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Experimental approach for gene therapy of pulmonary emphysema focusing on Klotho gene and GSTP1 gene

以Klotho基因和GSTP1基因为中心的肺气肿基因治疗实验方法

基本信息

批准号：
15590799
负责人：
TERAMOTO Shinji
金额：
$ 2.24万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

The gene polymorphism of exon 5 of glutathione S-transferases P1 (GSTP1) may predispose a smoker to the development of COPD. However, the direct association of the GSTP1 polymorphism and the development of emphysematous alteration of lungs after cigarette smoke exposure have not been examined. 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. Biochemical analysis revealed that chronic smoke exposure caused protease-antiprotease imbalance and oxidant-antioxidant imbalance in GSTP1/P2 null mouse.The results suggest that disruption of glutathione S-transferases pi class is susceptible to cigarette smoke-induced airway disease … More through protease-antiprotease imbalance and oxidant-antioxidant imbalance in mice.Each puff of a cigarette contains 1017 free radicals and about 4000 substrates including carcinogenic agents and other possible causative agents of COPD such as volatile aldehydes and hydrogen cyanide. Thus defects in the detoxification of these reactive species may predispose smokers to airflow obstruction and emphysema. Indeed the patients with slow mEPHX activity was significantly higher in patients with COPD, when compared to healthy controls. These findings have been supported by Pare and colleagues, who have assessed a well-characterized cohort of patients from the Lung Health Study.We have reported that the genetic polymorphism of exon 5 of smokers with of glutathione S-transferase P1 (GSTP1) is associated with the development of COPD in smokers. Because the GSTP1/Ile105 genotype is predominantly found in COPD (72%), but not in smokers without airflow limitation (52%), the GSTP1/Ile105 genotype may be less protective against xenobiotics in tobacco smoke. The recent data further supports that GSTP1/Ile105 homozygote is associated with an increase in IgE and histamine after challenge with diesel exhaust particles and allergens. Although cigarette smoking is the most important risk factor for the development of COPD, allergic airway inflammation, long-standing asthma, air pollutants, diesel exhaust particles, and xenobiotics may also cause irreversible airflow limitation such as COPD. It has been reported that the tunnel workers being exposed to gases and particles from blasting and diesel exhausts are likely to develop COPD (9). Therefore, subjects exposed to diesel exhaust particles are susceptibile to accelerated decline of lung function, resulting in COPD. There is growing evidence for the role of xenobiotics and antioxidant imbalance in the pathogenesis of airflow obstruction, which is supported by association studies between COPD and variants in epoxide hydrolase and GSTs that detoxify free radicals and other tobacco products (10-14). Before these associations are generally accepted, they must be subjected to scrutiny with further association studies in terms of ethnicity and COPD phenotypes. Less

谷胱甘肽S-转移酶P1（GSTP 1）第5外显子基因多态性可能是吸烟者发生COPD的易感基因。然而，GSTP 1多态性和吸烟后肺气肿改变的发展之间的直接联系尚未得到研究。我们研究了慢性烟雾吸入对谷胱甘肽S -转移酶P1/P2（GSTP 1）缺乏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。生化分析表明，慢性烟雾暴露导致GSTP 1/P2基因敲除小鼠蛋白酶-抗蛋白酶失衡和氧化剂-抗氧化剂失衡，提示谷胱甘肽S-转移酶pi类的破坏是香烟烟雾诱导的气道疾病的易感因素 ...更多信息通过蛋白酶-抗蛋白酶失衡和氧化剂-抗氧化剂失衡在小鼠中进行。每口香烟含有1017个自由基和大约4000个底物，包括致癌剂和其他可能导致COPD的物质，如挥发性醛和氰化氢。因此，这些活性物质的解毒缺陷可能使吸烟者容易发生气流阻塞和肺气肿。事实上，与健康对照组相比，COPD患者中mEPHX活性缓慢的患者显著更高。这些发现得到了帕雷及其同事的支持，他们评估了一组来自肺部健康研究的患者，我们报道了吸烟者谷胱甘肽S-转移酶P1（GST P1）外显子5的遗传多态性与吸烟者COPD的发生有关。由于GSTP 1/Ile 105基因型主要见于COPD（72%），而非无气流限制的吸烟者（52%），因此GSTP 1/Ile 105基因型对烟草烟雾中的外源性物质的保护性可能较低。最近的数据进一步支持GSTP 1/Ile 105纯合子与柴油机排气颗粒和过敏原激发后IgE和组胺的增加相关。虽然吸烟是COPD发展的最重要的危险因素，但过敏性气道炎症、长期哮喘、空气污染物、柴油机废气颗粒和外源性物质也可能导致不可逆的气流限制，如COPD。据报，隧道工人暴露于爆破和柴油废气产生的气体和颗粒，很可能患上慢性阻塞性肺病（9）。因此，暴露于柴油机排气颗粒的受试者容易加速肺功能下降，导致COPD。越来越多的证据表明外源性物质和抗氧化剂失衡在气流阻塞的发病机制中的作用，这得到了COPD与环氧化物水解酶和GST（可使自由基和其他烟草产品解毒）变体之间的关联研究的支持（10-14）。在这些相关性被普遍接受之前，必须对它们进行进一步的种族和COPD表型相关性研究的审查。少