4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a carcinogenic compound of cigarette smoke that generates electrophilic intermediates capable of damaging DNA. Recently, we have shown that NNK can modulate mediator production by alveolar macrophages (AM) and bronchial and alveolar epithelial cells, suggesting that cigarette smoke can alter lung immune response. Thus, we investigated the effect of NNK and cigarette smoke extract (CSE) on AM capacity to eliminate tumoral cells. Rat AM cell line, NR8383, was treated with NNK (500 microM) or CSE (3%) and stimulated with lipopolysaccharide (10 ng/ml). The release of cytotoxic mediators, tumor necrosis factor (TNF) and reactive oxygen species (ROS), was measured in cell-free supernatants using ELISA and superoxide anion production. TNF- and ROS-dependent cytotoxicity were studied using a (51)Chromium-release assay and WEHI-164 and P-815 cell lines. Treatment of AM with NNK and CSE for 18 h significantly inhibited AM TNF release. CSE exposure resulted in a significant increase of ROS production, whereas NNK did not. TNF-dependent cytotoxic activity of NR8383 and freshly isolated rat AM was significantly inhibited after treatment with NNK and CSE. Interestingly, although ROS production was stimulated by CSE and not affected by NNK, CSE inhibited AM ROS-dependent cytotoxicity. These results suggest that NNK may be one of the cigarette smoke components responsible for the reduction of pulmonary cytotoxicity. Thus, NNK may have a double pro-carcinogenic effect by contributing to DNA adduct formation and inhibiting AM cytotoxicity against tumoral cells.

译文

:4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁酮(NNK)是香烟烟雾的致癌化合物,可产生能够破坏DNA的亲电子中间体。最近,我们已经显示NNK可以调节肺泡巨噬细胞(AM)以及支气管和肺泡上皮细胞的介体产生,这表明香烟烟雾可以改变肺部免疫反应。因此,我们研究了NNK和香烟烟雾提取物(CSE)对AM消除肿瘤细胞能力的影响。用NNK(500 microM)或CSE(3%)处理大鼠AM细胞系NR8383,并用脂多糖(10 ng / ml)刺激。使用ELISA和超氧阴离子产生法在无细胞上清液中测量细胞毒性介质,肿瘤坏死因子(TNF)和活性氧(ROS)的释放。使用(51)铬释放试验以及WEHI-164和P-815细胞系研究了TNF-依赖性和ROS依赖性细胞毒性。用NNK和CSE治疗AM 18小时可显着抑制AM TNF释放。 CSE暴露导致ROS产生显着增加,而NNK则没有。用NNK和CSE处理后,NR8383和新鲜分离的大鼠AM的TNF依赖性细胞毒性活性被显着抑制。有趣的是,尽管CSE刺激了ROS的产生,而不受NNK的影响,但CSE抑制了AM ROS依赖性的细胞毒性。这些结果表明,NNK可能是引起肺细胞毒性降低的香烟烟雾成分之一。因此,通过促进DNA加合物的形成并抑制AM对肿瘤细胞的细胞毒性,NNK可能具有双重致癌作用。

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