Effective-component compatibility of Bufei Yishen formula II inhibits mucus hypersecretion of chronic obstructive pulmonary disease rats by regulating EGFR/PI3K/mTOR signaling

Abstract

Ethnopharmacological relevanceThe effective-component compatibility of Bufei Yishen formula I (ECC-BYF I), a combination of 10 compounds, including total ginsenosides, astragaloside IV, icariin, and paeonol, etc., is derived from Bufei Yishen formula (BYF). The efficacy and safety of ECC-BYF I is equal to BYF. However, the composition of ECC-BYF I needs to be further optimized. Based on the beneficial effects of BYF and ECC-BYF I on chronic obstructive pulmonary disease (COPD), this study aimed to optimize the composition of ECC-BYF I and to explore the effects and mechanisms of optimized ECC-BYF I (ECC-BYF II) on mucus hypersecretion in COPD rats. Materials and methodsECC-BYF I was initially optimized to six groups: optimized ECC-BYF I (OECC-BYF I)-A~F. Based on a COPD rat model, the effects of OECC-BYF I-A~F on COPD rats were evaluated. R-value comprehensive evaluation was used to evaluate the optimal formula, which was named ECC-BYF II. The changes in goblet cells and expression of mucins and the mRNA and proteins involved in the epidermal growth factor receptor/phosphoinositide-3-kinase/mammalian target of rapamycin (EGFR/PI3K/mTOR) pathway were evaluated to explore the effects and mechanisms of ECC-BYF II on mucus hypersecretion. ResultsECC-BYF I and its six optimized groups, OECC-BYF I-A~F, had beneficial effects on COPD rats in improving pulmonary function and lung tissue pathology, reducing inflammation and oxidative stress, and improving the protease/anti-protease imbalance and collagen deposition. R-value comprehensive evaluation found that OECC-BYF I-E (paeonol, icariin, nobiletin, total ginsenoside, astragaloside IV) was the optimal formula for improving the comprehensive effects (lung function: VT, MV, PEF, EF50, FVC, FEV 0.1, FEV 0.1/FVC; histological changes: MLI, MAN; IL-1β, IL-6, TNF-α, MMP-9, TIMP-1, T-AOC, LPO, MUC5AC, Collagen I and Collagen III). OECC-BYF I-E was named ECC-BYF II. Importantly, the effect of ECC-BYF II showed no significant difference from BYF and ECC-BYF I. ECC-BYF II inhibited mucus hypersecretion in COPD rats, which manifested as reducing the expression of MUC5AC and MUC5B and the hyperplasia rate of goblet cells. The mRNA and protein expression levels of EGFR, PI3K, Akt, and mTOR were increased in COPD rats and were obviously downregulated after ECC-BYF II administration. ConclusionECC-BYF II, which consists of paeonol, icariin, nobiletin, total ginsenoside and astragaloside IV, has beneficial effects equivalent to BYF and ECC-BYF I on COPD rats. ECC-BYF II significantly inhibited mucus hypersecretion, which may be related to the regulation of the EGFR/PI3K/mTOR pathway.