Department of Respiratory Medicine, Hunan Institute of Gerontology, Hunan Province Geriatric Hospital, Changsha, China.
Acta Biochim Biophys Sin (Shanghai). 2010 Sep;42(9):603-14. doi: 10.1093/abbs/gmq071. Epub 2010 Aug 7.
Oxidative stress is one of the major pathogenesis of chronic obstructive pulmonary disease (COPD). gamma-Glutamylcysteine synthetase (gamma-GCS) is one of the paramount antioxidant enzymes in COPD. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a ligand-activated transcription factor, which is activated by specific ligands such as rosiglitazone (RGZ), exerting multiple biological effects. PPARgamma coactivator-1alpha (PGC-1alpha) is a PPARgamma coactivator, which binds to PPARgamma by induction of PPARgamma ligands, co-activating PPARgamma target genes. Growing evidence has suggested that PPARgamma/PGC-1alpha can regulate multiple antioxidant genes. However, the effect of PPARgamma/PGC-1alpha on gamma-GCS during the development of COPD remains unclear. Here, we measured the expression levels of PPARgamma, PGC-1alpha and gamma-GCS, gamma-GCS activity and reactive oxygen species (ROS) contents in lungs of rats treated by cigarette smoke (CS) + lipopolysaccharide (LPS) and CS + LPS + RGZ, as well as lungs of patients suffered from COPD. Compared with lungs from CS + LPS-treated rats, lungs of RGZ-treated rats demonstrated markedly lower ROS contents, and remarkable increase of gamma-GCS activity and increase of the expression levels of PPARgamma, PGC-1alpha, and gamma-GCS. Furthermore, compared with controls, expression levels of PPARgamma, PGC-1alpha, and gamma-GCS significantly increased in the lungs of mild COPD patients, and progressively decreased in lungs of patients with moderate and severe COPD. gamma-GCS protein was positively correlated with FEV(1)%. PPARgamma and PGC-1alpha proteins were positively correlated with gamma-GCS activity and mRNA level. In conclusion, gamma-GCS showed compensatory upregulation in the early stage of COPD, which progressively decompensate with increasing COPD severity. The activation of the PPARgamma/PGC-1alpha pathway may protect against COPD progression by upregulating gamma-GCS and relieving oxidative stress.
氧化应激是慢性阻塞性肺疾病（COPD）的主要发病机制之一。γ-谷氨酰半胱氨酸合成酶（γ-GCS）是 COPD 中最重要的抗氧化酶之一。过氧化物酶体增殖物激活受体-γ（PPARγ）是一种配体激活的转录因子，被特定的配体如罗格列酮（RGZ）激活，发挥多种生物学作用。过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）是一种 PPARγ 共激活因子，通过诱导 PPARγ 配体与 PPARγ 结合，共同激活 PPARγ 靶基因。越来越多的证据表明，PPARγ/PGC-1α可以调节多种抗氧化基因。然而，PPARγ/PGC-1α在 COPD 发展过程中对γ-GCS 的影响尚不清楚。在这里，我们测量了香烟烟雾（CS）+脂多糖（LPS）和 CS+LPS+RGZ 处理的大鼠肺中 PPARγ、PGC-1α 和 γ-GCS 的表达水平、γ-GCS 活性和活性氧（ROS）含量，以及患有 COPD 的患者的肺。与 CS+LPS 处理的大鼠肺相比，RGZ 处理的大鼠肺中的 ROS 含量明显降低，γ-GCS 活性显著增加，PPARγ、PGC-1α 和 γ-GCS 的表达水平增加。此外，与对照组相比，轻度 COPD 患者肺中 PPARγ、PGC-1α 和 γ-GCS 的表达水平显著增加，而中度和重度 COPD 患者肺中则逐渐降低。γ-GCS 蛋白与 FEV1%呈正相关。PPARγ 和 PGC-1α 蛋白与 γ-GCS 活性和 mRNA 水平呈正相关。总之，γ-GCS 在 COPD 的早期阶段表现出代偿性上调，随着 COPD 严重程度的增加而逐渐失代偿。PPARγ/PGC-1α 通路的激活可能通过上调 γ-GCS 和减轻氧化应激来保护 COPD 进展。
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