Mossman Brooke T, Lounsbury Karen M, Reddy Sekhar P
Department of Pathology, University of Vermont College of Medicine, Burlington, VT 05405, USA.
Am J Respir Cell Mol Biol. 2006 Jun;34(6):666-9. doi: 10.1165/rcmb.2006-0047SF. Epub 2006 Feb 16.
Oxidants in cigarette smoke and generated from asbestos fibers activate mitogen-activated protein kinase (MAPK) signaling cascades in lung epithelial cells in vitro and in vivo. These signaling pathways lead to the enhanced ability of Jun and Fos family members (i.e., components of the activator protein [AP]-1 transcription factor) to activate transcription of a number of AP-1-dependent target genes involved in cell proliferation or death, differentiation, and inflammation. Research by the Basbaum laboratory has been critical in showing that mucin transcription in response to cigarette smoke and gram-positive bacteria is mediated through activation of the epidermal growth factor receptor and MAPK cascades. Work from our laboratories supports the concept that MAPK signaling and AP-1 transactivation by cigarette smoke and asbestos may synergize in lung epithelial cell injury, compensatory proliferation of lung epithelial cells, and carcinogenesis, supporting a mechanistic framework for the striking increases in lung cancer incidence in asbestos workers who smoke. Targeting of MAPKs and inter-related signaling cascades may be critical to the prevention of lung cancers and control of mucin overproduction in a number of lung diseases including asthma, cystic fibrosis, chronic bronchitis, and chronic obstructive pulmonary disease.
香烟烟雾中的氧化剂以及石棉纤维产生的氧化剂，在体外和体内均可激活肺上皮细胞中的丝裂原活化蛋白激酶（MAPK）信号级联反应。这些信号通路导致Jun和Fos家族成员（即激活蛋白[AP]-1转录因子的组成部分）激活许多参与细胞增殖或死亡、分化及炎症的AP-1依赖性靶基因转录的能力增强。巴斯鲍姆实验室的研究对于表明香烟烟雾和革兰氏阳性菌刺激下的黏蛋白转录是通过表皮生长因子受体和MAPK级联反应的激活来介导的这一点至关重要。我们实验室的研究支持这样一种观点，即香烟烟雾和石棉引发的MAPK信号传导及AP-1反式激活可能在肺上皮细胞损伤、肺上皮细胞代偿性增殖和致癌过程中产生协同作用，这为吸烟的石棉工人肺癌发病率显著增加提供了一个机制框架。针对MAPK及相关信号级联反应进行干预，对于预防肺癌以及控制包括哮喘、囊性纤维化、慢性支气管炎和慢性阻塞性肺疾病在内的多种肺部疾病中的黏蛋白过度产生可能至关重要。
