Maintenance of airway epithelial barrier integrity via the inhibition of AHR/EGFR activation ameliorates chronic obstructive pulmonary disease using effective-component combination

Abstract

Background: Airway epithelial barrier dysfunction is highly related to the pathogenesis of chronic obstructive pulmonary disease (COPD). Effective-component combination (ECC) derived from Bufei Yishen formula (BYF) is an effective treatment regimen for patients with COPD and has previously been found to attenuate COPD and airway epithelial inflammation in rats.

Purpose: To determine the mechanism underlying the protective effects of ECC-BYF against the disruption of the airway epithelial barrier in COPD.

Methods: The protective effects of ECC-BYF on the airway epithelial barrier were investigated in a rat COPD model. BEAS-2B epithelial cells were stimulated with cigarette smoke extract (CSE) to determine the direct effects of ECC-BYF on epithelial barrier function and aryl hydrocarbon receptor (AHR)/ epidermal growth factor receptor (EGFR) signaling.

Results: The results revealed that ECC-BYF attenuated COPD in rats and maintained the airway epithelial barrier by upregulating the expression of apical junction proteins, including occludin (OCC), zonula occludens (ZO)-1, and E-cadherin (E-cad). In BEAS-2B cells, ECC-BYF decreased permeability, increased transepithelial electrical resistance, and prevented the decrease in OCC, ZO-1, and E-cad expression induced by CSE exposure. In addition, transcriptomics and network analysis revealed that the protective effects of ECC-BYF may be related to multiple signaling pathways, including ErbB, AHR, and PI3K-Akt-mTOR pathways. ECC-BYF treatment suppressed the protein levels of p-EGFR and p-ERK1/2 and mRNA levels of CYP1A1 in CSE-exposed BEAS-2B cells as well as the protein levels of p-EGFR, p-ERK1/2, and CYP1A1 in the lungs of rats with COPD. In BEAS-2B cells, the AHR agonist FICZ weakened the protective effect of ECC-BYF on the epithelial barrier by suppressing the increase in ZO-1 and OCC expression induced by ECC-BYF and preventing the inhibitory effects of ECC-BYF on EGFR phosphorylation.

Conclusions: This is the first study to demonstrate the protective effect of ECC-BYF on airway epithelial barrier function. The underlying mechanism may be associated with the suppression of the AHR/EGFR pathway to promote apical junction protein adhesion.

Keywords: AHR/EGFR pathway; Airway epithelial barrier; COPD; ECC-BYF.