Inhibition of histone deacetylase 6 improves long-term survival in a lethal septic model.
Inhibition of histone deacetylase 6 improves long-term survival in a lethal septic model.
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DOI：
10.1097/ta.0000000000000510
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发表时间：
2015-02
期刊：
影响因子：
--
通讯作者：
Alam HB
中科院分区：
文献类型：
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作者：
Li Y;Zhao T;Liu B;Halaweish I;Mazitschek R;Duan X;Alam HB
背景：我们最近证明，亚eroylanilide羟肟酸是一种广谱组蛋白去乙酰化酶（HDAC）抑制剂，可抑制HDAC 1、2、3和6，可提高盲肠结扎和穿刺（CLP）致死性败血症小鼠模型的生存率。本研究旨在确定选择性抑制HDAC异构体对存活、关键细胞因子产生、器官损伤、细菌清除和细胞凋亡的影响。方法在实验1中，C57BL/6J小鼠给予CLP，并在1小时后腹腔注射(1)溶解于二甲基亚砜（DMSO）中的Tubastatin A （HDAC6抑制剂），(2)DMSO中的MS-275 （hdac1、2和3抑制剂），(3)仅注射DMSO。监测生存10天。实验2，CLP后1小时，用DMSO或Tubastatin a给药，假手术动物作为对照。在24小时或48小时收集腹膜液和血液样本，测量细胞因子。48小时的血液也用于测定细菌载量。取肝评估急性肝损伤。实验3用原代脾细胞评价细胞因子反应和吞噬作用。在不含或不含Tubastatin A的脂多糖刺激下培养巨噬细胞3小时和6小时，收集巨噬细胞，分析细胞凋亡情况。结果Tubastatin A治疗的动物，而MS-275治疗的动物存活率显著提高。此外，Tubastatin A显著抑制脂多糖刺激脾细胞的腹膜液和血浆以及上清液中细胞因子的产生。Tubastatin A显著减轻急性肝损伤，增加血细菌清除率和脾细胞吞噬，减少巨噬细胞凋亡。结论抑制hdac6可显著提高致死性CLP小鼠的存活率，减轻“细胞因子风暴”，减轻急性肝损伤，增加细菌清除率和免疫细胞吞噬能力，抑制巨噬细胞凋亡。
BACKGROUNDWe recently demonstrated that suberoylanilide hydroxamic acid, a broad-spectrum histone deacetylase (HDAC) inhibitor that inhibits HDACs 1, 2, 3, and 6, improves survival in a mouse model of cecal ligation and puncture (CLP)–induced lethal sepsis. The current study was undertaken to determine the effect of selective inhibition of HDAC isoform on survival, key cytokine production, organ injury, bacteria clearance, and cell apoptosis.METHODSIn Experiment 1, C57BL/6J mice were subjected to CLP and, 1 hour later, given intraperitoneal injections of (1) Tubastatin A (inhibitor of HDAC6) dissolved in dimethyl sulfoxide (DMSO),(2) MS-275 (inhibitor of HDACs 1, 2, and 3) in DMSO, and (3) DMSO only. Survival was monitored for 10 days. In Experiment 2, 1 hour after CLP, animals were treated with DMSO vehicle or Tubastatin A. Sham-operated animals served as control. Peritoneal fluid and blood samples were collected for measurement of cytokines at 24 hours or 48 hours. Blood at 48 hours was also used to determine bacteria load. Liver was harvested to evaluate acute liver injury. In Experiment 3, Primary splenocytes were used to assess cytokine responses and phagocytosis. Macrophages were cultured and harvested 3 hours and 6 hours after lipopolysaccharide stimulation in the absence or presence of Tubastatin A to analyze cell apoptosis.RESULTSAnimals treated with Tubastatin A, but not MS-275, displayed a significant improvement in survival. Moreover, Tubastatin A significantly inhibited cytokine production in peritoneal fluid and plasma as well as in supernatant from splenocytes stimulated with lipopolysaccharide. Tubastatin A significantly attenuated acute liver injury, increased blood bacteria clearance and splenocyte phagocytosis, and decreased macrophage apoptosis.CONCLUSIONHDAC6 inhibition significantly improves survival, reduces “cytokine storm,” attenuates acute livery injury, increases bacteria clearance and immune cell phagocytosis, and inhibits macrophage apoptosis in a lethal mouse CLP model.