Halaweish Ihab, Nikolian Vahagn, Georgoff Patrick, Li Yongqing, Alam Hasan B
Department of Surgery, University of Michigan, Ann Arbor, Michigan.
Shock. 2015 Aug;44 Suppl 1(0 1):6-16. doi: 10.1097/SHK.0000000000000319.
Traumatic injuries and their sequelae represent a major source of mortality in the United States and globally. Initial treatment for shock, traumatic brain injury, and polytrauma is limited to resuscitation fluids to replace lost volume. To date, there are no treatments with inherent prosurvival properties. Our laboratory has investigated the use of histone deacetylase inhibitors (HDACIs) as pharmacological agents to improve survival. This class of drugs acts through posttranslational protein modifications and is a direct regulator of chromatin structure and function, as well as the function of numerous cytoplasmic proteins. In models of hemorrhagic shock and polytrauma, administration of HDACIs offers a significant survival advantage, even in the absence of fluid resuscitation. Positive results have also been shown in two-hit models of hemorrhage and sepsis and in hemorrhagic shock combined with traumatic brain injury. Accumulating data generated by our group and others continue to support the use of HDACIs for the creation of a prosurvival phenotype. With further research and clinical trials, HDACIs have the potential to be an integral tool in the treatment of trauma, especially in the prehospital phase.
创伤性损伤及其后遗症是美国乃至全球主要的死亡原因。对于休克、创伤性脑损伤和多发伤的初始治疗仅限于使用复苏液来补充丢失的血容量。迄今为止，尚无具有内在促生存特性的治疗方法。我们实验室研究了使用组蛋白去乙酰化酶抑制剂（HDACIs）作为改善生存率的药物制剂。这类药物通过蛋白质翻译后修饰发挥作用，是染色质结构和功能以及众多细胞质蛋白功能的直接调节剂。在失血性休克和多发伤模型中，给予HDACIs可带来显著的生存优势，即使在未进行液体复苏的情况下也是如此。在出血和脓毒症的二次打击模型以及失血性休克合并创伤性脑损伤的模型中也显示出了阳性结果。我们团队及其他团队积累的数据持续支持使用HDACIs来创造促生存表型。随着进一步的研究和临床试验，HDACIs有可能成为创伤治疗中不可或缺的工具，尤其是在院前阶段。
