Oral <i>N</i>‐acetylcysteine attenuates pulmonary emphysema and alveolar septal cell apoptosis in smoking‐induced COPD in rats

Cai, Sanjun; Chen, Ping; Zhang, Cheng; Chen, Jianbo; Wu, Jie

doi:10.1111/j.1440-1843.2009.01511.x

Cited by 49 publications

(53 citation statements)

References 23 publications

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“…Morphological changes such as denudation of endothelium and endothelial cell apoptosis as well as functional alterations have been observed in the pulmonary vasculature in patients with COPD and experimental emphysema animal models (11)(12)(13). Consistent with this concept, evidenced such proposals in cell level, the current study demonstrated that CSE indeed induced the apoptotic cell deaths in ECV304 cells in means of dose-dependent and time-dependent manners.…”

Section: Discussionsupporting

confidence: 86%

“…In addition to the well-known mechanisms in which the chronic inflammation of airways, extracellular matrix destruction and oxidative stress are thought to contribute to the pathogenesis of COPD (3), the apoptosis of structural cells in the lung is recently suggested to be an important upstream event in the pathogenesis of COPD (4)(5)(6)(7)(8)(9). Our previous studies demonstrated that the apoptosis was involved in both alveolar epithelial cells and endothelial cells in the parenchyma of COPD and that the apoptotic cells were increased in emphysematous lung parenchyma in both animal model and patients (10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

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The role of cyclooxygenase-2 in the protection against apoptosis in vascular endothelial cells induced by cigarette smoking

et al. 2017

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Background: Apoptosis has been demonstrated to be an important upstream event in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cyclooxygenase-2 (COX-2) seems to be biologically relevant in COPD. However, the role of COX-2 in the apoptosis in vascular endothelial cells induced by cigarette smoke extract (CSE) remains to be elucidated. Our recent study found that the prostacyclin, one of the COX products in the microvascular endothelium, inhibited apoptosis in the emphysematous lungs of rats induced by CSE. In order to clarify the role of COX-2 in the apoptosis of vascular endothelial cells induced by CSE, we performed the present experiment to elucidate it. Methods: Twenty surgical lung specimens were obtained from 6 patients with COPD, 7 smoking controls and seven nonsmoking controls. The apoptotic index (AI) and COX-2 protein expression were detected in lung tissues. To further investigate the effects of CSE on the apoptosis and COX-2 expression in a human vascular endothelial cell line, the apoptosis rate and COX-2 expression were examined in human umbilical vein endothelial cells (ECV304) under exposure to varied concentrations of CSE as well as under exposure to 5.0% CSE for varied durations. Repeatedly, the apoptosis rate and COX-2 expression in ECV304 cells under 5.0% CSE were examined after exposing to varied concentrations of celecoxib, a highly selective COX-2 inhibitor. Results: Significantly increased AI and expression of COX-2 were found both in the lungs of patients with COPD and smoking controls compared with nonsmoking controls. The CSE induced apoptosis in ECV304 cells in means of both dose-dependent and time-dependent manners. The COX-2 was slightly expressed in the cells after exposing to 5% CSE for 3 and 6 h, and markedly expressed after the exposure time for 9 and 12 h, but vanished after 24 h of the exposure. Of interest, with the completely block of the COX-2 expression by celecoxib at 50.0 μmol/L, the apoptosis rate was markedly increased again in ECV304 cells under exposure to 5.0% CSE. Conclusions: Endothelial cell apoptosis and the expression of COX-2 protein were increased in both COPD patients and CSE-induced vascular endothelial cells. Of interest, it seems that the COX-2 probably had a protective role against the apoptosis in the vascular endothelial cells induced by cigarette smoking.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

The role of cyclooxygenase-2 in the protection against apoptosis in vascular endothelial cells induced by cigarette smoking

et al. 2017

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“…In this sense, we only appreciated a significant reduction at 10 m M , the highest concentration assayed, which was also in accordance with previous studies [47]. Recent studies have shown that NAC may ameliorate lung emphysema induced by elastase or cigarette smoke in animal models [49,50], which indicates that an active antioxidant therapy could be useful to ameliorate the emphysema progression in humans. Since neutrophil apoptosis resistance is a marker of neutrophil activation and oxidative stress and chronic inflammation increase neutrophil survival, it would be expected that NAC prevents apoptosis resistance.…”

Section: Discussionsupporting

confidence: 77%

Neutrophil Activation in Severe, Early-Onset COPD Patients versus Healthy Non-Smoker Subjects in vitro: Effects of Antioxidant Therapy

Milara¹,

Juan²,

Peiró³

et al. 2011

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Background: Neutrophils and oxidative stress have been implicated in the pathogenesis of COPD. Severe, early-onset COPD is characterized by a rapid decline in the lung function at an early age; however, nothing is known about neutrophil activation in COPD patients. Objectives: The aim of this study was to evaluate peripheral blood neutrophil activation in severe, early-onset COPD patients versus healthy non-smokers and the effect of N-acetyl-L-cysteine (NAC) on neutrophil activation in vitro. Methods: Neutrophils were isolated from 15 severe, early-onset COPD patients and 15 age-matched healthy subjects and stimulated with N-formyl- Met-Leu-Phe (fMLP) in the presence or absence of NAC (10 µM to 10 mM). Neutrophil chemotaxis, elastase release, reactive oxygen species (ROS), intracellular thiols and apoptosis were measured by Boyden chamber, spectrofluorometry, CMFDA and H₂DCF-DA dyes and by annexin V-FITC, respectively. Results: Chemotaxis of peripheral blood neutrophils from COPD patients in response to fMLP was 30% more increased than that observed in healthy subjects. Elastase release in response to fMLP was 2-fold higher in neutrophils from COPD patients versus healthy subjects. Intracellular thiol levels were 30% lower in COPD and ROS was approximately 30% higher in COPD versus healthy neutrophils. Spontaneous apoptosis showed no differences in both groups of patients and fMLP-induced apoptosis was higher in COPD. Pre-treatment with the antioxidant NAC effectively attenuated neutrophil chemotaxis, elastase release and ROS as well as effectively increased thiol levels in COPD. Conclusions: Neutrophils in severe, early-onset COPD patients are highly activated and this is alleviated by NAC in vitro.

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“…We found that SOD mimetic was more efficacious than NAC in attenuating elastase-induced airspace enlargement and lung function decline in WT mice. This is corroborated by the studies that show a slight protective effect of NAC against rat emphysema induced by elastase and CS exposure (48,49). Interestingly, SOD mimetic, but not NAC, exhibited a protective effect on elastase-induced emphysematous changes in SOD3 KO mice.…”

Section: Discussionsupporting

confidence: 70%

Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM

Yao

Arunachalam

Hwang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

175

166

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Extracellular superoxide dismutase (ECSOD or SOD3) is highly expressed in lungs and functions as a scavenger of O 2 • ─ . ECM fragmentation, which can be triggered by oxidative stress, participates in the pathogenesis of chronic obstructive pulmonary disease (COPD) through attracting inflammatory cells into the lungs. The level of SOD3 is significantly decreased in lungs of patients with COPD. However, the role of endogenous SOD3 in the development/progression of emphysema is unknown. We hypothesized that SOD3 protects against emphysema by attenuating oxidative fragmentation of ECM in mice. To test this hypothesis, SOD3-deficient, SOD3-transgenic, and WT C57BL/6J mice were exposed to cigarette smoke (CS) for 3 d (300 mg total particulate matter/m 3 ) to 6 mo (100 mg/m 3 total particulate matter) or by intratracheal elastase injection. Airspace enlargement, lung inflammation, lung mechanical properties, and exercise tolerance were determined at different time points during CS exposure or after elastase administration. CS exposure and elastase administration caused airspace enlargement as well as impaired lung function and exercise capacity in SOD3-null mice, which were improved in mice overexpressing SOD3 and by pharmacological SOD mimetic. These phenomena were associated with SOD3-mediated protection against oxidative fragmentation of ECM, such as heparin sulfate and elastin, thereby attenuating lung inflammatory response. In conclusion, SOD3 attenuates emphysema and reduces oxidative fragmentation of ECM in mouse lung. Thus, pharmacological augmentation of SOD3 in the lung may have a therapeutic potential in the intervention of COPD/emphysema.antioxidants | cigarette smoke | chronic obstructive pulmonary disease | oxidants | glutathione E xtracellular superoxide dismutase (ECSOD or SOD3) is one of the three SOD antioxidant enzyme isoforms, and is highly expressed in lungs and vessels (1, 2). It is located in the ECM, the junctions of airway epithelial cells, the surface of airway smooth muscle, and the lining of vessels of the lung. SOD3 functions as a superoxide anion scavenger, thereby attenuating oxidative stress, which may play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Acute loss of SOD3 in adult mice causes death, whereas low mortality rates are seen in SOD3-overexpressing animals exposed to hyperoxia, suggesting an essential role of SOD3 for survival (3,4). Accumulating evidence shows that SOD3 polymorphism is associated with a decline in lung function in rodents and humans, and susceptibility to COPD, which may be a result of alteration of its encoding protein structure, function, and level (5-14). However, it is unclear whether endogenous SOD3 participates in the development/ progression of the inflammatory response, leading to COPD/ emphysema.Cigarette smoke (CS) is the major etiological factor in the pathogenesis of COPD, which is characterized by chronic lung inflammation, parenchymal destruction (i.e., emphysema), and accelerated decline in lung function....

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Oral N‐acetylcysteine attenuates pulmonary emphysema and alveolar septal cell apoptosis in smoking‐induced COPD in rats

Abstract: NAC attenuates lung damage, pulmonary emphysema and alveolar septal cell apoptosis by partly reversing the decrease in VEGF secretion and VEGFR2 protein expression in smoking-induced COPD in rats.

Cited by 49 publications

References 23 publications

The role of cyclooxygenase-2 in the protection against apoptosis in vascular endothelial cells induced by cigarette smoking

The role of cyclooxygenase-2 in the protection against apoptosis in vascular endothelial cells induced by cigarette smoking

Neutrophil Activation in Severe, Early-Onset COPD Patients versus Healthy Non-Smoker Subjects in vitro: Effects of Antioxidant Therapy

Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM

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