PGC-1α与Nrf2协同调控γ-谷氨酰半胱氨酸合酶对大鼠COPD的作用  

Roles of PGC-1α and Nrf2 Synergistic Regulating γ-Glutamylcysteine Synthetase in Rats with Chronic Obstructive Pulmonary Disease

作　　者：李洁[1,2] 戴爱国 王梅芳 胡瑞成 朱黎明 

机构地区：[1]南华大学研究生院,湖南衡阳421001 [2]湖南省老年医院老年医学研究所呼吸疾病研究室,湖南长沙410016

出　　处：《中国呼吸与危重监护杂志》2009年第6期528-533,共6页Chinese Journal of Respiratory and Critical Care Medicine

基　　金：湖南省科技计划重点资助项目(No.2007FJ3016;No.2008FJ4206);湖南省科技计划项目(No.05JT1023;No.2007SK3080);湖南省医药卫生科研课题(No.B2005125;No.B2007166);湖南省自然科学基金(No.09JJ5021)

摘　　要：目的探讨过氧化物酶体增殖物激活受体γ辅激活因子1α(PGC-1α)和红系衍生的核因子相关因子2(Nrf2)对γ-谷氨酰半胱氨酸合酶(γ-GCS)表达的调控及其在COPD中的作用和意义。方法24只大鼠随机分为COPD组和对照组。COPD组用每日熏香烟和两次气管内滴入脂多糖(LPS)的方法制作COPD模型。观察大鼠的肺组织病理学改变,检测肺功能指标;应用免疫组化、Western blot、原位杂交和逆转录-聚合酶链反应检测肺组织中PGC-1α、Nrf2和γ-GCS的蛋白及mRNA表达情况。结果COPD组的肺功能指标(FEV0.3、FEV0.3/FVC、PEF)和光镜下COPD组肺组织病理变化符合COPD的特征性改变。PGC-1α、Nrf2 mRNA在两组大鼠肺组织中均有表达,且与γ-GCS mRNA的表达部位基本一致;PGC-1α、γ-GCS蛋白及mRNA表达在COPD组均显著高于对照组(P均<0.05);Nrf2蛋白表达在COPD组较对照组显著增高(P<0.01),而Nrf2 mRNA在两组表达无明显差异(P<0.05)。相关性分析显示PGC-1α蛋白与Nrf2蛋白及mRNA表达均呈正相关(r值分别为0.775和0.515,P均<0.01),PGC-1α、Nrf2蛋白与γ-GCS蛋白(r值分别为0.531和0.575,P均<0.01)及mRNA表达(r值分别为0.616和0.634,P<均0.01)均呈正相关。结论PGC-1α可能作为Nrf2的辅激活因子,通过辅助激活Nrf2,上调γ-GCS的基因表达;PGC-1α和Nrf2可能通过一个共同通路协同上调γ-GCS的基因表达,从而改善COPD的氧化/抗氧化失衡。Objective To explore the regulation of peroxisome proliferator-activated receptor coaetivator 1α （ PGC-1α） and NF-E2-related factor 2 （Nrf2） on expression of γ-glutamylcysteine synthetase （γ-GCS） ,and their roles in chronic obstructive pulmonary disease（COPD）. Methods Twenty-four SD rats were randomly divided into a COPD group and a normal control group. COPD model was established by intratracheal instillation of lipopolysaeeharide （LPS） and daily exposure to cigarette smog in the COPD group. The lung function was measured and the pathological changes were observed. The protein and mRNA expressions of PGC-1α, Nrf2, and γ-GCS in lung tissue were measured by immunohistochemistry, Western blot, in site hybridization （ISH）, and reverse transeription-polymerase chain reaction （RT-PCR）, respectively. Results In the COPD group, the pulmonary function （ FEv0.3 , FEV0.3/FVC, PEF） damage and lung pathological changes were conformed as morphological characteristics of COPD. The mRNA of PGC-lct and Nrf2 expressed in lung tissues of two group rats in the region consistent with γ-GCS mRNA. The protein and mRNA expressions of PGC-1α and γ-GCS were markedly increased in the COPD group（ all P 〈0. 05 ） ,and the protein expression of Nrf2 was obviously up-regulated （P 〈 0. 01 ）, while Nrf2 mRNA had no significant difference between the two groups（ P 〉 0. 05 ）. Linear correlation analysis showed that the level of PGC-1α protein was positively correlated with the levels of Nrf2 protein and mRNA （ r = 0. 775,0. 515, all P 〈0. 01 ）, and the levels of PGC-Iot and Nr/2 protein were positively correlated with the levels of γ-GCS protein （r = 0. 531,0. 575, all P 〈 0. 01 ） and mRNA （ r = 0. 616,0. 634, all P 〈 0. 01 ）. Conclusions PGC-1α,which may serve as a co-activator of Nrf2, can up-regulate the expression of γ-GCS gene cooperatively with Nrf2 through a common pathway, which might involve in the oxidative and antioxidative mechanism in the pathogenesis of

关 键 词：慢性阻塞性肺疾病 过氧化物酶体增殖物激活受体γ辅激活因子-1α 红系衍生的核因子相关因子2 Γ-谷氨酰半胱氨酸合酶 

分 类 号：R563.9[医药卫生—呼吸系统]