Avasimibe Alleviates Disruption of the Airway Epithelial Barrier by Suppressing the Wnt/β-Catenin Signaling Pathway.
Avasimibe Alleviates Disruption of the Airway Epithelial Barrier by Suppressing the Wnt/β-Catenin Signaling Pathway.
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DOI：
10.3389/fphar.2022.795934
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发表时间：
2022
影响因子：
5.6
通讯作者：
Cai S
中科院分区：
文献类型：
--
作者：
Zhou Z;Liang S;Zhou Z;Liu J;Meng X;Zou F;Yu C;Cai S
Avasimibe（Ava）是一种乙酰辅酶A乙酰转移酶1（ACAT 1）特异性抑制剂，由于其在人体中具有优异且安全的抗炎作用，因此是治疗动脉粥样硬化的既定药物。然而，其对哮喘的疗效尚未报道。我们首先向屋尘螨（HDM）诱导的哮喘小鼠给予不同浓度的阿伐他汀;结果显示，与HDM组相比，20 mg/kg阿伐他汀最显著地降低了支气管肺泡灌洗液（BALF）中IL-4和IL-5的产生以及血清中总IgE，并且阿伐他汀治疗还表现出粘液分泌减少，杯状细胞和基底细胞减少，但纤毛细胞增加。阿伐他汀组HDM诱导的粘附连接蛋白（AJ）再分布明显减少。然而，阿伐他汀并不降低肺组织中的胆固醇酯比率或细胞内的胆固醇酯，这是阿伐他汀的主要作用。进一步的分析证实，avasimibe不依赖于调节胆固醇代谢而损害上皮基底细胞增殖，并且我们使用基因表达Omnibus（GEO）数据库分析数据集，然后发现KRT 5基因（基底细胞标志物）表达与β-连环蛋白基因相关。此外，我们发现，β-catenin定位于细胞膜上的avasimibe处理。Avasimibe还减少了细胞质中的β-连环蛋白磷酸化，并灭活了由HDM诱导的Wnt/β-连环蛋白信号传导途径，从而减轻了气道上皮屏障破坏。综上所述，这些发现表明，阿伐麦布有可能成为过敏性哮喘的一种新的治疗选择。
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.
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影响因子：
82.9
作者：
Erbay, Ebru;Babaev, Vladimir R.;Mayers, Jared R.;Makowski, Liza;Charles, Khanichi N.;Snitow, Melinda E.;Fazio, Sergio;Wiest, Michelle M.;Watkins, Steven M.;Linton, MacRae F.;Hotamisligil, Goekhan S.
通讯作者：
Hotamisligil, Goekhan S.
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影响因子：
15.3
作者：
Finotto, S;De Sanctis, G T;Lehr, H A;Herz, U;Buerke, M;Schipp, M;Bartsch, B;Atreya, R;Schmitt, E;Galle, P R;Renz, H;Neurath, M F
通讯作者：
Neurath, M F
影响因子：
17.1
作者：
Drake MG;Scott GD;Blum ED;Lebold KM;Nie Z;Lee JJ;Fryer AD;Costello RW;Jacoby DB
通讯作者：
Jacoby DB
影响因子：
4.7
作者：
Gao Y;Xu D;Li H;Xu J;Pan Y;Liao X;Qian J;Hu Y;Yu G
通讯作者：
Yu G
细胞外热休克蛋白 90α 通过激活 RhoA/MLC 信号传导介导 HDM 诱导的支气管上皮屏障功能障碍
影响因子：
5.8
作者：
Dong HM;Le YQ;Wang YH;Zhao HJ;Huang CW;Hu YH;Luo LS;Wan X;Wei YL;Chu ZQ;Li W;Cai SX
通讯作者：
Cai SX