Loke zupa decoction attenuates bronchial EMT-mediated airway remodelling in chronic asthma through the PI3K-Akt/HIF-1α signaling pathway

Abstract

Context Loke zupa decoction (Lok) is a well-established classic Chinese folk remedy for asthma. Objective We sought to investigate the effect and mechanism of Lok on asthma airway remodelling and provide novel insights for the prevention and treatment of asthma. Materials and methods For in vitro experiments, BEAS-2B cells were assigned into six groups: Control, TGF-β1 (10 μM), TGF-β1 + Lok-20, TGF-β1 + Lok-40, TGF-β1 + Lok-80 μg/mL and TGF-β1 + SB431542 (5 μM). CCK8 and wound healing assays were performed. For in vivo experiments, 60 female BALB/c mice were randomly divided into 5 groups: Control, model, Lok-4.55, Lok-9.1, and DEX group. Lok was administrated by gavage during the challenge stage for 8 consecutive weeks (4.55 and 9.1 g/kg/day). We investigated airway inflammation and airway remodelling in the lungs and verified the activation status of EMT-related markers and the PI3K-Akt/HIF-1α signalling pathway. Results In vitro , Lok efficiently inhibited TGF-β1-induced BEAS-2B cell proliferation ability (cell viability 165% vs. 105%) and migration (migration areas 85% vs. 35%) without affecting their normal growth (IC50 274.2 µg/mL at 48 h). In vivo , Lok effectively protected mice from asthma, as evidenced by decreased histological damage and level of cytokines in BALF (IL-4, IL-13 and TGF-β1) by 17%–77%. Mechanistic research revealed that Lok reduced the levels of EMT-related molecules and significantly downregulated the PI3K-Akt/HIF-1α signalling pathway. Discussion and conclusions Our findings provide novel insights into the protective effect of Lok on asthma and the underlying mechanisms, providing a theoretical basis and potential treatment possibilities for this patient population.

PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, relieves airway hyperresponsiveness, mucus hypersecretion and inflammation in a murine asthma model

“…The MAPK/Akt pathway is an important signaling pathway in asthma formation that participates in airway remodeling and inflammation (Liu et al 2023 ; Lyu et al 2022 ; Jin et al 2023 ). To further identify the possible involved signaling pathway, we determined the expression levels of MAPK and Akt, which are important components of the MAPK/Akt pathway (Ma et al 2016 ; Bai et al 2022 ; Liu et al 2015 ).…”

Approach for Elucidating the Molecular Mechanism of Epithelial to Mesenchymal Transition in Fibrosis of Asthmatic Airway Remodeling Focusing on Cl− Channels

“…Yadav et al reported that the inhibition of aldose reductase prevents TGF-β1-induced EMT in airway epithelial cells and airway remodeling in ovalbumin (OVA)-induced asthmatic model mice via inhibiting the TGF-β1/PI3K/AKT/GSK-3β signaling pathway [ 55 ]. Additionally, Liu et al reported that Lok, which is a traditional folk medicine widely used in northwest China for asthma, inhibits EMT in OVA-induced asthmatic model mice and TGF-β1-induced EMT in airway epithelial cells through inhibiting the PI3K/AKT/HIF-1α signaling pathway [ 56 ]. These results indicate that TGF-β1 activates the PI3K/AKT signaling pathway in a Smad-independent manner during EMT, which causes fibrosis in asthmatic airway remodeling.…”