Bcl-2 protects against hyperoxia-induced apoptosis through inhibition of the mitochondria-dependent pathway☆

Métrailler-Ruchonnet, Isabelle; Pagano, Alessandra; Carnesecchi, Stéphanie; Ody, Christiane; Donati, Yves; Argiroffo, Constance Barazzone

doi:10.1016/j.freeradbiomed.2007.01.008

Cited by 66 publications

(56 citation statements)

References 59 publications

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“…However, it is not clear at this point whether NOX1-derived ROS are responsible for direct genotoxic stress or whether the DNA strand breaks are also due to caspase activation by redox-sensitive cell death pathways (e.g., JNK and ERK). Indeed, it is likely that caspase activation is not sufficient to fully account for the DNA strand breaks observed in response to hyperoxia because (1) in this study, we observed a smaller number of caspase-3-positive cells, as compared with TUNEL-positive cells; and (2) in previous studies we found that administration of pan-caspase inhibitor (Z-VAD) was not sufficient to rescue hyperoxia-induced cell death (3,50). If direct genotoxic stress through NOX1-derived ROS is a contributor to hyperoxic lung damage, it is essential to inhibit ROS formation at a significantly upstream level.…”

Section: Discussionmentioning

confidence: 66%

NADPH Oxidase-1 Plays a Crucial Role in Hyperoxia-induced Acute Lung Injury in Mice

Carnesecchi¹,

Deffert²,

Pagano³

et al. 2009

Am J Respir Crit Care Med

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137

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Rationale: Hyperoxia-induced acute lung injury has been used for many years as a model of oxidative stress mimicking clinical acute lung injury and the acute respiratory distress syndrome. Excess quantities of reactive oxygen species (ROS) are responsible for oxidative stress-induced lung injury. ROS are produced by mitochondrial chain transport, but also by NADPH oxidase (NOX) family members. Although NOX1 and NOX2 are expressed in the lungs, their precise function has not been determined until now. Objectives: To determine whether NOX1 and NOX2 contribute in vivo to hyperoxia-induced acute lung injury. Methods: Wild-type and NOX1-and NOX2-deficient mice, as well as primary lung epithelial and endothelial cells, were exposed to room air or 100% O 2 for 72 hours. Measurements and Main Results: Lung injury was significantly prevented in NOX1-deficient mice, but not in NOX2-deficient mice. Hyperoxia-dependent ROS production was strongly reduced in lung sections, in isolated epithelial type II cells, and lung endothelial cells from NOX1-deficient mice. Concomitantly, lung cell death in situ and in primary cells was markedly decreased in NOX1-deficient mice. In wild-type mice, hyperoxia led to phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), two mitogen-activated protein kinases involved in cell death signaling, and to caspase-3 activation. In NOX1-deficient mice, JNK phosphorylation was blunted, and ERK phosphorylation and caspase-3 activation were decreased. Conclusions: NOX1 is an important contributor to ROS production and cell death of the alveolocapillary barrier during hyperoxia and is an upstream actor in oxidative stress-induced acute lung injury involving JNK and ERK pathways in mice.

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Section: Discussionmentioning

confidence: 66%

NADPH Oxidase-1 Plays a Crucial Role in Hyperoxia-induced Acute Lung Injury in Mice

Carnesecchi¹,

Deffert²,

Pagano³

et al. 2009

Am J Respir Crit Care Med

Self Cite

137

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“…Others have shown that BCL2 expression is associated with protection of OLs from different celldeath inducers (Burgmaier et al, 2000;FitzGerald et al, 2003). Recently, it was shown that the overexpression of BCL2 was able to prevent hyperoxia-induced cell death in a murine fibrosarcoma cell line, by affecting mitochondria-dependent apoptotic pathways and increasing intracellular antioxidant compounds (Metrailler-Ruchonnet et al, 2007). The present in vitro study in conjunction with our previous in vivo findings suggest that the principal mechanism of cell death in oligodendrocytes and neurons in response to hyperoxia is apoptosis (Felderhoff-Mueser et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Hyperoxia Causes Maturation-Dependent Cell Death in the Developing White Matter

Gerstner

DeSilva²,

Genz³

et al. 2008

J. Neurosci.

160

145

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Periventricular leukomalacia is the predominant injury in the preterm infant leading to cerebral palsy. Oxygen exposure may be an additional cause of brain injury in these infants. In this study, we investigated pathways of maturation-dependent oligodendrocyte (OL) death induced by hyperoxia in vitro and in vivo. Developing and mature OLs were subjected to 80% oxygen (0 -24 h). Lactate dehydrogenase (LDH) assay was used to assess cell viability. Furthermore, 3-, 6-, and 10-d-old rat pups were subjected to 80% oxygen (24 h), and their brains were processed for myelin basic protein staining. Significant cell death was detected after 6 -24 h incubation in 80% oxygen in pre-OLs (O4ϩ,O1Ϫ), but not in mature OLs (MBPϩ). Cell death was executed by a caspase-dependent apoptotic pathway and could be blocked by the pan-caspase inhibitor zVAD-fmk. Overexpression of BCL2 (Homo sapiens B-cell chronic lymphocytic leukemia/lymphoma 2) significantly reduced apoptosis. Accumulation of superoxide and generation of reactive oxygen species (ROS) were detected after 2 h of oxygen exposure. Lipoxygenase inhibitors 2,3,5-trimethyl-6-(12-hydroxy-5-10-dodecadiynyl-1,4-benzoquinone and N-benzyl-N-hydroxy-5-phenylpentamide fully protected the cells from oxidative injury. Overexpression of superoxide dismutase (SOD1) dramatically increased injury to pre-OLs but not to mature OLs. We extended these studies by testing the effects of hyperoxia on neonatal white matter. Postnatal day 3 (P3) and P6 rats, but not P10 pups, showed bilateral reduction in MBP (myelin basic protein) expression with 24 h exposure to 80% oxygen. Hyperoxia causes oxidative stress and triggers maturation-dependent apoptosis in pre-OLs, which involves the generation of ROS and caspase activation, and leads to white matter injury in the neonatal rat brain. These observations may be relevant to white matter injury observed in premature infants.

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“…Thus, protection from hyperoxia in our Bcl-2-overexpressing mice is likely the result of inhibition of ROS production by exogenous Bcl-2 expression. In addition, Bcl-2 has been suggested to inhibit hyperoxia-induced cell death by modulating mitochondria-dependent apoptotic pathways and increasing intracellular antioxidants (28). Recent studies also suggest that glutathione (GSH) binding by Bcl-2 plays a central role in the mitochondrial antioxidant function of Bcl-2 (17,26).…”

Section: Discussionmentioning

confidence: 99%

IL-6 Protects against Hyperoxia-Induced Mitochondrial Damage via Bcl-2–Induced Bak Interactions with Mitofusions

Waxman¹,

Kolliputi²

2009

Am J Respir Cell Mol Biol

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Overexpression of IL-6 markedly diminishes hyperoxic lung injury, hyperoxia-induced cell death, and DNA fragmentation, and enhances Bcl-2 expression. We hypothesized that changes in the interactions between Bcl-2 family members play an important role in the IL-6-mediated protective response to oxidative stress. Consistent with this hypothesis, we found that IL-6 induced Bcl-2 expression, both in vivo and in vitro, disrupted interactions between proapoptotic and antiapoptotic factors, and suppressed H 2 O 2 -induced loss of mitochondrial membrane potential in vitro. In addition, IL-6 overexpression in mice protects against hyperoxia-induced lung mitochondrial damage. The overexpression of Bcl-2 in vivo prolonged the survival of mice exposed to hyperoxia and inhibited alveolar capillary protein leakage. In addition, apoptosis-associated DNA fragmentation was substantially reduced in these animals. This IL-6-mediated protection was lost when Bcl-2 was silenced, demonstrating that Bcl-2 is an essential mediator of IL-6 cytoprotection. Finally, Bcl-2 blocked the dissociation of Bak from mitofusion protein (Mfn) 2, and inhibited the interaction between Bak and Mfn1. Taken together, our results suggest that IL-6 induces Bcl-2 expression to perform cytoprotective functions in response to oxygen toxicity, and that this effect is mediated by alterations in the interactions between Bak and Mfns.

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Bcl-2 protects against hyperoxia-induced apoptosis through inhibition of the mitochondria-dependent pathway☆

Cited by 66 publications

References 59 publications

NADPH Oxidase-1 Plays a Crucial Role in Hyperoxia-induced Acute Lung Injury in Mice

NADPH Oxidase-1 Plays a Crucial Role in Hyperoxia-induced Acute Lung Injury in Mice

Hyperoxia Causes Maturation-Dependent Cell Death in the Developing White Matter

IL-6 Protects against Hyperoxia-Induced Mitochondrial Damage via Bcl-2–Induced Bak Interactions with Mitofusions

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