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. 2008 Jul 15;230(2):150-8.
doi: 10.1016/j.taap.2008.02.005. Epub 2008 Feb 15.

"V体育ios版" NF-kappaB inhibition is involved in tobacco smoke-induced apoptosis in the lungs of rats

Cai-Yun Zhong  1 , Ya Mei Zhou, Kent E Pinkerton
Affiliations

NF-kappaB inhibition is involved in tobacco smoke-induced apoptosis in the lungs of rats (VSports app下载)

Cai-Yun Zhong et al. Toxicol Appl Pharmacol. .

Abstract

Apoptosis is a vital mechanism for the regulation of cell turnover and plays a critical role in tissue homeostasis and development of many disease processes. Previous studies have demonstrated the apoptotic effect of tobacco smoke; however, the molecular mechanisms by which tobacco smoke triggers apoptosis remain unclear VSports手机版. In the present study we investigated the effects of tobacco smoke on the induction of apoptosis in the lungs of rats and modulation of nuclear factor-kappa B (NF-kappaB) in this process. Exposure of rats to 80 mg/m(3) tobacco smoke significantly induced apoptosis in the lungs. Tobacco smoke resulted in inhibition of NF-kappaB activity, noted by suppression of inhibitor of kappaB (IkappaB) kinase (IKK), accumulation of IkappaBalpha, decrease of NF-kappaB DNA binding activity, and downregulation of NF-kappaB-dependent anti-apoptotic proteins, including Bcl-2, Bcl-xl, and inhibitors of apoptosis. Initiator caspases for the death receptor pathway (caspase 8) and the mitochondrial pathway (caspase 9) as well as effector caspase 3 were activated following tobacco smoke exposure. Tobacco smoke exposure did not alter the levels of p53 and Bax proteins. These findings suggest the role of NF-kappaB pathway in tobacco smoke-induced apoptosis. .

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Figures

Fig. 1
Fig. 1
Results of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) of rat lungs. A: H & E staining of an area of squamous metaplasia in the main airway path of rats exposed to 80 mg/m3 tobacco smoke. B: TUNEL labeling in the main airway path. Arrows indicate TUNEL-positive cells. C: Apoptotic index (the percentage of apoptotic nuclei of the total number of nuclei counted) in airways and parenchyma. Values represent mean ± SE (n=6). **p<0.01, compared with FA. Magnification bar represents 50 microns.
Fig. 2
Fig. 2
Effect of tobacco smoke on NF-κB activity. A: Electrophoretic mobility shift assay to show NF-κB-DNA binding activity in rat lungs. Lane 1, competition assay; lanes 2–5, filtered air (FA); lanes 6–9, 30 mg/m3 tobacco smoke; lanes 10–13, 80 mg/m3 tobacco smoke. B: Densitometry of NF-κB -DNA binding activity. Data are expressed as means ± SE (n=4). **p<0.01, compared with FA.
Fig. 3
Fig. 3
Effect of tobacco smoke on the expression of NF-κB subunits. A: Western blot analysis of NF-κB p65 and p50 in the nuclei of rat lungs. Lanes 1–3, filtered air (FA); lanes 4–6, 30 mg/m3 tobacco smoke; lanes 7–9, 80 mg/m3 tobacco smoke. B: Densitometry of Western blot results for NF-κB subunits. Values are presented as means ± SE (n=3). *p<0.05, compared with FA.
Fig. 4
Fig. 4
Effect of tobacco smoke on the NF-κB activation pathway. Western blot analysis of IκB-α, IκB-β, p-IKKα, p–IKKβ (A) and HSP70 (C). Lanes 1–3, FA; lanes 4–6, 30 mg/m3 tobacco smoke; lanes 7–9, 80 mg/m3 tobacco smoke. Densitometry of Western blot results for IκB-α, IκB-β, p-IKKα, p–IKKβ (B) and HSP70 (D). Values are presented as means ± SE (n=3). **p<0.01, compared with FA.
Fig. 5
Fig. 5
Effect of tobacco smoke on the expression of NF-κB – dependent anti-apoptotic proteins. A: Western blot analyses of Bcl-2, Bcl-xl, c-IAP1, c-IAP2 and XIAP in rat lungs. Lanes 1–3, FA; lanes 4–6, 30 mg/m3 tobacco smoke; lanes 7–9, 80 mg/m3 tobacco smoke. B: Densitometry of Western blot results. Values are presented as means ± SE (n=3). *p<0.05, compared with FA ; **p<0.01, compared with FA.
Fig. 6
Fig. 6
Effect of tobacco smoke on the expression of p53 and Bax. A: Western blot analyses of p53 and Bax in the lungs of rats. Lanes 1–3, FA; lanes 4–6, 30 mg/m3 tobacco smoke; lanes 7–9, 80 mg/m3 tobacco smoke. B: Densitometry of Western blotting results. Values are presented as means ± SE (n=3).
Fig. 7
Fig. 7
Effect of tobacco smoke on caspase activation. A: Western blot analyses of caspases 8, 9 and 3 in the lungs of rats. Lanes 1–3, FA; lanes 4–6, 30 mg/m3 tobacco smoke; lanes 7–9, 80 mg/m3 tobacco smoke. B: Densitometry of Western blot results. Values are presented as means ± SE (n=3). *p<0.05, compared with FA; **p<0.01, compared with FA.
Fig. 8
Fig. 8
Proposed model of the role of NF-κB pathway in tobacco smoke-induced apoptosis in the lungs of rats. Through suppression of IKK and induction of HSP70, tobacco smoke inhibits NF-κB activity and downregulates NF-κB -dependent anti-apoptotic proteins, including members of Bcl-2 and c-IAPs, leading to caspase activation of both mitochondial (caspase 9) and death receptor (caspase 8) pathways as well as the effector caspase (caspase 3), eventually inducing apoptosis.
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References

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