Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock
Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock
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DOI：
10.1152/ajpgi.00022.2002
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发表时间：
2002-07-01
影响因子：
4.5
通讯作者：
Fink, MP
中科院分区：
文献类型：
--
作者：
Yang, R;Gallo, DJ;Fink, MP
丙酮酸是一种有效的活性氧清除剂，已被证明在许多氧化还原介导的组织或器官损伤模型中是有益的。然而，丙酮酸在溶液中不稳定，因此不适合作为治疗剂开发。在这里，丙酮酸乙酯被认为比母体化合物更稳定，它是在含钙的平衡盐溶液[林格丙酮酸乙酯溶液(REPS)]中配制的，并在失血性休克和复苏(HS/R)小鼠模型中进行了评估。用REPS替代乳酸林格液(RLS)复苏可显著提高HS/R后24 h的存活率，减少细菌移位至肠系膜淋巴结，并在4 h时抑制回肠黏膜对FITC标记的右旋糖苷(4,000 Da)的通透性增加。REPS替代RLS处理的小鼠在4 h时循环丙氨酸转氨酶水平也较低。Reps替代RLS处理可减少HS/R后肝脏和结肠粘膜核因子-kappaB的活化，并降低肝、回肠和/或结肠粘膜中诱导型一氧化氮合酶、肿瘤坏死因子、环氧合酶-2和白细胞介素6的表达。这些数据支持这样的观点，即用REPS复苏可以调节HS/R小鼠的炎症反应，减轻肝细胞和肠粘膜的损伤。
Administration of pyruvate, an effective scavenger of reactive oxygen species, has been shown to be salutary in numerous models of redox-mediated tissue or organ injury. Pyruvate, however, is unstable in solution and, hence, is not attractive for development as a therapeutic agent. Herein, ethyl pyruvate, which is thought to be more stable than the parent compound, was formulated in a calcium-containing balanced salt solution [Ringer ethyl pyruvate solution (REPS)] and evaluated in a murine model of hemorrhagic shock and resuscitation (HS/R). Resuscitation with REPS instead of Ringer lactate solution (RLS) significantly improved survival at 24 h and abrogated bacterial translocation to mesenteric lymph nodes and the development of increased ileal mucosal permeability to FITC-labeled dextran (4,000 Da) at 4 h. Mice treated with REPS instead of RLS also had lower circulating levels of alanine aminotransferase at 4 h. Treatment with REPS instead of RLS decreased activation of nuclear factor-kappaB in liver and colonic mucosa after HS/R and also decreased the expression of inducible nitric oxide synthase, tumor necrosis factor, cyclooxygenase-2, and interleukin-6 mRNA in liver, ileal mucosa, and/or colonic mucosa. These data support the view that resuscitation with REPS modulates the inflammatory response and decreases hepatocellular and gut mucosal injury in mice subjected to HS/R.