Coordinate Control of Expression of Nrf2 Mediated Genes in the Human Small Airway Epithelium Highly Responsive to Cigarette Smoking.

Hubner, RH; Schwartz, J D; De, BP; Ferris, Barbara; Hackett, NR; Crystal, RG

doi:10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a4159

Cited by 7 publications

(9 citation statements)

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“…53 Our results suggest the critical role of Nrf2/Keap1 pathway in the stimulation of oxidative stress by chronic tobacco exposure because cigarette smoke exposure resulted in the activation of Nrf2 mRNA expression that counteract the immense oxidative stress that accompanies this trigger. These results are supported by a recent study, 54 which demonstrated that Nrf2 is activated in the small airway epithelium of healthy smokers. Other in vitro studies on different cells types have also suggested the increased Nrf2 expression in response to cigarette smoke extracts, 55 indicating the protective role of Nrf2 in cigarette smoke-induced health disorders.…”

Section: Discussionsupporting

confidence: 87%

Antioxidant N-acetyl cysteine reverses cigarette smoke-induced myocardial infarction by inhibiting inflammation and oxidative stress in a rat model

Khanna

Mehra

2012

Laboratory Investigation

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The contribution of chronic tobacco exposure in determining post-myocardial infarction (MI) left ventricular (LV) remodeling and possible therapeutic strategies has not been investigated systematically. In this small animal investigation, we demonstrate that chronic tobacco smoke exposure leading up to acute MI in rats is associated with greater histological extent of myocardial necrosis and consequent worse LV function. These findings are associated with increased transcriptomic expression of pro-inflammatory cytokines, tissue repair molecules and markers of oxidative stress in the myocardium. The results demonstrate that an N-acetyl cysteine (NAC) treatment significantly reduced tobacco-exposed induced infarct size and percent fractional shortening. A significantly increased LV end-systolic diameter was observed in tobacco-exposed sham compared to tobacco-naïve sham (4.92 ± 0.41 vs 3.45 ± 0.33; Po0.05), and tobacco-exposed MI compared to tobacco-naïve MI (8.24±0.3 vs 6.1±0.49; Po0.01) rats. Decreased intracardiac mRNA expression of the markers of inflammation, tissue repair and oxidative stress and circulating levels of pro-inflammatory cytokines accompanied these positive effects of NAC. The treatment of tobacco-exposed MI rats with NAC resulted in significantly increased levels of intracardiac mRNA expression of antioxidants, including superoxide dismutase, thioredoxin and nuclear factor-E2-related factor 2, as well as circulating levels of glutathione (7 ± 0.12 vs 10 ± 0.18; Pp0.001), where the levels were almost identical to the tobacco-naïve sham rats. These findings identify a novel post-infarction therapy for amelioration of the adverse effects of tobacco exposure on the infracted myocardium and advocate the use of dietary supplement antioxidants for habitual smokers to prevent and reverse cardiovascular adverse effects in the absence of successful achievement of cessation of smoking. Globally, tobacco smoke exposure remains a significant risk for the development of acute myocardial infarction (MI) irrespective of ethic or gender disparities. Exposure to tobacco smoke increases inflammation, oxidative stress 1-10 and decreases antioxidant expression. [11][12][13][14][15] Direct and indirect studies have demonstrated that oxidative stress from reactive oxygen species (ROS) generated through mitochondria, xanthine oxidase, and the NADPH oxidase system 16-21 is one of the important factors in the pathogenesis of myocardial ischemia. Decreased infarct size in superoxide dismutase (SOD)-producing transgenic mice suggests direct evidence for the role of involvement of ROS in MI. 22,23 In limited investigations, the use of antioxidants such as mercaptopropionyl glycine, edaravone and probucol have demonstrated varied effects on remodeling in animal models of MI, [24][25][26][27][28][29][30][31][32] with improvement in collagen content and histological changes. In this study, we sought to delineate the role of chronic tobacco smoke leading up to an acute MI by focusing on oxidative stress coupled with inflammat...

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Section: Discussionsupporting

confidence: 87%

Antioxidant N-acetyl cysteine reverses cigarette smoke-induced myocardial infarction by inhibiting inflammation and oxidative stress in a rat model

Khanna

Mehra

2012

Laboratory Investigation

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“…Consistent with this concept, the present study revealed a strong correlation between EGF expression and the genes related to the Nrf2-dependent oxidative stress response in the airway epithelium of smokers previously reported by our group (39). Thus, in conjunction with previous observations of compromised junctional barrier integrity in the airway epithelium of smokers (10)(11)(12), our present data suggest that smoking can activate physiologically silenced EGF-EGFR signaling in the airway epithelium by inducing EGF production by ciliated cells as part of the oxidative stress response and potentially allowing access of EGF to the EGFR-enriched BC compartment containing stem/progenitor cells of the airway epithelium.…”

Section: Egf-egfr Segregation In the Airway Epithelium And Smokingsupporting

confidence: 92%

“…Similar to other smoking-associated molecular changes in the airway epithelium (12,39), EGF expression varied considerably, demonstrating marked up-regulation in a subset of smokers. Given that smoking-induced pathological changes in the airway epithelium, including squamous metaplasia (7), and smokingassociated diseases, such as chronic obstructive pulmonary disease and lung cancer, develop in <25% of smokers (40,41), and considering the capability of EGF to alter airway epithelial phenotype demonstrated in the present study, it is possible that increased expression of EGF in the airway epithelium defines a distinct subset of smokers susceptible to the development of smoking-related airway pathology.…”

Section: Egf-egfr Segregation In the Airway Epithelium And Smokingmentioning

confidence: 64%

EGF shifts human airway basal cell fate toward a smoking-associated airway epithelial phenotype

Shaykhiev

Zuo

Chao

et al. 2013

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

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The airway epithelium of smokers acquires pathological phenotypes, including basal cell (BC) and/or goblet cell hyperplasia, squamous metaplasia, structural and functional abnormalities of ciliated cells, decreased number of secretoglobin (SCGB1A1)-expressing secretory cells, and a disordered junctional barrier. In this study, we hypothesized that smoking alters airway epithelial structure through modification of BC function via an EGF receptor (EGFR)-mediated mechanism. Analysis of the airway epithelium revealed that EGFR is enriched in airway BCs, whereas its ligand EGF is induced by smoking in ciliated cells. Exposure of BCs to EGF shifted the BC differentiation program toward the squamous and epithelial-mesenchymal transition-like phenotypes with down-regulation of genes related to ciliogenesis, secretory differentiation, and markedly reduced junctional barrier integrity, mimicking the abnormalities present in the airways of smokers in vivo. These data suggest that activation of EGFR in airway BCs by smoking-induced EGF represents a unique mechanism whereby smoking can alter airway epithelial differentiation and barrier function.airway epithelial barrier | progenitor cell | cigarette smoking

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“…Since the metabolism of nicotine by CYP2A6 is the principal pathway by which nicotine is removed from the circulation, an association between the CYP2A6 activity and cigarette consumption has been suggested [5,6]. Cigarette smoking is known to cause oxidative stress, which activates Nrf2 [25,26]. In addition, tobacco is a substantial source of cadmium, supported by the fact that the serum cadmium level of smokers is 3 folds higher than that of non-smokers [27].…”

Section: Discussionmentioning

confidence: 99%

Human CYP2A6 is regulated by nuclear factor-erythroid 2 related factor 2

Yokota

Higashi

Fukami

et al. 2011

Biochemical Pharmacology

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Human CYP2A6 is responsible for the metabolism of nicotine and coumarin as well as the metabolic activation of tobacco-related nitrosamines. Earlier studies revealed that CYP2A6 activity was increased by dietary cadmium or cruciferous vegetables, but the underlying mechanisms remain to be clarified. In the present study, we investigated the possibility that Nrf2 might be involved in the regulation of CYP2A6. Real-time RT-PCR analysis revealed that the CYP2A6 mRNA level in human hepatocytes was significantly (P < 0.01, 1.4 fold) induced by 10 µM sulforaphane (SFN), a typical activator of Nrf2. A computer-based search identified three putative antioxidant response elements (AREs) in the 5'-flanking region of the CYP2A6 gene at positions -1212, -2444, and -3441, termed ARE1, ARE2, and ARE3, respectively. Electrophoretic mobility shift assays demonstrated that Nrf2 bound only to ARE1. Luciferase assays using HepG2 cells revealed that the overexpression of Nrf2 significantly increased the reporter activities of the constructs containing a 30-bp fragment that included ARE1. However, the activity of the construct containing the intact 5'-flanking region (-1 to -1395) including ARE1 was not increased by the overexpression of Nrf2. In contrast, when the reporter construct was injected into mice via the tail vein, the reporter activity in the liver was significantly (P < 0.05, 1.9 fold) increased by SFN (1 mg/head) administration. In conclusion, we found that human CYP2A6 is regulated via Nrf2, suggesting that CYP2A6 is induced under oxidative stress.

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Coordinate Control of Expression of Nrf2 Mediated Genes in the Human Small Airway Epithelium Highly Responsive to Cigarette Smoking.

Cited by 7 publications

References 0 publications

Antioxidant N-acetyl cysteine reverses cigarette smoke-induced myocardial infarction by inhibiting inflammation and oxidative stress in a rat model

Antioxidant N-acetyl cysteine reverses cigarette smoke-induced myocardial infarction by inhibiting inflammation and oxidative stress in a rat model

EGF shifts human airway basal cell fate toward a smoking-associated airway epithelial phenotype

Human CYP2A6 is regulated by nuclear factor-erythroid 2 related factor 2

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