Avasimibe Alleviates Disruption of the Airway Epithelial Barrier by Suppressing the Wnt/β-Catenin Signaling Pathway.

Zicong Zhou,Jieyi Liu,Fei Zou,Changhui Yu,Zili Zhou,Shaoxi Cai,Xiaojing Meng,Shixiu Liang

doi:10.3389/fphar.2022.795934

Zicong Zhou, Jieyi Liu + Show 6 more

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https://doi.org/10.3389/fphar.2022.795934

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Abstract

Avasimibe (Ava) is an acetyl-CoA acetyltransferase 1 (ACAT1) specific inhibitor and an established medicine for atherosclerosis, owing to its excellent and safe anti-inflammation effects in humans. However, its efficacy in asthma has not yet been reported. We first administered varying concentrations of avasimibe to house dust mite (HDM)-induced asthmatic mice; results showed that 20 mg/kg avasimibe most significantly reduced IL-4 and IL-5 production in bronchoalveolar lavage fluid (BALF) and total IgE in serum, and the avasimibe treatment also exhibited lower mucus secretion, decreased goblet and basal cells but increased ciliated cells compared to the HDM group. And the redistribution of adherens junction (AJ) proteins induced by HDM was far more less upon avasimibe administration. However, avasimibe did not reduce the cholesterol ester ratio in lung tissues or intracellular cholesterol ester, which is avasimibe’s main effect. Further analysis confirmed that avasimibe impaired epithelial basal cell proliferation independent of regulating cholesterol metabolism and we analyzed datasets using the Gene Expression Omnibus (GEO) database and then found that the KRT5 gene (basal cell marker) expression is correlated with the β-catenin gene. Moreover, we found that β-catenin localized in cytomembrane upon avasimibe treatment. Avasimibe also reduced β-catenin phosphorylation in the cytoplasm and inactivated the Wnt/β-catenin signaling pathway induced by HDMs, thereby alleviating the airway epithelial barrier disruption. Taken together, these findings indicated that avasimibe has potential as a new therapeutic option for allergic asthma.

Highlights

Allergic asthma is a common, complex chronic pulmonary disease, characterized by bronchoconstriction, reversible airways hyperresponsiveness, and sensitivity to inhaled environmental irritants (Finotto et al, 2001; Percopo et al, 2014; Drake et al, 2018)
Repetitive chronic inflammation destroys the integrity of the airway epithelial barrier, thereby allowing environmental toxicants to reach the subepithelial tissue and further impairing airway tissue and exacerbating asthmatic symptoms (Jude et al, 2019)
Our research has first focused on the association between cholesterol metabolism homeostasis and airway epithelial barrier disruption in asthma, since the former plays a critical role in inflammatory disorder

Summary

Introduction

Allergic asthma is a common, complex chronic pulmonary disease, characterized by bronchoconstriction, reversible airways hyperresponsiveness, and sensitivity to inhaled environmental irritants (Finotto et al, 2001; Percopo et al, 2014; Drake et al, 2018). To address the underlying pathogenesis, many researchers have engaged in studies that focused on inhibitors of critical factors, such as anti-IL-4, anti-IL-33, or targeting TSLP/TSLPR axis, to be Avasimibe Helps to Treat Asthma therapeutically beneficial in asthma (Qin et al, 2015; Emdin et al, 2018) They have obtained numerous results, there is still a long distance from the laboratories to the clinical treatments. Desquamation and denudation of the epithelium are significant features of the airway epithelial barrier disruption in asthma (Finotto et al, 2001; Lundblad et al, 2011; Drake et al, 2018; Wei et al, 2020)

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