[Action mechanism of Guben Kechuan Granules in rat models of chronic obstructive pulmonary disease based on Nrf2/SLC7A11/GPX4 signaling pathway].

Abstract

This paper aims to investigate the action mechanism of Guben Kechuan Granules in the treatment of chronic obstructive pulmonary disease(COPD) based on the nuclear factor erythroid 2-related factor 2(Nrf2)/solute carrier family 7 member 11(SLC7A11)/glutathione peroxidase 4(GPX4) signaling pathway. In this study, a COPD rat model was constructed using lipopolysaccharide(LPS) combined with porcine pancreatic elastase(PPE). The rats were divided into a low-dose Guben Kechuan Granule group(0.54 g·kg~(-1)), a high-dose Guben Kechuan Granule group(1.08 g·kg~(-1)), and a dexamethasone group(0.2 mg·kg~(-1)). After four weeks of intervention, the body weight and pulmonary function of rats were examined; the pathological changes of lung tissue were observed by hematoxylin-eosin(HE) staining; the mitochondrial structure of lung tissue was observed by transmission electron microscope(TEM); the levels of malondialdehyde(MDA), reduced glutathione(GSH), Fe~(2+), and total iron ions in lung tissue were detected by biochemical assays; the inflammatory factor levels in serum were measured by enzyme-linked immunosorbent assay(ELISA) kits; the protein expressions of Nrf2, SLC7A11, and GPX4 in lung tissue were detected by Western blot; the mRNA levels of Nrf2, SLC7A11, and GPX4 in lung tissue were determined by real-time quantitative polymerase chain reaction(RT-qPCR). The results show that compared with those in the model group, the rats in the Guben Kechuan Granule group exhibit significantly increased body weight, improved pulmonary function, and alleviated pathological injury and inflammation in lung tissue. The levels of tumour necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin-6(IL-6), interleukin-8(IL-8), and transforming growth factor-β(TGF-β) in serum were markedly decreased, while the level of interleukin-10(IL-10) was significantly elevated. Mitochondrial damage in lung tissue was significantly alleviated, with intact double-layer membrane structure and recovered morphology of inner membrane cristae. In addition, the levels of MDA, Fe~(2+), and total iron ions in lung tissue were reduced, whereas the GSH level was restored. These findings demonstrate that Guben Kechuan Granules could effectively alleviate oxidative stress and ferroptosis, improve pulmonary function, and alleviate inflammation in COPD rats. Molecular mechanistic studies reveal that the mice in the Guben Kechuan Granule group exhibit significantly up-regulated protein and mRNA expressions of Nrf2, SLC7A11, and GPX4 in lung tissue, compared with those in the model group. In summary, Guben Kechuan Granules can effectively improve pulmonary function and alleviate inflammation in COPD rats. Its action mechanism may be associated with activating the Nrf2/SLC7A11/GPX4 pathway and inhibiting ferroptosis in lung tissue.