and PI3-K-Akt signaling. Neurofibromin-deficient EC exhibited enhanced proliferation and network formation in response to VEGF and hypoxia via an Akt-dependent mechanism. In response to hyperoxia/hypoxia, Nf1+/− retinas exhibited increased vessel dropout and neovascularization when compared with WT retinas. Neovascularization was similar between Nf1+/− and Nf1flox/+;Tie2cre retinas, but capillary drop out in Nf1flox/+;Tie2cre retinas was significantly reduced when compared with Nf1+/− retinas.ConclusionsThese data suggest that neurofibromin expression is essential for controlling endothelial cell proliferation and retinal neovascularization and therapies targeting neurofibromin-deficient EC may be beneficial.

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“…(39) (40) (41) (42) Health care professionals become appropriately concerned when an infant is hypoxemic, but hyperoxemia due to excess oxygen administration is frequent. Because of the association of hyperoxemia with brain damage, gene changes, and cancer, (43) (44) (45) (46) (47) there is a need for education about judicious use of oxygen supplementation and potential damaging effects of hyperoxemia.…”

Section: Introductionmentioning

confidence: 99%

Oxygen Saturation in the Newborn and the Importance of Avoiding Hyperoxia-Induced Damage

Sola

2015

NeoReviews

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Dr Sola has disclosed he works part-time for Masimo Corp. as vice president, medical affairs, neonatology. This commentary does contain a discussion of an unapproved/ investigative use of a commercial product/ device. Educational GapThere is a need for education about judicious use of oxygen supplementation and potential damaging effects of hyperoxemia. AbstractWhen a newborn has suspected or confirmed hypoxemia, clinical measures for evaluation and treatment are started without delay, which is appropriate. Oxygen is among the most widely used drugs in neonatal care, but the adverse effects of excess oxygen administration, hyperoxemia, and hyperoxia are not addressed in a similar way. This review describes issues of clinical significance related to oxygenation and saturation targets with the main objective of decreasing morbidities associated with excess oxygen use.Objectives After completing this article, readers should be able to:1. Improve understanding of oxygenation and saturation. 2. Advance knowledge for considering excess oxygen as a neonatal health hazard. 3. Increase attentiveness on issues related to targeting of oxygen saturation. 4. Collaborate to improve clinical practice and outcomes.

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Hypoxia–Reoxygenation Affects Whole-Genome Expression in the Newborn Eye

Cited by 6 publications

References 44 publications

Increased expression of inflammatory genes in the neonatal mouse brain after hyperoxic reoxygenation

Increased expression of inflammatory genes in the neonatal mouse brain after hyperoxic reoxygenation

Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization

Oxygen Saturation in the Newborn and the Importance of Avoiding Hyperoxia-Induced Damage

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