Department of Surgery, Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114, USA.
Shock. 2009 Nov;32(5):517-23. doi: 10.1097/SHK.0b013e3181a44c79.
We have recently found that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, improves survival in a lethal model of hemorrhagic shock in rats. The purpose of the present study was to determine whether SAHA treatment would prevent LPS-induced septic shock and improve the survival in a murine model. C57BL/6J mice were randomly divided into two groups. Experimental mice were given intraperitoneal SAHA (50 mg/kg) in vehicle dimethyl sulfoxide fluid (n = 10). The control mice (n = 10) received vehicle dimethyl sulfoxide only. They were injected with LPS (20 mg/kg, i.p.) 2 h later, and the animals from the treatment group were given a second dose of SAHA. Survival was monitored during the next 7 days. In a parallel study, mice treated with or without SAHA were subjected to LPS insult while normal (sham) mice serviced as controls. 1) Lungs were harvested at 3 and 48 h for analysis of gene expression and pathologic changes, respectively; 2) spleens were isolated for analysis of neutrophilic cell population. In addition, RAW264.7 mouse macrophages were cultured to assess the effects of SAHA on LPS-induced inflammation in vitro. All mice in the control group that were subjected to LPS challenge died in less than 48 h. However, SAHA-treated animals displayed a significantly higher 1-week survival rate (87.5%) compared with the control group (0%). Moreover, LPS insult decreased the acetylation of histone proteins (H2A, H2B, and H3), elevated the levels of TNF-alpha in vivo (circulation) and in vitro (culture medium), increased the neutrophilic cell population in the spleen, enhanced the expression of TNF-alpha and IL-1beta genes in lung tissue, and augmented the pulmonary neutrophil infiltration. In contrast, SAHA treatment markedly attenuated all of these LPS-induced alterations. We report for the first time that administration of SAHA (50 mg/kg) significantly attenuates a variety of inflammatory markers and improves long-term survival after a lethal LPS insult.
我们最近发现，一种组蛋白去乙酰化酶抑制剂——琥珀酰亚胺基戊二酰基羟肟酸（SAHA），可以提高大鼠失血性休克致死模型的存活率。本研究的目的是确定 SAHA 治疗是否能预防 LPS 诱导的感染性休克，并提高小鼠模型的存活率。C57BL/6J 小鼠被随机分为两组。实验组小鼠腹腔注射 SAHA（50mg/kg）溶于二甲基亚砜溶液（n=10）。对照组小鼠（n=10）仅接受二甲基亚砜溶液注射。2 小时后，实验组和对照组小鼠均腹腔注射 LPS（20mg/kg），实验组小鼠再给予第二剂 SAHA。在接下来的 7 天内监测动物的存活情况。在一项平行研究中，给予或不给予 SAHA 治疗的小鼠接受 LPS 刺激，正常（假手术）小鼠作为对照。1）分别于 3 小时和 48 小时采集肺组织，用于分析基因表达和病理变化；2）分离脾脏，分析中性粒细胞群体。此外，还培养 RAW264.7 小鼠巨噬细胞，以评估 SAHA 对 LPS 诱导的体外炎症的影响。所有接受 LPS 刺激的对照组小鼠在不到 48 小时内全部死亡。然而，给予 SAHA 治疗的小鼠的 1 周存活率（87.5%）显著高于对照组（0%）。此外，LPS 刺激降低了组蛋白蛋白（H2A、H2B 和 H3）的乙酰化水平，增加了体内（循环）和体外（培养基）TNF-α的水平，增加了脾脏中性粒细胞群体，增强了肺组织 TNF-α和 IL-1β基因的表达，并加剧了肺部中性粒细胞浸润。相比之下，SAHA 治疗显著减弱了所有这些 LPS 诱导的改变。我们首次报道，给予 SAHA（50mg/kg）可显著减轻多种炎症标志物，并改善致死性 LPS 刺激后的长期存活率。
