Cai Bolin, Chen Fei, Lin Xingchun, Miller Edmund, Szabo Csaba, Deitch Edwin A, Ulloa Lusi
Laboratory of Anti-inflammatory Signaling and Surgical Immunology, University of Medicine and Dentistry of New Jersey, USA.
Crit Care Med. 2009 Mar;37(3):860-8. doi: 10.1097/CCM.0b013e31819b8237.
Severe hemorrhage is a common cause of death despite the recent advances in critical care. Conventional resuscitation fluids are designed to reestablish tissue perfusion, but they fail to prevent lethal inflammatory responses. Our previous studies indicate that ethyl pyruvate (EP) inhibits tumor necrosis factor (TNF) production from macrophages. Here, we analyze whether EP can provide a therapeutic anti-inflammatory value to resuscitation fluids.
Laboratory animal experiments.
Animal research laboratory at university medical school.
Adult male Sprague-Dawley rats.
Lethal hemorrhage over 15 minutes to reach a mean arterial blood pressure of 35-40 mm Hg and subsequent maintenance of this mean arterial blood pressure for another 15 minutes. Resuscitation was limited to 15 mL/kg Hextend with or without EP.
Resuscitation with Hextend supplemented with EP rescued all the animals from lethal hemorrhage. Unlike conventional fluids, EP inhibited the production of inflammatory and cardiodepressant factors such as TNF and high mobility group B protein-1. From a pharmacologic perspective, resuscitation with EP was particularly effective inhibiting TNF production in the spleen and the heart. Unlike other anti-inflammatory strategies, EP mitigated systemic inflammation through a mechanism independent of the spleen. At the molecular level, EP inhibited both poly(ADP-ribose) polymerase and p65RelA DNA binding without affecting IkappaBalpha activation.
EP may be a promising anti-inflammatory supplement to improve survival during resuscitation in critical care.
尽管重症监护领域最近取得了进展，但严重出血仍是常见的死亡原因。传统的复苏液旨在重建组织灌注，但它们无法预防致命的炎症反应。我们之前的研究表明，丙酮酸乙酯（EP）可抑制巨噬细胞产生肿瘤坏死因子（TNF）。在此，我们分析EP是否可为复苏液提供治疗性抗炎价值。
实验动物研究。
大学医学院的动物研究实验室。
成年雄性Sprague-Dawley大鼠。
15分钟内造成致死性出血，使平均动脉血压达到35 - 40 mmHg，随后将该平均动脉血压维持15分钟。复苏仅限于使用含或不含EP的15 mL/kg Hextend。
用补充了EP的Hextend进行复苏可使所有动物从致死性出血中获救。与传统液体不同，EP可抑制炎症和心脏抑制因子如TNF和高迁移率族B蛋白-1的产生。从药理学角度来看，用EP进行复苏在抑制脾脏和心脏中TNF的产生方面特别有效。与其他抗炎策略不同，EP通过一种独立于脾脏的机制减轻全身炎症。在分子水平上，EP抑制聚（ADP-核糖）聚合酶和p65RelA与DNA的结合，而不影响IkappaBalpha的激活。
EP可能是一种有前景的抗炎补充剂，可提高重症监护复苏期间的生存率。
