Epithelial Cell Death Is an Important Contributor to Oxidant-mediated Acute Lung Injury

Budinger, G.S.; Mutlu, Gökhan M.; Urich, Daniela; Soberanes, Saul; Buccellato, Leonard J.; Hawkins, Keenan A.; Chiarella, Sergio E.; Radigan, Kathryn A.; Eisenbart, James; Agrawal, Hemant; Berkelhamer, Sara; Hekimi, Siegfried; Zhang, Jianke; Perlman, Harris; Schumacker, Paul T.; Jain, Manu; Chandel, Navdeep S.

doi:10.1164/rccm.201002-0181oc

Cited by 102 publications

(80 citation statements)

References 64 publications

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“…Previous studies from our laboratory and others have demonstrated that these cell death mediators are critical regulators of HALI (30,50,56). To understand the mechanism of increased HALI in NOS2 null mutant young adult mice, we documented increased expression of Ang2, a molecule previously shown by us to be a critical regulator of cell death in HALI (23).…”

Section: Nos2mentioning

confidence: 74%

“…The involvement of key cell death regulators in the process of HALI has been reported by us (23,27,28,49) and others (50). Aside from the membrane (extrinsic) pathway that triggers cell surface "death receptors," such as Fas, which binds Fas-L and activates caspase 8 (51,52), many other stimuli use mitochondrial dysfunction to signal the cell death response.…”

Section: Nos2mentioning

confidence: 83%

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Increased Hyperoxia-Induced Lung Injury in Nitric Oxide Synthase 2 Null Mice Is Mediated via Angiopoietin 2

Bhandari

Choo-Wing

Harijith

et al. 2012

Am J Respir Cell Mol Biol

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Supplemental oxygen is frequently prescribed. However, prolonged exposure to high concentrations of oxygen causes hyperoxic acute lung injury (HALI), which manifests as acute respiratory distress syndrome in adults and leads to bronchopulmonary dysplasia in newborns (NBs). Nitric oxide (NO), NO synthases (NOSs), and angiopoietin (Ang) 2 have been implicated in the pathogenesis of HALI. However, the mechanisms of the contributions of NOS/NO and the relationship(s) between NOS/NO and Ang2 have not been addressed. In addition, the relevance of these moieties in adults and NBs has not been evaluated. To address these issues, we compared the responses in hyperoxia of wild-type (NOS [1/1]) and NOS null (2/2) young adult and NB mice. When compared with NOS21/1 adult controls, NOS2 2/2 animals manifest exaggerated alveolar-capillary protein leak and premature death. These responses were associated with enhanced levels of structural cell death, enhanced expression of proapoptotic regulatory proteins, and Ang2. Importantly, silencing RNA knockdown of Ang2 decreased the levels of cell death and the expression of proapoptotic mediators. These effects were at least partially NOS2 specific, and were development dependent, because survival was similar in adult NOS3 1/1 and NOS3 2/2 mice and NB NOS2 1/1 and NOS2 2/2 mice, respectively. These studies demonstrate that NOS2 plays an important protective role in HALI in adult animals. They also demonstrate that this response is mediated, at least in part, by the ability of NOS2 to inhibit hyperoxia-induced Ang2 production and thereby decrease Ang2-induced tissue injury.Keywords: cytokines; hyperoxia; lung Supplemental oxygen is commonly employed to counteract tissue hypoxemia. Although this is lifesaving in most circumstances, prolonged exposure to high concentrations of oxygen can lead to untoward effects. In the lung, exposure to hyperoxia is characterized by an inflammatory response (mediated by cytokines) and breakdown of the alveolar-capillary barrier, leading to pulmonary edema and endothelial and epithelial cell injury/ death (1). In adults, hyperoxic acute lung injury (HALI) causes acute respiratory distress syndrome (2). In neonates, HALI has been shown to lead to a pulmonary phenotype suggestive of bronchopulmonary dysplasia (3). Hence, HALI is a major cause of morbidity and mortality in both adult (2) and neonatal (3,4) populations.In addition, nitric oxide (NO) is known to have oxidant effects (5), and has been implicated in the pathogenesis of HALI. NO is generated via the action of NO synthases (NOSs). The inflammatory response in HALI is initiated and propagated, to a large extent, by the release of cytokines (1), which are known to induce NOS (6, 7). Most data suggest that hyperoxia exposure up-regulates inducible NOS (NOS2) and endothelial NOS (NOS3) expression in adult (8-16) and neonatal (7,(16)(17)(18)(19) lungs. In ALI and cell death, the endogenous production of NO is said to be mostly contributed by up-regulation of NOS2 in the lung (20)(21)(22).Previous work...

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Section: Nos2mentioning

confidence: 74%

Section: Nos2mentioning

confidence: 83%

Increased Hyperoxia-Induced Lung Injury in Nitric Oxide Synthase 2 Null Mice Is Mediated via Angiopoietin 2

Bhandari

Choo-Wing

Harijith

et al. 2012

Am J Respir Cell Mol Biol

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“…Hyperoxia results in increased pulmonary expression of NF-kB-regulated proapoptotic proteins (BAX [46]), proinflammatory cytokines (IL-1b, CXCL1 [3,47]), and pro-oxidant enzymes (COX-2 [48]). We found hyperoxia-induced induction of BAX, IL-1b, CXCL1, and COX-2 in both WT and AKBI mice.…”

Section: Discussionmentioning

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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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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“…Mclk1 +/− mice lack one copy of an enzyme that is necessary for the synthesis of the antioxidant and redox co-factor ubiquinone [47]. This leads to numerous metabolic changes but in particular to an increase in mitochondrial oxidative stress [48], which is deleterious under some experimental conditions [49]. Surprisingly these mutant mice not only live longer than wild-type siblings [50], they also show a much slower development of biomarkers of aging, including a slower loss of mitochondrial function [51].…”

Section: Ros Signaling Affects Aging and Lifespanmentioning

confidence: 99%

Taking a “good” look at free radicals in the aging process

Hekimi

Lapointe

Yang

2011

Trends in Cell Biology

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512

373

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The mitochondrial free radical theory of aging (MFRTA) proposes that aging is caused by damage to macromolecules from mitochondrial reactive oxygen species (ROS). This is based on the observed association of the rate of aging and the aged phenotype with the generation of ROS and with oxidative damage. The theory has led to the strong conviction in the general public that the consumption of antioxidants is crucial to health and beneficial to lifespan. However, a variety of recent findings convincingly demonstrate that ROS generation and oxidative damage cannot be the cause of aging. Here we propose that ROS play a role in mediating a stress response to agedependent damage, which could generate the observed correlation between aging and ROS without implying that ROS cause aging. Redefining our understanding of the relationship between ROS and agingMitochondria are a major source of reactive oxygen species (ROS), a type of molecule that includes free radicals such as superoxide. ROS spontaneously oxidize and damage macromolecules such as proteins, lipids and nucleic acids. Cells and organisms are said to be sustaining oxidative stress when an imbalance between ROS generation and detoxification or repair leads to an increase in the level of ROS-dependent damage. The mitochondrial free radical theory of aging (MFRTA) has provided an attractive framework that integrates numerous observations about the generation, the toxicity and the detoxification of ROS, as well as about how these parameters change with the physiological state of cells and organisms and with chronological age. The theory proposes that aging is actually caused by the toxicity of ROS through a vicious cycle in which ROS damage to the constituents of mitochondria leads to the generation of more ROS. The theory is based on numerous observations, including (1) that there is a strong correlation between chronological age and the level of ROS generation and oxidative damage, (2) that mitochondrial function is gradually lost during aging, (3) that inhibition of mitochondrial function can enhance ROS production, and (4) that several age-dependent diseases are associated with severe increases in oxidative stress.The strength of the MFRTA is that it provides a framework for many observations while also stating a plausible causal theory of aging. Furthermore, it provided a clear research program by proposing a theory to be tested as well as by suggesting that decreasing the generation of ROS will result in health benefits. In fact the MFRTA is often taught in textbooks and in *

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Epithelial Cell Death Is an Important Contributor to Oxidant-mediated Acute Lung Injury

Cited by 102 publications

References 64 publications

Increased Hyperoxia-Induced Lung Injury in Nitric Oxide Synthase 2 Null Mice Is Mediated via Angiopoietin 2

Increased Hyperoxia-Induced Lung Injury in Nitric Oxide Synthase 2 Null Mice Is Mediated via Angiopoietin 2

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

Taking a “good” look at free radicals in the aging process

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