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The role of xenobiotic enzyme (Glutathione S-transferase P1) in the pathogenesis of chronic obstructive pulmonary disease.

异生酶（谷胱甘肽 S-转移酶 P1）在慢性阻塞性肺疾病发病机制中的作用。

基本信息

批准号：
12670550
负责人：
MATSUSE Takeshi
金额：
$ 2.43万
依托单位：
Yokohama City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670550/
关键词：
Xenobiotic enzyme Glutathione S-transferase P1 Apoptosis Necrosis cigarette smoke pulmonary emphysema COPD

项目摘要

Cigarette smoking is thought to be a major risk factor in various lung diseases, including chronic obstructive pulmonary disease. In this study, we investigated the viability of human lung fibroblast-derived HFL-1 cells in different concentrations of the cigarette smoke extract (CSE). CSE induced apoptosis at lower concentrations (10-25 %) and necrosis at higher concentrations (50-100 %). We also examined effects of glutathione S-transferase P1 (GSTP1), one of the xenobiotic metabolizing and antioxidant enzymes in the lung, against the cytotoxicity of CSE. Our results indicated that the level of HFL-1 cell death was decreased upon transfection of a GSTP1 expression vector and was increased by GSTP1 antisense vector transfection. Therefore, transient over-expression and under-expression of GSTP1 appeared to inhibit and enhance the cytotoxic effects of CSE on HFL-1, suggesting that GSTP1 may have protective effects against cigarette smoke in the airway cells. In addition, we examined the effects of chronic smoke inhalation on the function and morphology of lungs in mice lacking glutathione S-transferases P1/P2 (GSTP1). After 16 weeks of cigarette smoke exposure, a significant airspace size enlargement along with a leftward shift of the pressure-volume (P-V) curve was observed in GSTP1/2 null mice but not in control mice, when compared with the same strain of mice with air exposure. The results suggest that disruption of glutathione S-transferases pi class is susceptible to cigarette smoke-induced pulmonary emphysema in mice.

吸烟被认为是各种肺部疾病的主要危险因素，包括慢性阻塞性肺病。在这项研究中，我们研究了人肺成纤维细胞衍生的HFL-1细胞在不同浓度的香烟烟雾提取物（CSE）中的活力。CSE在较低浓度（10- 25%）下诱导细胞凋亡，在较高浓度（50- 100%）下诱导坏死。我们还研究了谷胱甘肽S-转移酶P1（GSTP 1），在肺中的异生物质代谢和抗氧化酶之一，对CSE的细胞毒性的影响。我们的研究结果表明，HFL-1细胞死亡的水平降低后，转染的GST 1表达载体和GST 1反义载体转染增加。因此，GSTP 1的瞬时过表达和低表达可抑制和增强CSE对HFL-1的细胞毒性作用，提示GSTP 1可能对气道细胞具有香烟烟雾的保护作用。此外，我们研究了慢性烟雾吸入对缺乏谷胱甘肽S-转移酶P1/P2（GSTP 1）的小鼠肺功能和形态的影响。香烟烟雾暴露16周后，与暴露于空气中的同品系小鼠相比，在GSTP 1/2敲除小鼠中观察到显著的空域尺寸增大沿着，压力-容积（P-V）曲线显著移位，但在对照小鼠中未观察到。结果表明，谷胱甘肽S-转移酶pi类的破坏是香烟烟雾诱导的小鼠肺气肿的易感性。