高渗盐水与丙戊酸在致死性大鼠两击模型中的协同作用。
Synergistic effects of hypertonic saline and valproic acid in a lethal rat two-hit model.
机构信息
Division of Trauma, Emergency Surgery and Surgical Critical Care, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
出版信息
J Trauma Acute Care Surg. 2013 Apr;74(4):991-7; discussion 997-8. doi: 10.1097/TA.0b013e31828583e3.
BACKGROUND
Hemorrhagic shock (HS) followed by an infection ("second hit") can lead to severe systemic inflammatory response and multiple-organ failure. Studies have shown that resuscitation with hypertonic saline (HTS) can blunt the inflammatory response. We demonstrated that large doses of valproic acid (VPA, 300 mg/kg), a histone deacetylase inhibitor, improves survival in a rodent two-hit model (HS followed by cecal ligation and puncture [CLP]). In the present study, we examined whether combination of HTS with VPA would allow us to achieve survival advantage at a lower dose of VPA (200 mg/kg).
METHODS
Male Sprague-Dawley rats were subjected to HS (50% blood loss) and randomized into five groups (n = 7-8 per group) as follows: (1) isotonic sodium chloride solution (ISCS), (2) 7.5% saline, (3) VPA, (4) ISCS + VPA, and (5) HTS + VPA. After 24 hours, they underwent CLP, followed by the same doses of ISCS, HTS, and/or VPA and were monitored for 10 days. In a parallel experiment, blood, peritoneal irrigation fluid and lung homogenate were subjected to enzyme-linked immunosorbent assay 3 hours and 24 hours after CLP to measure myeloperoxidase activity and proinflammatory cytokines tumor necrosis factor α and interleukin 1β levels. Western blotting was performed to investigate the expression of pentraxin 3 protein in the lung homogenate at 24 hours after CLP. Hematoxylin and eosin staining of lungs at the 24 hours were performed to quantify the degree of acute lung injury.
RESULTS
HTS + VPA treatment significantly improved survival (87.5%), compared with the other groups (14.3%; p < 0.05), while attenuating peritoneal myeloperoxidase levels and proinflammatory cytokine tumor necrosis factor α and interleukin 1β levels in the serum, peritoneal cavity, and lung. The degree of acute lung injury and expression of pentraxin 3 in the lung were significantly reduced in the HTS + VPA group.
CONCLUSION
This is the first study to show that VPA and HTS can work synergistically to attenuate inflammation and improve survival in a lethal two-hit model.
背景
出血性休克（HS）后继发感染（“二次打击”）可导致严重的全身炎症反应和多器官衰竭。研究表明，高渗盐水（HTS）复苏可减轻炎症反应。我们曾证明，大剂量的丙戊酸（VPA，300mg/kg），一种组蛋白去乙酰化酶抑制剂，可改善啮齿动物两打击模型（HS 后行盲肠结扎和穿孔术[CLP]）的存活率。在本研究中，我们研究了 HTS 与 VPA 联合使用是否可以在较低剂量的 VPA（200mg/kg）下获得生存优势。
方法
雄性 Sprague-Dawley 大鼠接受 HS（50%失血）并随机分为五组（每组 7-8 只）：（1）等渗氯化钠溶液（ISCS），（2）7.5%盐水，（3）VPA，（4）ISCS+VPA，和（5）HTS+VPA。24 小时后，它们接受 CLP，然后给予相同剂量的 ISCS、HTS 和/或 VPA，并监测 10 天。在平行实验中，在 CLP 后 3 小时和 24 小时，通过酶联免疫吸附试验测量髓过氧化物酶活性和促炎细胞因子肿瘤坏死因子α和白细胞介素 1β水平，以检测血液、腹腔灌洗液和肺匀浆中的水平。通过 Western blot 检测肺匀浆中 pentraxin 3 蛋白在 CLP 后 24 小时的表达。在 24 小时时对肺进行苏木精和伊红染色，以量化急性肺损伤的程度。
结果
HTS+VPA 治疗可显著提高存活率（87.5%），与其他组（14.3%；p<0.05）相比，同时减轻血清、腹腔和肺中的腹腔髓过氧化物酶水平和促炎细胞因子肿瘤坏死因子α和白细胞介素 1β水平。HTS+VPA 组的急性肺损伤程度和肺中 pentraxin 3 的表达明显降低。
结论
这是第一项研究表明，VPA 和 HTS 可以协同作用，减轻致命性两打击模型中的炎症反应并提高存活率。
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