2004 Fiscal Year Final Research Report Summary
Experimental approach for gene therapy of pulmonary emphysema focusing on Klotho gene and GSTP1 gene
| Project/Area Number |
15590799
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | The University of Tokyo |
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Principal Investigator |
TERAMOTO Shinji The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 講師 (50282629)
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| Co-Investigator(Kenkyū-buntansha) |
NAGASE Takahide The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (40208004)
KAWAGUCHI Hiroshi The University of Tokyo, Faculty of Medicine, Associate Professor, 医学部附属病院, 助教授 (40282660)
大賀 栄次郎 東京大学, 医学部附属病院, 助手
OHGA Fujiro The University of Tokyo, Faculty of Medicine, Assistant
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| Project Period (FY) |
2003 – 2004
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| Keywords | COPD / Gene Therapy / Glutathione S-transferase P1 / klotho gene / chronic tabacco exposure / Adenovirus vector / apoptosis |
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| Research Abstract |
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
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