Reversible Cigarette Smoke Extract–Induced DNA Damage in Human Lung Fibroblasts

Kim, Huijung; Liu, Xiangde; Kobayashi, Tetsu; Conner, Heather; Kohyama, Tadashi; Wen, Fu Qiang; Fang, Qiuhong; Abe, Shinji; Bitterman, Peter B.; Rennard, Stephen I.

doi:10.1165/rcmb.2002-0300oc

Cited by 77 publications

(67 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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

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

show abstract

“…The process was repeated with one cigarette used for each 10 ml of medium. The generated cigarette smoke extract solution was filtered (0.22 mm) to remove large particles (26)(27)(28)(29). The resulting solution was designated a 100% cigarette smoke extract solution.…”

Section: Preparation Of Cigarette Smoke Extractmentioning

confidence: 99%

Cigarette Smoke Alters Respiratory Syncytial Virus–Induced Apoptosis and Replication

Groskreutz

Monick²,

Babor³

et al. 2009

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Individuals exposed to cigarette smoke have a greater number and severity of viral infections, including respiratory syncytial virus (RSV) infections, than do nonsmokers, but the cellular mechanism is unknown. Our objective was to determine the mechanism by which cigarette smoke augments viral infection. We hypothesize that cigarette smoke causes necrosis and prevents virus-induced cellular apoptosis, and that this is associated with increased inflammation and viral replication. Primary airway epithelial cells were exposed to cigarette smoke extract for 2 days, followed by 1 day of RSV exposure. Western blot detection of cleaved caspases 3 and 7 showed less apoptosis when cells were treated with cigarette smoke before viral infection. This finding was confirmed with ELISA and TUNEL detection of apoptosis. Measures of cell viability, including propidium iodide staining, ATP assay, and cell counts, indicated that cigarette smoke causes necrosis rather than virus-induced apoptosis. Using plaque assay and fluorescently-labeled RSV, we showed that although there were less live cells in the cigarette smoke-pretreated group, viral load was increased. The effect was inhibited by pretreatment of cells with N-acetylcysteine and aldehyde dehydrogenase, suggesting that the effect was primarily mediated by reactive aldehydes. Cigarette smoke causes necrosis rather than apoptosis in viral infection, resulting in increased inflammation and enhanced viral replication.

show abstract

“…MMA and ADMA are metabolized by dimethylarginine dimethylaminohydrolase (DDAH) to L-citrulline and methylamines (43). Therefore, impaired DDAH activity results in the accumulation of endogenous NOS inhibitors (34, 35), thereby impairing NO production.On the basis of the findings described above, the present experiments were designed to investigate whether or not enzyme activities and factors involved in the NO generation pathway are affected in rabbit corpus cavernosum after administration of cigarette smoke extract (CSE) (22,29,58,59) for a better understanding of the mechanisms causing ED with cigarette smoking. …”

mentioning

confidence: 99%

Alterations of NOS, arginase, and DDAH protein expression in rabbit cavernous tissue after administration of cigarette smoke extract

Imamura¹,

Waseda²,

Marinova³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

Cigarette smoking is an independent risk factor for vasculogenic erectile dysfunction (ED). Nitric oxide (NO) has been demonstrated to be the principal mediator of cavernous smooth muscle relaxation and penile erection. Therefore, we examined whether or not enzyme activities and factors involved in the NO generation pathway are affected in rabbit corpus cavernosum after administration of nicotine-and tar-free cigarette smoke extract (CSE). CSE was prepared by bubbling a stream of cigarette smoke into phosphate-buffered saline. CSE was injected subcutaneously into adult male rabbits once a day for 5 wk. In the CSE group, significantly decreased cyclic GMP production as a marker of NO generation was associated with attenuated overall nitric oxide synthase (NOS) activity, enhanced arginase activity, accumulation of endogenous NOS inhibitors such as monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), and decreased dimethylarginine dimethylaminohydrolase (DDAH) activity as an metabolizing enzyme of endogenous NOS inhibitors. Neuronal NOS (nNOS) and DDAH I protein expression were decreased without altering endothelial NOS expression, while arginase I expression was upregulated. These results suggest that impaired NO production would result from blunted NOS activity, which is possibly brought about by the downregulation of nNOS protein, accumulation of endogenous NOS inhibitors, and enhanced arginase activity together with upregulation of arginase I protein in cavernous tissue. The impaired DDAH activity due to decreased expression of DDAH I protein would result in an accumulation of endogenous NOS inhibitors with CSE. These alterations may be relevant to induction of the erectile dysfunction following CSE. erectile dysfunction; nitric oxide generation pathway; anti-asymmetric dimethylarginine antibody; immunohistochemistry; Western blot ACCORDING TO FELDMAN ET AL. (18) and McVary et al. (39), there are strong parallels and shared risks among smoking, coronary artery disease, atherosclerosis, and erectile dysfunction (ED). Clinical and basic science studies provide strong indirect evidence that smoking may affect penile erection by impairment of endothelium-dependent smooth muscle relaxation. Numerous studies have shown endothelial dysfunction in ED in smokers and experimental models. A recent review summarized some proposed mechanisms such as the way in which free radicals and aromatic compounds decrease the endothelial synthesis of nitric oxide (NO), causing impaired endotheliumdependent relaxation of arteries, which is the earliest clinical sign of endothelial dysfunction (45). NO has been demonstrated to be the principal mediator of cavernous smooth muscle relaxation and penile erection (4, 14, 24, 30, 46 -48). However, the precise mechanisms of impairment of NO production with cigarette smoking have not been fully elucidated.NO production, on one hand, depends on nitric oxide synthase (NOS) activity and NOS protein expression. There are reports describing that NOS activity was decreased in the human ...

show abstract

Reversible Cigarette Smoke Extract–Induced DNA Damage in Human Lung Fibroblasts

Cited by 77 publications

References 31 publications

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

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

Cigarette Smoke Alters Respiratory Syncytial Virus–Induced Apoptosis and Replication

Alterations of NOS, arginase, and DDAH protein expression in rabbit cavernous tissue after administration of cigarette smoke extract

Contact Info

Product

Resources

About