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

谷胱甘肽S转移酶P1基因第5外显子的基因多态性可能是吸烟者发生慢性阻塞性肺疾病的易感因素。然而，GSTP1基因多态与香烟烟雾暴露后肺气肿改变的直接相关性尚未被研究。我们观察了慢性烟雾吸入对谷胱甘肽S转移酶P1/P2缺失小鼠肺功能和形态的影响。香烟烟雾暴露16周后，与同一品系暴露在空气中的小鼠相比，GSTP1/2缺失小鼠的空域面积显著扩大，压力-体积(P-V)曲线左移，而对照组小鼠则没有。生化分析显示，慢性烟雾暴露可引起GSTP1P2基因缺失小鼠的蛋白水解酶-抗蛋白酶失衡和氧化-抗氧化失衡，提示谷胱甘肽S转移酶pi类基因的紊乱是香烟烟雾所致呼吸道疾病…的易感因素每一口香烟含有1017个自由基和大约4000种底物，包括致癌物质和其他可能导致慢性阻塞性肺疾病的物质，如挥发性醛和氰化氢。因此，这些活性物质的解毒缺陷可能会使吸烟者容易患上气流阻塞和肺气肿。事实上，与健康对照组相比，慢性阻塞性肺疾病患者中mEPHX活性缓慢的患者显著更高。这些发现得到了Pare和他的同事的支持，他们评估了一组来自肺健康研究的具有良好特征的患者。我们报告了带有谷胱甘肽S转移酶P1的吸烟者外显子5的基因多态与吸烟者慢性阻塞性肺疾病的发生有关。由于GSTP1/Ile105基因主要在COPD中发现(72%)，而不是在没有气流限制的吸烟者中发现(52%)，因此GSTP1/Ile105基因对烟草烟雾中的异物的保护作用可能较弱。最近的数据进一步支持GSTP1/Ile105纯合子与柴油机尾气颗粒物和过敏原攻击后IgE和组胺的增加有关。虽然吸烟是COPD发生的最重要的危险因素，但过敏性呼吸道炎症、长期存在的哮喘、空气污染物、柴油废气颗粒和异物也可能导致不可逆转的气流受限，如COPD。据报道，隧道工人暴露在爆破和柴油废气中的气体和颗粒物中，很可能会患上慢性阻塞性肺病(COPD)(9)。因此，暴露在柴油尾气颗粒物中的受试者容易出现肺功能加速下降，导致COPD。越来越多的证据表明，外源物质和抗氧化剂失衡在气流阻塞的发病机制中发挥了作用，这一点得到了COPD与环氧化物水解酶和GSTs变体之间的关联研究的支持，GSTs可以为自由基和其他烟草产品解毒(10-14)。在这些关联被普遍接受之前，必须对它们进行审查，并就种族和COPD表型进行进一步的关联研究。较少

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