The Mechanism Of Avasimibe Suppressing House Dust Mites-induced Proliferation Of Airway Epithelial Basal Cells

1 BackgroundThere is a clear correlation between lipid metabolism,including cholesterol metabolism,and chronic inflammation.Avasimibe inhibits acyl-CoA:cholesteryl transferases(ACATs)to reduce the conversion of intracellular free cholesterol to cholesterol esters,thereby playing a role in regulating cholesterol metabolism.Allergic asthma is characterized by typical chronic inflammatory,researches on asthma and lipid metabolism are gradually increased in recent years,but the underlying mechanism between drug-based regulation of cholesterol metabolism and asthma is still rarely reported.This study aims to start from the drug-based regulation of cholesterol metabolism to find new targets and clues for the treatment of allergic asthma.2 Method(1)The efficacy of avasimibe in the treatment of asthma mice was determined through animal experiments:the mice were randomly divided into control groups,allergic asthma group and treatment groups,and the model of allergic asthma mice were administrated by house dust mites,then avasimibe was given for treatment;at last the results were analyzed by detecting allergic asthma-related indicators.(2)Exploring the intrinsic mechanism of avasimibe’s improvement in asthma through cell experiments:using house dust mites to stimulate airway epithelial cells to construct an in vitro model of allergic asthma,and exploring the mechanism of Avasimibe’s effect on improving allergic asthma through immunoblotting,qPCR,cell proliferation assay,immunofluorescence and other experiments,as well as through the analysis of data sets in the GEO database.3 Result(1)Avasimibe reduced the airway inflammation of the asthma mice induced by house dust mites,suppressed the activation and proliferation of sub-epithelial smooth muscle cells,decreased airway resistance,repressed proliferation of airway epithelial basal cells,alleviated goblet metaplasia,decreased mucus secretion,and increased ciliated cells in vivo.(2)Avasimibe inhibited redistribution of the adherens junctions proteins in airway epithelial cells induced by house dust mites,then alleviated the disruption of airway epithelial barrier in vivo and in vitro.(3)The effect that avasimibe suppressed proliferation of epithelial basal cells was independent to its pharmacological effects in cholesterol metabolism in vitro.(4)The analysis in GEO database demonstrated that KRT5 gene up-regulation in the airway epithelial cells in severe asthma patients was found to have a positive correlation with the gene expression of CTNNB1 in airway epithelial cells.(5)By inhibiting phosphorylation at the β-catenin S552 site,avasimibe anchoredβ-catenin to the cell membrane,reduced the destruction of the airway epithelial barrier induced by house dust mites;inhibited the phosphorylations of β-catenin S552 and S675 to hinder its binding to transcription factors;and inhibited the expression of non-phosphorylated active β-catenin,thereby inhibited the activity of the Wnt/β-catenin signaling pathway,and ultimately played a role in reduced the proliferation of airway epithelial cells induced by house dust mites.4 ConclusionAdministrating avasimibe to asthmatic mice alleviated allergic inflammation and airway remodeling in the airways of mice;avasimibe reduced the redistribution ofβ-catenin induced by house dust mites through inhibited the phosphorylation site ofβ-catenin,then alleviated the destruction of the airway epithelial barrier;and inhibited the activity of the Wnt/β-catenin signaling pathway,resulted in a decrease in airway epithelial basal cell proliferation caused by house dust mites,thereby improved asthma airway remodeling.These results provided new targets and ideas for the clinical treatment in allergic asthma.