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Smoking sensitivity for the development of pulmonary emphysema and genetic polymorphisms in alveolar macrophage-derived proteinases

吸烟对肺气肿发展的敏感性和肺泡巨噬细胞衍生蛋白酶的遗传多态性

基本信息

批准号：
12470138
负责人：
YAMAGUCHI Kazuhiro
金额：
$ 6.66万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470138/
关键词：
pulmonary emphysema smoking chest CT MMP-9 cathepsin S cystatin C CYP2A6 cystatin C MMP-1 TIMP-2 肺機能 Cathepsin S HRCT 経年変化

项目摘要

COPD is defined by airflow obstruction caused by various mechanisms including alveolar destruction, airway hypersecretion, fibrosis of the airway wall, and remodeling of pulmonary vasculature. Genetic polymorphisms may be responsible for each process of the development of COPD. The present study aimed to elucidate the genetic factors involved in emphysematous changes of the lung in Japanese smokers by introducing diffusing capacity, low attenuation area score and the diameter of main pulmonary artery on chest CT images, and quantitative measures of exposure to smoking, as analytical parameters of COPD phenotypes, in addition to FEV1.0 which was solely utilized for genetical studies of COPD. Our study demonstrated that genetic polymorphisms in MMP-9 and cathepsin S, both of which are known to have potent elastase activity derived from alveolar macrophages, contribute to sensitivity to smoking for the development of pulmonary emphysema. In addition, CYP_2A_6, which metabolizes nicotine and activates procarcinogens, was related to emphysematous changes besides its effect on smoking habit. Genetic polymorphism of cystatin C, a main inhibitor of cathepsin S, was associated with the diameter of pulmonary artery, suggesting its role in the remodeling of pulmonary artery. CYP_2A_6 deletion polymorphism was also related to the tendency to become habitual smokers and the difficulty in cessation of smoking. These results suggest that smoking cessation programs including genetical analysis will give smokers a stronger motivation to quit smoking and help them utilize nicotine replacement therapy. Moreover, if genetical factors for individual phenotypes of COPD were identified, the pathogenesis of this complex category of pulmonary diseases may be better understood and the appropriate treatment for each disease process may be developed.

COPD定义为由各种机制引起的气流阻塞，包括肺泡破坏、气道高分泌、气道壁纤维化和肺血管重塑。遗传多态性可能是COPD发生发展的各个过程的原因。本研究旨在阐明日本吸烟者肺气肿性改变的遗传因素，除了用于COPD遗传学研究的FEV1.0外，还引入了弥散能力、低衰减面积评分和胸部CT图像上的主肺动脉直径，以及暴露于吸烟的定量测量，作为COPD表型的分析参数。我们的研究表明，MMP-9和组织蛋白酶S的遗传多态性，这两个都是已知的有强大的弹性蛋白酶活性来自肺泡巨噬细胞，有助于吸烟的肺气肿的发展的敏感性。此外，代谢尼古丁和激活前致癌物的CYP_2A_6除了与吸烟习惯有关外，还与肺气肿的变化有关。组织蛋白酶S的主要抑制剂半胱氨酸蛋白酶抑制剂C的基因多态性与肺动脉直径相关，提示其在肺动脉重塑中的作用。CYP_2A_6基因缺失多态性与吸烟者的吸烟倾向及戒烟困难有关。这些结果表明，包括基因分析在内的戒烟计划将给吸烟者更强的戒烟动机，并帮助他们利用尼古丁替代疗法。此外，如果确定了COPD个体表型的遗传因素，则可以更好地理解这一复杂类别的肺部疾病的发病机制，并可以开发针对每个疾病过程的适当治疗。