Positive correlation between PPARgamma/PGC-1alpha and gamma-GCS in lungs of rats and patients with chronic obstructive pulmonary disease.

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.