Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital/Harvard Medical School, Boston, USA.
J Trauma Acute Care Surg. 2012 Dec;73(6):1461-70. doi: 10.1097/TA.0b013e3182782641.
We have previously demonstrated that valproic acid (VPA), a histone deacetylase inhibitor, can improve survival after hemorrhagic shock (HS), protect neurons from hypoxia-induced apoptosis, and attenuate the inflammatory response. We have also shown that administration of 6% hetastarch (Hextend [Hex]) after traumatic brain injury (TBI) decreases brain swelling, without affecting size of the lesion. This study was performed to determine whether addition of VPA to Hex would decrease the lesion size in a clinically relevant large animal model of TBI + HS.
Yorkshire swine (42-50 kg) were instrumented to measure hemodynamic parameters, intracranial pressure, and brain tissue oxygenation. A custom-designed, computer-controlled cortical impact device was used to create a TBI through a 20-mm craniotomy: 15-mm cylindrical tip impactor at 4-m/s velocity, 100-millisecond dwell time, and 12-mm penetration depth. Volume-controlled hemorrhage was started (40% blood volume) concurrent with the TBI. After 2 hours of shock, animals were randomized to one of three resuscitation groups (n = 7 per group) as follows: (1) isotonic sodium chloride solution; (2) 6% hetastarch, Hex; and (3) Hex and VPA 300 mg/kg (Hex + VPA). Volumes of Hex matched the shed blood, whereas that of the isotonic sodium chloride solution was three times the volume. VPA treatment was started after an hour of shock. After 6 hours of postresuscitation monitoring, brains were sectioned into 5-mm slices and stained with 2, 3, 5-Triphenyltetrazolium chloride to quantify the lesion size (mm) and brain swelling (percent change compared with uninjured side). Levels of acetylated histone H3 were determined to quantify acetylation, and myeloperoxidase and interleukine-1β (IL-1β) levels were measured as markers of brain inflammation.
Combination of 40% blood loss with cortical impact and a period of shock (2 hours) and resuscitation resulted in a highly reproducible brain injury. Lesion size and brain swelling in the Hex + VPA group (1,989 [156.8] mm, and 19% [1.6%], respectively) were significantly smaller than the isotonic sodium chloride solution group (3,335 [287.9] mm and 36% [2.2%], respectively). Hex alone treatment significantly decreased the swelling (27% [1.6%]) without reducing the lesion size. The number of CD11b-positive cells as well as myeloperoxidase and IL-1 levels in the brains were significantly reduced by the VPA treatment.
In a combined HS and TBI model, treatment with artificial colloid (Hex) improves hemodynamic parameters and reduces swelling, without affecting the actual size of the brain lesion. Addition of VPA effectively reduces both the size of brain lesion and associated swelling by attenuating the inflammatory response.
我们之前已经证明，组蛋白去乙酰化酶抑制剂丙戊酸（VPA）可以改善出血性休克（HS）后的存活率，保护神经元免受缺氧诱导的凋亡，并减轻炎症反应。我们还表明，创伤性脑损伤（TBI）后给予 6%羟乙基淀粉（Hextend [Hex]）可减少脑水肿，而不影响病变大小。本研究旨在确定 VPA 是否会在 TBI + HS 的临床相关大动物模型中减小病变大小。
将约克夏猪（42-50 公斤）进行仪器化，以测量血流动力学参数、颅内压和脑组织氧合。使用定制的、计算机控制的皮质撞击装置通过 20 毫米开颅术创建 TBI：15 毫米圆柱形尖端撞击器以 4 米/秒的速度、100 毫秒的停留时间和 12 毫米的穿透深度。开始进行容量控制出血（40%血容量），同时进行 TBI。休克 2 小时后，动物随机分为三组复苏组（每组 7 只）：（1）等渗氯化钠溶液；（2）6%羟乙基淀粉，Hex；和（3）Hex 和 300 毫克/千克 VPA（Hex + VPA）。Hex 的体积与失血量相匹配，而等渗氯化钠溶液的体积是其三倍。VPA 治疗在休克 1 小时后开始。复苏后监测 6 小时后，将大脑切成 5 毫米切片，并用 2、3、5-三苯基氯化四唑染色，以量化病变大小（mm）和脑肿胀（与未受伤侧相比的百分比变化）。测定乙酰化组蛋白 H3 的水平以量化乙酰化，测量髓过氧化物酶和白细胞介素-1β（IL-1β）水平作为脑炎症的标志物。
皮质撞击和休克（2 小时）和复苏期间 40%失血量的组合导致了高度可重复的脑损伤。Hex + VPA 组的病变大小和脑肿胀（1989 [156.8] mm 和 19% [1.6%]）明显小于等渗氯化钠溶液组（3335 [287.9] mm 和 36% [2.2%]）。单独使用 Hex 可显著减少肿胀（27% [1.6%]）而不减少病变大小。VPA 治疗还显著减少了大脑中 CD11b 阳性细胞以及髓过氧化物酶和 IL-1 水平。
在 HS 和 TBI 联合模型中，人工胶体（Hex）治疗可改善血流动力学参数并减少肿胀，而不影响脑损伤的实际大小。添加 VPA 通过减轻炎症反应，有效减小脑损伤的大小和相关肿胀。
