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

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 beta-catenin gene. Moreover, we found that beta-catenin localized in cytomembrane upon avasimibe treatment. Avasimibe also reduced beta-catenin phosphorylation in the cytoplasm and inactivated the Wnt/beta-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.

Automated summary

The study found that avasimibe could reduce the production of inflammatory factors, lower the level of immunoglobulin E, and improve the secretion and distribution of airway epithelial cells in house dust mite-induced asthmatic mice. Furthermore, avasimibe alleviated the changes in adherens junction proteins induced by house dust mites through the regulation of beta-catenin activation and cellular localization, thus improving the integrity of the airway epithelial barrier.