PCI-34051对HDAC8的选择性抑制通过miR-381-3p-TGFβ3轴减轻哮喘中的炎症和气道重塑。
Selective HDAC8 inhibition by PCI-34051 attenuates inflammation and airway remodeling in asthma miR-381-3p-TGFβ3 axis.
作者信息
Bai Shiyao, Su Xinming, Kong Delei, Feng Chenye, Zhang Xiaochun, Pan Ying, Zhao Jieyu, Sun Jiamin, Li Wenyang
机构信息
Department of Respiratory and Critical Care Medicine, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China.
Department of Laboratory Medicine, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China.
出版信息
J Transl Int Med. 2025 Jan 10;12(6):592-601. doi: 10.1515/jtim-2023-0135. eCollection 2024 Dec.
BACKGROUND AND OBJECTIVES
Histone deacetylase (HDAC) families regulate various physical processes and the development of several diseases. The role of HDACs in asthma development and progression worths further investigation. This study aims to evaluate the effect of HDACs in a mouse model of asthma.
METHODS
HDAC8 selective inhibitor PCI-34051 was administered to a mouse model of ovalbumin-sensitized and challenged asthma. Airway responsiveness, serum cytokines, histological changes of the airway, and expression levels of α-SMA, β-actin, VEGFR, VEGF, GAPDH, HDAC8, TGF-β3, CD 105, p-ERK 1/2, ERK 1/2, PI3K, p-AKT, AKT, and PDK1 were evaluated. The miR-381-3p level was also measured.
RESULTS
All classic histologic and cellular changes of asthma in inflammation and airway remodeling were altered by HDAC8 inhibitor PCI-34051 via regulation of the miR-381-3p level and its downstream gene, TGF-β3. Inhibition of TGF-β3 further reduced the activation of ERK, PI3K, AKT, and PDK1.
CONCLUSION
In a mouse model, HDAC8 inhibitor PCI-34051 exhibits comprehensive control of asthmatic changes, including inflammation and airway remodeling.
背景与目的
组蛋白去乙酰化酶（HDAC）家族调节多种生理过程及多种疾病的发展。HDACs在哮喘发展和进展中的作用值得进一步研究。本研究旨在评估HDACs在哮喘小鼠模型中的作用。
方法
将HDAC8选择性抑制剂PCI-34051应用于卵清蛋白致敏和激发的哮喘小鼠模型。评估气道反应性、血清细胞因子、气道组织学变化以及α-SMA、β-肌动蛋白、血管内皮生长因子受体（VEGFR）、血管内皮生长因子（VEGF）、甘油醛-3-磷酸脱氢酶（GAPDH）、HDAC8、转化生长因子-β3（TGF-β3）、CD105、磷酸化细胞外信号调节激酶1/2（p-ERK 1/2）、细胞外信号调节激酶1/2（ERK 1/2）、磷脂酰肌醇-3激酶（PI3K）、磷酸化蛋白激酶B（p-AKT）、蛋白激酶B（AKT）和丙酮酸脱氢酶激酶1（PDK1）的表达水平。同时检测miR-381-3p水平。
结果
HDAC8抑制剂PCI-34051通过调节miR-381-3p水平及其下游基因TGF-β3，改变了哮喘炎症和气道重塑中所有典型的组织学和细胞变化。抑制TGF-β3进一步降低了ERK、PI3K、AKT和PDK1的激活。
结论
在小鼠模型中，HDAC8抑制剂PCI-34051对哮喘变化具有全面的控制作用，包括炎症和气道重塑。
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