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

Waxman, Aaron B.; Kolliputi, Narasaiah

doi:10.1165/rcmb.2008-0302oc

Cited by 80 publications

(75 citation statements)

References 34 publications

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“…The expression of NF-kB-regulated proand antiapoptotic proteins was assessed on the basis of previous reports linking them to hyperoxic exposure (10,32,33). Consistent with hyperoxia-induced NFkB activation, both WT and AKBI mice demonstrated induction of BAX mRNA and protein expression at 96 hours of exposure ( Figures 5A-5C).…”

Section: Antiapoptotic and Antioxidant Nf-kb Target Gene Expression Imentioning

confidence: 72%

“…Given these facts, both antiinflammatory and antiapoptotic strategies have been employed to attenuate hyperoxic lung injury. Although anti-inflammatory interventions have met variable success (5)(6)(7)(8)(9), increasing the expression of antiapoptotic factors in transgenic murine models results in attenuated hyperoxic lung injury (10)(11)(12). These studies suggest that preventing hyperoxia-induced apoptosis can prevent lung injury, but the transcriptional mechanism mediating expression of these factors is largely unknown.…”

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confidence: 99%

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IκBβ-Mediated NF-κB Activation Confers Protection against Hyperoxic Lung Injury

Michaelis

Agboke

Liu

et al. 2014

Am J Respir Cell Mol Biol

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Supplemental oxygen is frequently used in an attempt to improve oxygen delivery; however, prolonged exposure results in damage to the pulmonary endothelium and epithelium. Although NF-kB has been identified as a redox-responsive transcription factor, whether NF-kB activation exacerbates or attenuates hyperoxic lung injury is unclear. We determined that sustained NF-kB activity mediated by IkBb attenuates lung injury and prevents mortality in adult mice exposed to greater than 95% O 2 . Adult wild-type mice demonstrated evidence of alveolar protein leak and 100% mortality by 6 days of hyperoxic exposure, and showed NF-kB nuclear translocation that terminated after 48 hours. Furthermore, these mice showed increased expression of NF-kB-regulated proinflammatory and proapoptotic cytokines. In contrast, mice overexpressing the NF-kB inhibitory protein, IkBb (AKBI), demonstrated significant resistance to hyperoxic lung injury, with 50% surviving through 8 days of exposure. This was associated with NF-kB nuclear translocation that persisted through 96 hours of exposure. Although induction of NFkB-regulated proinflammatory cytokines was not different between wild-type and AKBI mice, significant up-regulation of antiapoptotic proteins (BCL-2, BCL-XL) was found exclusively in AKBI mice. We conclude that sustained NF-kB activity mediated by IkBb protects against hyperoxic lung injury through increased expression of antiapoptotic genes.Keywords: NF-kB; IkB; hyperoxic lung injury; apoptosis; inflammation Clinical RelevanceOxygen therapy is commonly employed in an attempt to improve oxygen delivery, and yet prolonged exposure results in lung injury. No pharmacologic strategies to attenuate hyperoxic lung injury have been identified. We show that enhancing hyperoxia-induced NF-kB activity attenuates lung injury, and thus represents a potential therapeutic target.The first studies demonstrating the lethal effect of inspiring high concentrations of oxygen were published over a century ago (1). Due to this toxicity, hyperoxic exposure has been widely used in animal studies to induce and study acute lung injury (2). Despite this, no pharmacologic therapies to attenuate hyperoxic lung injury have been identified.Hyperoxia induces proinflammatory cytokine expression (3), and results in pulmonary endothelial and epithelial cell death (4). Given these facts, both antiinflammatory and antiapoptotic strategies have been employed to attenuate hyperoxic lung injury. Although anti-inflammatory interventions have met variable success (5-9), increasing the expression of antiapoptotic factors in transgenic murine models results in attenuated hyperoxic lung injury (10-12). These studies suggest that preventing hyperoxia-induced apoptosis can prevent lung injury, but the transcriptional mechanism mediating expression of these factors is largely unknown.Hyperoxia-induced NF-kB activation has been documented in both pulmonary epithelial and endothelial cells (13). Whether this response is protective or injurious is unclear. Some in vivo s...

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Section: Antiapoptotic and Antioxidant Nf-kb Target Gene Expression Imentioning

confidence: 72%

mentioning

confidence: 99%

IκBβ-Mediated NF-κB Activation Confers Protection against Hyperoxic Lung Injury

Michaelis

Agboke

Liu

et al. 2014

Am J Respir Cell Mol Biol

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“…The present studies add to our understanding of the relationship(s) between BRP-39/YKL-40 and apoptosis by demonstrating that these chilectins inhibit the oxidant-induced cell death of alveolar type II cells. Although the mechanism of this protection is not clear, it is tempting to speculate that the phosphatidylinositol 3 kinase-Akt pathway is involved, because studies from our laboratory have demonstrated that BRP-39/YKL-40 is a potent activator of Akt (31), and Akt can confer cytoprotection in HALI (46)(47)(48)(49). In combination, these studies allow for the speculation that BRP-39 and YKL-40 are critical regulators of cell death that inhibit oxidant injury and confer structural cell cytoprotection at physiologic concentrations, and prolong the survival of inflammatory cells, and contribute to antigen sensitization, chronic inflammation, and tissue remodeling when elevated.…”

Section: Discussionmentioning

confidence: 99%

The Chitinase-like Proteins Breast Regression Protein-39 and YKL-40 Regulate Hyperoxia-induced Acute Lung Injury

Sohn

Kang²,

Mizunuma³

et al. 2010

Am J Respir Crit Care Med

102

118

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Rationale: Prolonged exposure to 100% O 2 causes hyperoxic acute lung injury (HALI), characterized by alveolar epithelial cell injury and death. We previously demonstrated that the murine chitinase-like protein, breast regression protein (BRP)-39 and its human homolog, YKL-40, inhibit cellular apoptosis. However, the regulation and roles of these molecules in hyperoxia have not been addressed. Objectives: We hypothesized that BRP-39 and YKL-40 (also called chitinase-3-like 1) play important roles in the pathogenesis of HALI. Methods: We characterized the regulation of BRP-39 during HALI and the responses induced by hyperoxia in wild-type mice, BRP-39-null (2/2) mice, and BRP-39 2/2 mice in which YKL-40 was overexpressed in respiratory epithelium. We also compared the levels of tracheal aspirate YKL-40 in premature newborns with respiratory failure. Measurements and MainResults: These studies demonstrate that hyperoxia inhibits BRP-39 in vivo in the murine lung and in vitro in epithelial cells. They also demonstrate that BRP-39 2/2 mice have exaggerated permeability, protein leak, oxidation, inflammatory, chemokine, and epithelial apoptosis responses, and experience premature death in 100% O 2 . Lastly, they demonstrate that YKL-40 ameliorates HALI, prolongs survival in 100% O 2 , and rescues the exaggerated injury response in BRP-39 2/2 animals. In accord with these findings, the levels of tracheal aspirate YKL-40 were lower in premature infants treated with hyperoxia for respiratory failure who subsequently experienced bronchopulmonary dysplasia or death compared with those that did not experience these complications.Conclusions: These studies demonstrate that hyperoxia inhibits BRP-39/YKL-40, and that BRP-39 and YKL-40 are critical regulators of oxidant injury, inflammation, and epithelial apoptosis in the murine and human lung.

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“…This has been related to the fundamental underlying function of Bcl-2 proteins, possibly in mitochondrial energetics (68), which influences mitochondrial morphology and function. Although the mechanism through which Bcl-2 family proteins regulate mitochondrial morphogenesis is not well understood, studies suggest close interactions between Bcl-2 family proteins and the dynamin-like GTPases Drp1 and MFN1/2 that physically mediate mitochondrial outer membrane fission and fusion, respectively (67,69,70). In this study we show that TREM-1 induces Bcl-2 and increases the expression of MFN1 and MFN2, which increases mitochondrial integrity and thus inhibits apoptosis.…”

Section: Discussionmentioning

confidence: 47%