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Roles of Bach1、Keap1、PERK、Nrf2 Regulating γ-glutamylcysteine Synthetase in Chronic Obstructive Pulmonary Disease

Author: GaoJunLi
Tutor: DaiAiGuo
School: Nanhua University
Course: Respiration within the science
Keywords: γ- glutamyl cysteine ??synthase Regulation Chronic obstructive Pulmonary disease
CLC: R563.9
Type: Master's thesis
Year: 2008
Downloads: 185
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Abstract

Objective: nuclear factor erythroid-derived lungs of rats by chronic obstructive pulmonary disease (COPD) associated factor -2 (NF-E2 related factor 2, Nrf2), BTB-CNC allogeneic homolog 1 (BTB and CNC homology 1 , Bach1), Keap1 (Kelch-like ECH associating protein 1), PERK (PKR-like endoplasmic reticulum kinase) and gamma-glutamyl cysteine ??synthetase (γ-GCS) expression, exploration Bach1, Nrf2 and Keap1 , of PERK and gamma-GCS role and significance in chronic obstructive pulmonary disease (COPD), and to explore its mechanism of action, for the the COPD pathogenesis new theoretical basis, and to provide new strategies and methods for their treatment. Method: sub-animal experiments and clinical trials. Animal experiments: healthy male SD rats 16, were randomly divided COPD model group and the control group, n = 8. Smoked cigarettes daily and twice intratracheal instillation of lipopolysaccharide (LPS) production COPD rat model. Determination of rat lung function and pathological morphological changes observed in rat lung tissue; γ-GCS activity in the lung tissue of rats were detected by in situ hybridization and reverse transcription polymerase chain reaction (RT-PCR) detection of lung tissue Nrf2, Bach1, Keap1 , γ-GCS mRNA expression. Immunohistochemistry and immunoblotting (western blot) analysis of γ-GCS in lung tissue and Nrf2, Keap1, Bach1, P-PERK the is protein levels. 2 clinical trials: surgical removal of the lung tissue of patients with lung cancer, 18 cases underwent pulmonary function testing in all patients with preoperative diagnosis of COPD standards enacted in 2002 by the Chinese Medical Association, the COPD group and the control group nine cases, RT-PCR Nrf2, Bach1 and γ-GCS mRNA expression in lung tissue, western blot analysis of lung tissue Bach1, Nrf2 and protein levels of γ-GCS. Results: 1.COPD rats of FEV0.3 and a FEV0.3/FVC% compared with the control group decreased (P lt; 0.05). Lung histopathological changes characteristic changes of COPD. Γ-GCS and Nrf2mRNA 2.COPD rats bronchial epithelial cell cytoplasm was strongly positive expression; the control group showed a weak positive expression in the corresponding parts of the two sets of images absorbance difference was statistically significant (P lt; 0.01), Bach1 and Keap1mRNA in the two groups were expressed, the difference was not statistically significant (P gt; 0.05). RT-PCR showed that there is a certain amount of γ-GCS and Nrf2mRNA expression in the lungs of the control group, but relative to the COPD group still lower (P lt; 0.01), no significant differences (P gt expression of Bach1mRNA two groups; 0.05) . 3 Immunohistochemistry showed: the COPD rats bronchial epithelial cells Nrf2, γ-GCS and P-PERK protein expression significantly increased compared with the control group; Bach1 and Keap1 protein expression in the control group showed no significant difference. Nuclear / cytoplasmic protein separation and Western blot showed that the the Nrf2 protein mainly expressed in the cytoplasm in the control group, in the cytoplasm of the COPD group, the nucleus was expressed, and significantly increased higher than that of the control group (P lt; 0.01), However, the level in the nucleus was significantly higher in the control group; Bach1 protein expression in the nucleus, in the COPD group was mainly expressed in the cytoplasm, and between the two groups was no significant difference (P gt; 0.05); Keap1 control and COPD groups are primarily expressed in the cytoplasm, between the two groups was no significant difference (P gt; 0.05); significantly enhanced P-PERK protein expression in the COPD group. 5. Situ hybridization showed that: γ-GCS and Nrf2 mRNA expression was significantly increased in the lung tissue of COPD patients compared with the control group difference was statistically significant (P lt; 0.01), and of Bach1 mRNA expression in the two groups There was no significant difference (P gt; 0.05); immunohistochemical results show: Nrf2 and γ-GCS protein in COPD patients group of lung tissue expression significantly, with the control group, compare the visible differences significant difference (P lt; 0.01) Bach1 protein in the lung tissue of COPD patients compared with the control group showed no significant difference. Linear correlation analysis 6.SPSS11.0 software visible nuclear Nrf2 protein expression the γ-GCSmRNA and its protein expression was positively correlated, p-PERK protein expression in rats and clinical trials with Nrf2 protein and γ-GCS mRNA expression expression was positively correlated with the ratio of nuclear Bach1 / Nrf2 protein γ-GCS, FEV0.3, FEV0.3/FVC% negative correlation. Conclusion: 1. Changes in regulation of γ-GCS expression in the nucleus Nrf2 and Bach1 protein levels play an important role in the mechanisms of oxidant / antioxidant imbalance in COPD. 2. Keap1 mainly expressed in the cytoplasm, and may play a role in the regulation of Nrf2 protein stability. 3. P-PERK signaling kinases may activate Nrf2 raised γ-GCS, and thereby plays an important role in the pathogenesis of COPD.

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