Schuller Hildegard M, Plummer Howard K, Jull Brian A
Department of Pathology, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996, USA.
Anat Rec A Discov Mol Cell Evol Biol. 2003 Jan;270(1):51-8. doi: 10.1002/ar.a.10019.
Pulmonary neuroendocrine cells (PNECs) have been implicated in the development of small cell lung carcinoma (SCLC) and pediatric asthma, and smoking is a risk factor for both diseases. We as well as others have shown that the alpha(7) nicotinic acetylcholine receptor (alpha(7) nAChR) regulates the release of 5-hydroxytryptamine (5-HT, serotonin) in PNECs and SCLC. Serotonin is an autocrine growth factor for PNECs and SCLC and acts as broncho-constrictor. We found that nicotine and its nitrosated carcinogenic derivative 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) bind to the alpha(7) nAChR in SCLC and PNECs, resulting in the influx of Ca(2+), release of 5-HT, and activation of a mitogenic pathway mediated by protein kinase C (PKC), Raf-1, mitogen activated protein kinase (MAPK) and c-myc. Exposure to 10% CO(2) acted synergistically. Unstimulated SCLC cells from smokers demonstrated high base levels of 5-HT release and of individual downstream signaling components in comparison to PNECs. Subchronic exposure of PNECs to NNK up-regulated the alpha(7) nAChR and its associated serotonergic mitogenic pathway in PNECs, an effect that may contribute to the development of SCLC in smokers and pediatric asthma in children of mothers who smoke.
肺神经内分泌细胞（PNECs）与小细胞肺癌（SCLC）和小儿哮喘的发生有关，而吸烟是这两种疾病的危险因素。我们以及其他人已经表明，α7烟碱型乙酰胆碱受体（α7 nAChR）调节PNECs和SCLC中5-羟色胺（5-HT，血清素）的释放。血清素是PNECs和SCLC的自分泌生长因子，起支气管收缩剂的作用。我们发现尼古丁及其亚硝化致癌衍生物4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）与SCLC和PNECs中的α7 nAChR结合，导致Ca（2+）内流、5-HT释放以及由蛋白激酶C（PKC）、Raf-1、丝裂原活化蛋白激酶（MAPK）和c-myc介导的促有丝分裂途径的激活。暴露于10% CO（2）起协同作用。与PNECs相比，吸烟者未受刺激的SCLC细胞显示出5-HT释放和单个下游信号成分的高基础水平。PNECs亚慢性暴露于NNK会上调PNECs中的α7 nAChR及其相关的血清素能促有丝分裂途径，这种效应可能有助于吸烟者患SCLC以及吸烟母亲的子女患小儿哮喘。
