Cigarette Smoke Extract Induces DNA Damage but Not Apoptosis in Human Bronchial Epithelial Cells

Liu, Xiangde; Conner, Heather; Kobayashi, Tetsu; Kim, Huijung; Wen, Fuqiang; Abe, Shinji; Fang, Qiuhong; Wang, Xingqi; Hashimoto, Mitsuyoshi; Bitterman, Peter B.; Rennard, Stephen I.

doi:10.1165/rcmb.2003-0341oc

Cited by 100 publications

(91 citation statements)

References 26 publications

(28 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This may be one reason why lung cancer is prone to occur in smokers. Higher CSE concentration or longer periods of stimulation with CSE leads to apoptosis or even necrosis, consistent with the results from other researchers [35,36]. Besides treatment factors, cell type [37] is also one factor that can affect cell apoptosis or necrosis when stimulated.…”

Section: Discussionsupporting

confidence: 91%

AP-2α expression and cell apoptosis of the lung tissue of rats with COPD and ECV304 cells stimulated by cigarette smoke extract

Chen

et al. 2011

Chin. Sci. Bull.

View full text Add to dashboard Cite

An increasing body of evidence suggests that apoptosis of structural cells in the lung might be an important upstream event in the pathogenesis of chronic obstructive pulmonary disease (COPD). AP-2α is one of the important transcription factors involved in the modulation of apoptosis in carcinogenesis and idiopathic-dilated cardiomyopathy. The relationship between AP-2α and apoptosis in COPD remains to be elucidated. The aim of the present study was to investigate the expression of AP-2α in the lung tissues of rats with COPD induced by smoking and its possible protective effect on cigarette smoke extract (CSE) induced endothelial cell apoptosis. Sprague-Dawley rats (n = 24) were randomly assigned to normal and COPD groups. The COPD group was exposed to smoke from 20 commercial unfiltered cigarettes for 80 d before morphological assessment of the lung tissue was performed. The expression of AP-2α in lung tissues was measured by Western blotting. To demonstrate the relationship between apoptosis and AP-2α, in vitro cell experiments were carried out. Cells were treated with different concentrations of CSE before proliferation was measured by MTT. Apoptosis was then determined by Hoechst staining and the expression of cleaved caspase-3 and AP-2α by Western blotting over time following treatment with 5% CSE. Cells were then infected with an AP-2α adenovirus vector and the expression of cleaved caspase-3 and AP-2α was compared to the control groups by Western blotting. The COPD group showed larger air spaces and significant decrease of FEV 0.3 /FVC compared with the rats in the control group (P<0.05). The expression of AP-2α was significantly higher in the lung tissue of rats with COPD compared with those of controls (P<0.05). In the ECV304 cells, CSE induced apoptosis (P<0.01) and caspase-3 activation in a time-dependent manner and reduced the cell proliferation rate in a dose-dependent manner (P<0.005). Moreover, 5% CSE treatment increased endogenous AP-2α protein expression. AP-2α overexpression inhibited 5% CSE-induced cell apoptosis and activated caspase-3 expression (P<0.05) AP-2α protects ECV304 cells against CSE-induced apoptosis and may play an important role in smoking induced-apoptosis in COPD. AP-2α, apoptosis, cigarette smoke extract, COPD, vascular endothelial cell Citation:Li J L, Chen Y, Chen P, et al. AP-2α expression and cell apoptosis of the lung tissue of rats with COPD and ECV304 cells stimulated by cigarette smoke extract. Chinese Sci Bull, 2011Bull, , 56: 1562Bull, −1568Bull, , doi: 10.1007 Chronic obstructive pulmonary disease (COPD) is one of the major public health problems because of its high morbidity and mortality, but its pathogenesis remains enigmatic.

show abstract

Section: Discussionsupporting

confidence: 91%

AP-2α expression and cell apoptosis of the lung tissue of rats with COPD and ECV304 cells stimulated by cigarette smoke extract

Chen

et al. 2011

Chin. Sci. Bull.

View full text Add to dashboard Cite

show abstract

“…Although the role of apoptosis in CSE-induced cell death remains incompletely understood (33)(34), we demonstrate that CSE exposure induces an extrinsic apoptotic pathway involving DISC formation and downstream activation of caspases-8/caspase-3 in MRC-5 cells (Figs. 1 and 2).…”

Section: Discussionmentioning

confidence: 83%

Protein Kinase Cα and ζ Differentially Regulate Death-Inducing Signaling Complex Formation in Cigarette Smoke Extract-Induced Apoptosis

Park

Kim

Lee

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

Cigarette smoke, a major risk factor in emphysema, causes cell death by incompletely understood mechanisms. Death-inducing signaling complex (DISC) formation is an initial event in Fas-mediated apoptosis. We demonstrate that cigarette smoke extract (CSE) induces DISC formation in human lung fibroblasts (MRC-5) and promotes DISC trafficking from the Golgi complex to membrane lipid rafts. We demonstrate a novel role of protein kinase C (PKC) in the regulation of DISC formation and trafficking. The PKC isoforms, PKCα, ζ, ε, and η, were activated by CSE exposure. Overexpression of wild-type PKCα inhibited, while PKCζ promoted, CSE-induced cell death. Dominant-negative (dn)PKCζ protected against CSE-induced cell death by suppressing DISC formation and caspase-3 activation, while dnPKCα enhanced cell death by promoting these events. DISC formation was augmented by wortmannin, an inhibitor of PI3K. CSE-induced Akt phosphorylation was reduced by dnPKCα, but it was increased by dnPKCζ. Expression of PKCα in vivo inhibited DISC formation, caspase-3/8 activation, lung injury, and cell death after prolonged cigarette smoke exposure, whereas expression of PKCζ promoted caspase-3 activation. In conclusion, CSE-induced DISC formation is differentially regulated by PKCα and PKCζ via the PI3K/Akt pathway. These results suggest that modulation of PKC may have therapeutic potential in the prevention of smoke-related lung injury.

show abstract

“…It has been shown that CSE induces reversible DNA damage and that oxidants play a role in this damage in human lung fibroblasts and epithelial cells (20,23). The reduced mRNA induction of RIG-I could be caused by direct damage to the DNA segment of this important pathogen sensor.…”

Section: Discussionmentioning

confidence: 99%

Cigarette smoke extract suppresses the RIG-I-initiated innate immune response to influenza virus in the human lung

Patel

Booth

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

Cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD) and predisposes subjects to severe respiratory tract infections. Epidemiological studies have shown that cigarette smokers are seven times more likely to contract influenza infection than nonsmokers. The mechanisms underlying this increased susceptibility are poorly characterized. Retinoic acid-inducible gene (RIG)-I is believed to play an important role in the recognition of, and response to, influenza virus and other RNA viruses. Our study focused on how cigarette smoke extract (CSE) alters the influenza-induced proinflammatory response and suppresses host antiviral activity in the human lung using a unique lung organ culture model. We first determined that treatment with 2–20% CSE did not induce cytotoxicity as assessed by LDH release. However, CSE treatment inhibited influenza-induced IFN-inducible protein 10 protein and mRNA expression. Induction of the major antiviral cytokine IFN-β mRNA was also decreased by CSE. CSE also blunted viral-mediated RIG-I mRNA and protein expression. Inhibition of viral-mediated RIG-I induction by CSE was prevented by the antioxidants N-acetyl-cysteine and glutathione. These findings show that CSE suppresses antiviral and innate immune responses in influenza virus-infected human lungs through oxidative inhibition of viral-mediated induction of the pattern recognition receptor RIG-I. This immunosuppressive effect of CSE may play a role in the enhanced susceptibility of smokers to serious influenza infection in the lung.

show abstract

Cigarette Smoke Extract Induces DNA Damage but Not Apoptosis in Human Bronchial Epithelial Cells

Cited by 100 publications

References 26 publications

AP-2α expression and cell apoptosis of the lung tissue of rats with COPD and ECV304 cells stimulated by cigarette smoke extract

AP-2α expression and cell apoptosis of the lung tissue of rats with COPD and ECV304 cells stimulated by cigarette smoke extract

Protein Kinase Cα and ζ Differentially Regulate Death-Inducing Signaling Complex Formation in Cigarette Smoke Extract-Induced Apoptosis

Cigarette smoke extract suppresses the RIG-I-initiated innate immune response to influenza virus in the human lung

Contact Info

Product

Resources

About