核心组蛋白分子过乙酰化与慢性阻塞性肺疾病糖皮质激素抵抗

Histone acetylation related to corticosteroid resistance in chronic obstructive pulmonary disease

染色体核心组蛋白分子作为各种炎症因子和炎症信号转导的关键性终端蛋白质分子,具有基因转录“开关”分子的功能,其活性受组蛋白转乙酰酶/脱乙酰酶(HAT/HDAC)的调节。HAT活性增高,组蛋白分子过乙酰化,DNA表现为解链效应,促进基因转录;而HDAC活性增高则出现相反的效应,基因转录变沉默。HAT和HDAC的动态平衡对基因的转录活性和炎症反应程度的调节起关键作用。慢性阻塞性肺疾病(COPD)肺部氧化应激反应的持续存在,明显降低了肺组织HDAC酶的活性,组蛋白乙酰化/去乙酰化平衡被打破,组蛋白分子过乙酰化、炎症蛋白基因的转录和炎症蛋白的合成得到加强,阻断了糖皮质激素的抗炎症反应效应。小剂量氨茶碱恢复COPD肺组织HDAC活性,减少炎症介质和细胞因子合成和释放,能够改善气道炎症对糖皮质激素治疗的反应性。

Core histone around which DNA is wound plays akey role as a terminal protein of inflammatory signal transducfion on gene transcription. Acetylation of core histone opens up the chromatin structure allowing gene transcription and synthesis of inflammatory proteins to proceed, whereas deacetylated histone reverses this process and switches off inflammatory gene transcription. The balance between histone acetyl-transferase （HAT） and deacetyiase （HDAC） determines the state of histone acetylation. In COPD, oxidants from cigarette smoke or inflammatory cells modify and deactivate HDAC in lung macrophages, and attenuate corticosteroid inhibition of inflammatory cytokines-stimulated histone acetylation and prompt inflammatory gene transcription. Low-dose theophylline induces HDAC activity in epithelial cells and macrophages in lung tissue, and decreases inflammatory gene expression and restores corticosteroid responses in COPD.