组蛋白去乙酰化酶２在慢性气道炎症性疾病糖皮质激素抵抗中的研究进展

Research progress of histone deacetylase 2 in glucocorticoid resistance in chronic airway inflammatory diseases

摘要

慢性气道炎症性疾病是一类影响上下呼吸道以及肺实质的异质性疾病。糖皮质激素（glucocorticoid，GC）是目前临床上治疗该类疾病常用的抗炎药物之一，但部分患者给予足够的GC疗程后疗效不理想，即出现糖皮质激素抵抗（glucocorticoid resistance，GCR）现象，这为治疗该类疾病增加了困难，故阐明GCR的发病机理是其防治的关键。近年来相关研究提示，组蛋白去乙酰化酶２（histone deacetylase 2，HDAC 2）表达水平及活性下降使糖皮质激素受体α（glucocorticoid receptor α，GRα）抑制促炎基因表达的能力降低进而导致GCR的发生，且慢性气道炎症性疾病中HDAC 2表达水平和活性下降是气道氧化应激背景下HDAC 2的共价修饰、磷脂酰肌醇-3-激酶（phosphatidylinositol-3-kinase，PI3K）/蛋白激酶B（protein kinase B，PKB/Akt）信号通路升高及STING通路激活的结果，这将为慢性气道炎症性疾病GC敏感性的恢复提供新的理论依据和思路。

Abstract

Chronic airway inflammatory disease is a kind of heterogeneous disease affecting the upper and lower respiratory tracts and lung parenchyma. Glucocorticoid (GC) is one of the most commonly used anti-inflammatory drugs in the clinical treatment of these diseases. However, some patients with sufficient GC treatment have unsatisfactory efficacy, that is, the phenomenon of glucocorticoid resistance (GCR), increasing the difficulty in the treatment of these diseases. Therefore, elucidating the pathogenesis of GCR is the key to its prevention and treatment. In recent years, relevant studies have suggested that the decrease in histone deacetylase 2 (HDAC 2) expression level and activity reduces the ability of the glucocorticoid receptor α (GRα) to inhibit the expression of pro-inflammatory genes, leading to the occurrence of GCR. Furthermore, the decrease in HDAC 2 expression and activity in chronic inflammatory diseases of the airways is the result of covalent modification of HDAC 2, the increase of PI3K/Akt signaling pathway, and the activation of the STING pathway under the background of airway oxidative stress, which will provide a new theoretical basis and idea for recovering GC sensitivity in chronic inflammatory diseases of the airways.

关键词

组蛋白去乙酰化酶２ / 慢性气道炎症性疾病 / 糖皮质激素 / 糖皮质激素抵抗 / 氧化应激

Key words

Histone deacetylase 2 / Chronic airway inflammatory disease / Glucocorticoid / Glucocorticoid resistance / Oxidative stress

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基金资助

国家自然科学基金面上项目(81970865)

“四个一批”科技兴医创新计划项目(2022XM06)

山西省回国留学人员科研资助项目(2021-172)

山西省留学回国人员科技活动择优资助项目(20240049)