Overexpression of manganese superoxide dismutase by N-acetylcysteine in hyperoxic lung injury

Nagata, Kazuhiro; Iwasaki, Yoshinobu; Yamada, Tadaaki; Yuba, Tatsuya; Kono, Kenji; Hosogi, Shigekuni; Ohsugi, Shuji; Kuwahara, Hiroomi; Marunaka, Yoshinori

doi:10.1016/j.rmed.2006.07.017

Cited by 57 publications

(41 citation statements)

References 31 publications

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“…First, JNK phosphorylation activates the transcription factor AP-1, which translocates to the nucleus to regulate the expression of various genes, such as FasL, p53, c-myc, and bcl-2 family members. Second, ROS are specifically detected in mitochondria or submitochondrial particles [39], inducing the oxidation of mitochondrial proteins. JNK activation by ROS further induces the loss of mitochondrial membrane potential, phosphorylation of downstream proteins such as Bim, Bcl-xl and Bcl-2, and cleavage of Bid [39,40], leading to subsequent release of various proapoptotic factors.…”

Section: Discussionmentioning

confidence: 99%

“…Second, ROS are specifically detected in mitochondria or submitochondrial particles [39], inducing the oxidation of mitochondrial proteins. JNK activation by ROS further induces the loss of mitochondrial membrane potential, phosphorylation of downstream proteins such as Bim, Bcl-xl and Bcl-2, and cleavage of Bid [39,40], leading to subsequent release of various proapoptotic factors. Recently, Zhou et al [41] provided evidence that phosphorylated JNK translocates to mitochondria and subsequently phosphorylates the E1α subunit of pyruvate dehydrogenase.…”

Section: Discussionmentioning

confidence: 99%

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An agonistic monoclonal antibody against DR5 induces ROS production, sustained JNK activation and Endo G release in Jurkat leukemia cells

2009

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

An agonistic monoclonal antibody against DR5 induces ROS production, sustained JNK activation and Endo G release in Jurkat leukemia cells

2009

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“…NAC is a precursor of GSH (25), which is one of the most important mechanisms for protecting cells and tissue from reactive oxygen species (ROS). GSH and NAC act as free oxygen radical scavengers (26). However, the mechanism by which NAC protects against lung injury remains to be fully elucidated.…”

mentioning

confidence: 99%

N-Acetylcysteine Protects Murine Alveolar Type II Cells from Cigarette Smoke Injury in a Nuclear Erythroid 2–Related Factor–2–Independent Manner

Messier

Day²,

Kleeberger³

et al. 2013

Am J Respir Cell Mol Biol

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Emphysema is caused by the cigarette smoke (CS)-induced destruction of alveolar wall septa, and CS is the main risk factor for chronic obstructive pulmonary disease (COPD). To study the mechanisms of response to this insult, we focused on oxidant-induced lung injury and the potential role of nuclear erythroid 2-related factor-2 (Nrf2), which is a key regulator of the antioxidant defense system. We studied the protective role of N-acetylcysteine (NAC) against the injury of alveolar type II (ATII) cells induced by CS in vivo and in vitro. ATII cells were isolated and purified using magnetic MicroBeads (Miltenyi Biotec, Auburn, CA) from Nrf2 2/2 mice and wild-type mice. We analyzed pulmonary injury, inflammation, glutathione (GSH) concentrations, the expression of glutathione cysteine ligase catalytic subunit mRNA, glutathione cysteine ligase modifier subunit mRNA, and glutathione reductase mRNA, and Nrf2, heme oxygenase-1, and nicotinamide adenine dinucleotide phosphate-reduced:quinone oxireductase levels by Western blotting, TUNEL assay, and immunocytofluorescence for 4-hydroxynonenal as a marker of oxidative stress. We found that CS induced greater injury in ATII cells obtained from Nrf2 2/2 mice than from wild-type mice. Furthermore, NAC attenuated the injuries by CS in ATII cells obtained from wild-type mice both in vivo and in vitro. Moreover, NAC decreased the injury of ATII cells obtained from Nrf2 2/2 mice. Our results suggest that Nrf2-GSH signaling is important for the protective activity of NAC. In addition, in ATII cells deficient in Nrf2, this compound can provide partial protection through its reactive oxygen species-scavenging activities. Targeting the antioxidant system regulated by Nrf2 may provide an effective strategy against lung injury in COPD.Keywords: murine alveolar type II cells; lung; Nrf2; NAC; cigarette smoke Chronic obstructive pulmonary disease (COPD) is currently the third-leading cause of death in the United States (1, 2), and mortality rates continue to rise. Emphysema is caused by the destruction of the alveolar wall septa, which is brought about by cigarette smoke (CS) and its associated lung inflammation (3, 4). CS is a complex mixture of different chemicals, including free radicals and other oxidants. Cell death (both apoptosis and necrosis) by CS has been shown to produce oxidant injury both in vitro and in vivo (5-7). However, the exact mechanism underlying CS-induced alveolar epithelial cell death in COPD remains unclear.The nuclear erythroid 2-related factor-2 (Nrf2) transcription factor is a key determinant of COPD susceptibility (8-11), and one of the critical regulators of cellular redox status (12, 13). Nrf2 is required for the constitutive and inducible expression of the glutathione cysteine ligase catalytic subunit (GCLC) and the glutathione cysteine ligase modifier subunit (GCLM), which are required for glutathione (GSH) synthesis (14). Nrf2 also regulates the expression of other cellular antioxidant genes, such as heme oxygenase-1 (HO-1) and nicotinamide adenine din...

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“…We also show that this is not due to a generalized oxidative stress response, nor does it involve the transcription factor NF-E2-related factor 2 (Nrf2). Instead, the AhR regulates the expression of superoxide dismutases (SOD), cellular antioxidants that confer protection against lung injury (29,30). These results, in concert with our recently published work (26), support the hypothesis that the AhR is a novel and central regulator of pathogenic processes implicated in COPD etiology and progression-inflammation and cell death.…”

mentioning

confidence: 99%

Genetic Ablation of the Aryl Hydrocarbon Receptor Causes Cigarette Smoke-induced Mitochondrial Dysfunction and Apoptosis

Souza

Zago

Pollock

et al. 2011

Journal of Biological Chemistry

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Overexpression of manganese superoxide dismutase by N-acetylcysteine in hyperoxic lung injury

Abstract: These findings suggest that the antioxidant properties of NAC in hyperoxic lung injury involve a decrease in mitochondrial ROS in association with the induction of MnSOD, in addition to its role as a precursor of GSH.

Cited by 57 publications

References 31 publications

An agonistic monoclonal antibody against DR5 induces ROS production, sustained JNK activation and Endo G release in Jurkat leukemia cells

An agonistic monoclonal antibody against DR5 induces ROS production, sustained JNK activation and Endo G release in Jurkat leukemia cells

N-Acetylcysteine Protects Murine Alveolar Type II Cells from Cigarette Smoke Injury in a Nuclear Erythroid 2–Related Factor–2–Independent Manner

Genetic Ablation of the Aryl Hydrocarbon Receptor Causes Cigarette Smoke-induced Mitochondrial Dysfunction and Apoptosis

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