Moritz Robert, Mangum Lee, Voelker Chet, Garcia Gerardo, Wenke Joseph
Combat Wound Care Group (CRT4), US Army Institute of Surgical Research, Fort Sam Houston, Texas, USA.
Orthopaedic Surgery and Rehabilitation, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA.
Trauma Surg Acute Care Open. 2023 Jul 19;8(1):e001074. doi: 10.1136/tsaco-2022-001074. eCollection 2023.
Valproic acid (VPA), a histone deacetylase inhibitor, has shown improved outcomes when used as a pharmaceutical intervention in animal studies of hemorrhage, septic shock, and combined injuries. This study was designed to investigate the ability of VPA to mitigate ischemia-reperfusion injury produced by prolonged tourniquet application to an extremity.
The ischemia-reperfusion model in anesthetized rats was established using hemorrhage and a 3-hour tourniquet application. VPA was administered intravenously prior to tourniquet wear and removal. Ischemia-reperfusion injury was evaluated by investigating pathway signaling, immune modulation of cytokine release, remote organ injury, and skeletal muscle function during convalescence.
We found that VPA sustained Protein kinase B (Akt) phosphorylation and Insulin-like growth factor signaling and modulated the systemic release of interleukin (IL)-1β, tumor necrosis factor alpha, and IL-6 after 2 hours of limb reperfusion. Additionally, VPA attenuated a loss in glomerular filtration rate at 3 days after injury. Histological and functional evaluation of extremity skeletal muscle at 3, 7, and 21 days after injury, however, demonstrated no significant differences in myocytic degeneration, necrotic formation, and maximal isometric tetanic torque.
Our results demonstrate that VPA sustains early prosurvival cell signaling, reduces the inflammatory response, and improves renal function in a hemorrhage with prolonged ischemia and reperfusion model. However, these do not translate into meaningful preservation in limb function when applied as a pharmaceutical augmentation to tourniquet wear.
IV.
丙戊酸（VPA）是一种组蛋白脱乙酰酶抑制剂，在出血、脓毒症休克及复合伤的动物研究中作为药物干预使用时，已显示出更好的结果。本研究旨在调查VPA减轻因长时间使用止血带扎住肢体而产生的缺血再灌注损伤的能力。
使用出血及3小时的止血带应用，在麻醉大鼠中建立缺血再灌注模型。在扎止血带及松开前静脉注射VPA。通过研究恢复期间的信号通路、细胞因子释放的免疫调节、远处器官损伤及骨骼肌功能来评估缺血再灌注损伤。
我们发现，VPA在肢体再灌注2小时后维持蛋白激酶B（Akt）磷酸化及胰岛素样生长因子信号传导，并调节白细胞介素（IL）-1β、肿瘤坏死因子α及IL-6的全身释放。此外，VPA减轻了损伤后3天时肾小球滤过率的降低。然而，在损伤后3天、7天及21天对肢体骨骼肌进行的组织学和功能评估显示，在肌细胞变性、坏死形成及最大等长强直扭矩方面无显著差异。
我们的结果表明，在长时间缺血和再灌注的出血模型中，VPA维持早期促生存细胞信号传导，减轻炎症反应并改善肾功能。然而，当作为止血带使用的药物增强剂应用时，这些并未转化为对肢体功能的有效保护。
IV级
