A critical role for Fas/CD‐95 dependent signaling pathways in the pathogenesis of hyperoxia‐induced brain injury

Dzietko, Mark; Boos, Vinzenz; Sifringer, Marco; Polley, Oliver; Gerstner, Bettina; Genz, Kerstin; Endesfelder, Stefanie; Börner, Constanze; Jacotot, Étienne; Chauvier, David; Obladen, Michael; Bührer, Christoph; Felderhoff‐Mueser, Ursula

doi:10.1002/ana.21516

Cited by 40 publications

(54 citation statements)

References 49 publications

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“…However, serious limitations of the study design dictate caution in applying these results to newborn resuscitation. The optimal oxygen saturation for extremely low-birth-weight infants during the first weeks of life is still not defined, but premature infants could be subjected to relative hyperoxia much earlier because of a dramatic rise in oxygen tissue tension compared with intrauterine conditions [7,25,26]. …”

Section: Discussionmentioning

confidence: 99%

Deleterious Effect of Hyperoxia at Birth on White Matter Damage in the Newborn Rat

et al. 2011

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White matter damage (WMD) remains the leading cause of cerebral palsy in children born prematurely. The release of an excessive amount of reactive oxygen species is recognized as a risk factor for WMD. We hypothesize that free radical injury during reoxygenation at birth may be harmful to the immature white matter and may underlie, at least in part, the pathogenesis of WMD. We tested this hypothesis in rat pups delivered from normoxic pregnant rats, and by investigating an animal model based on protracted antenatal hypoxia in the pregnant rat and mimicking the main features of human WMD in rat pups. From embryonic day (E)5 to E21, the pregnant rats were placed in a chamber supplied with a gas mixture that either induced hypoxia (FiO₂ = 10%) or maintained normoxia (FiO₂ = 21%). On E21, the dams were removed from the chamber and housed under either normoxia (FiO₂ = 21%), hyperoxia (FiO₂ = 60%) or slowly reoxygenated (FiO₂ from 15% at E21 to 21% at postnatal day 7). Postnatal hyperoxia was associated with a significantly increased density of activated microglial cells (+105%) and TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling)-positive cells (+85%) within the developing white matter. Myelin content (–31%) and mature oligodendrocyte density (–37%) in the normal developing white matter were significantly decreased by postnatal hyperoxia. Postnatal hyperoxia significantly potentiated the myelination delay and oligodendroglial dysmaturation induced by antenatal hypoxia. In contrast, progressive reoxygenation at birth did not induce any change in white matter inflammation, myelination and cell death as compared with normoxic controls, and prevented most of the WMD observed following antenatal hypoxia. This study demonstrates a deleterious effect of hyperoxia at birth on the developing white matter in normal rat pups. Postnatal hyperoxia worsened the WMD induced by antenatal hypoxia. Hyperoxia at birth should be avoided in preterm infants at risk of WMD.

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Section: Discussionmentioning

confidence: 99%

Deleterious Effect of Hyperoxia at Birth on White Matter Damage in the Newborn Rat

et al. 2011

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“…(Dzietko et al, 2008). Inhibition of apoptotic signaling pathways has been shown to protect the brain from ischemic injury (Dzietko et al, 2008). We examined the effect of SR-A deficiency on the Fas-mediated apoptotic signaling pathway after cerebral I/R.…”

Section: Ischemia-reperfusion-induced Phosphorylation Of Irak and Ijbmentioning

confidence: 99%

Scavenger Receptor Class-A Has a Central Role in Cerebral Ischemia–Reperfusion Injury

Chen

Fang

Liu

et al. 2010

J Cereb Blood Flow Metab

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The innate immune response is involved in the pathophysiology of cerebral ischemia-reperfusion (I/R) injury. Recent evidence suggests that scavenger receptors have a role in the induction of innate immunity. In this study, we examined the role of scavenger receptor A (SR-A) in focal cerebral I/R injury. Both SR-A À/À mice (n = 10) and age-matched wild-type (WT) mice (n = 9) were subjected to focal cerebral ischemia (60 minutes), followed by reperfusion (for 24 hours). Infarct size was determined by TTC (triphenyltetrazolium chloride) staining. The morphology of neurons in the brain sections was examined by Nissl's staining. Activation of intracellular signaling was analyzed by western blot. Cerebral infarct size in SR-A À/À mice was significantly reduced by 63.9% compared with WT mice after cerebral I/R. In SR-A À/À mice, there was less neuronal damage in the hippocampus compared with WT mice. Levels of FasL, Fas, FADD, caspase-3 activity, and terminal deoynucleotidyl transferase-mediated 2 0 -deoxyuridine 5 0 -triphosphate-biotin nick end labelingpositive apoptotic cells were significantly increased in WT mice after cerebral I/R, but not in SR-A À/À mice. Cerebral I/R increased nuclear factor-jB activation in WT mice, but not in SR-A À/À mice. These data suggest that SR-A has a central role in cerebral I/R injury and that suppression of SR-A may be a useful approach for ameliorating brain injury in stroke patients.

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“…These regions include cortical areas, basal ganglia, hypothalamus, hippocampus and white matter tracts. On a molecular level, cell death is accompanied by induction of proapoptotic pathways [2,3] , oxidative stress [4,5] and a reduction in neurotrophindependent pathways, including that of Jak2/extracellular signal-regulated kinase (ERK) [1,2] . Hyperoxia exposure in the first week of rodent life also causes microvascular degeneration and altered brain mass and function at the age of 30 days [6] .…”

Section: Introductionmentioning

confidence: 99%

Erythropoietin Attenuates Hyperoxia-Induced Cell Death by Modulation of Inflammatory Mediators and Matrix Metalloproteinases

Sifringer¹,

Genz²,

Brait³

et al. 2009

Dev Neurosci

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Oxygen toxicity appears to contribute to the pathogenesis of adverse neurological outcome in survivors of preterm birth. In infant rodent brains, hyperoxia triggers widespread apoptotic neurodegeneration, induces proinflammatory cytokines and inhibits growth factor signaling cascades. Since a tissue-protective effect has been observed for recombinant erythropoietin (rEpo), we hypothesized that rEpo would influence the expression of proinflammatory cytokines and matrix metalloproteinase (MMP)-2 and MMP-9. Six-day-old Wistar rats were exposed to 80% oxygen for 2–48 h and received 20,000 IU rEpo i.p. Sex-matched littermates kept in room air and injected with normal saline or rEpo served as controls. Treatment with rEpo significantly reduced hyperoxia-induced upregulation of the proinflammatory cytokines IL-1β and IL-18 in infant rodent brains on the mRNA and protein levels. In parallel, gelatin zymography in hyperoxia-treated immature rat brains revealed an upregulation of active MMP-2 which was reduced by concomitant rEpo treatment. Furthermore, hyperoxia induced upregulation of MMP-9 following 12 h of oxygen exposure and this was attenuated by rEpo treatment. Our results suggest that rEpo generates its protective effect against oxygen toxicity through a reduction of proinflammatory mediator levels.

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A critical role for Fas/CD‐95 dependent signaling pathways in the pathogenesis of hyperoxia‐induced brain injury

Cited by 40 publications

References 49 publications

Deleterious Effect of Hyperoxia at Birth on White Matter Damage in the Newborn Rat

Deleterious Effect of Hyperoxia at Birth on White Matter Damage in the Newborn Rat

Scavenger Receptor Class-A Has a Central Role in Cerebral Ischemia–Reperfusion Injury

Erythropoietin Attenuates Hyperoxia-Induced Cell Death by Modulation of Inflammatory Mediators and Matrix Metalloproteinases

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