丙戊酸对肠缺血再灌注致急性肺损伤大鼠模型的影响。
Effect of valproic acid on acute lung injury in a rodent model of intestinal ischemia reperfusion.
机构信息
Department of Surgery, Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
出版信息
Resuscitation. 2012 Feb;83(2):243-8. doi: 10.1016/j.resuscitation.2011.07.029. Epub 2011 Aug 6.
OBJECTIVES
Acute lung injury (ALI) can develop during the course of many clinical conditions, and is associated with significant morbidity and mortality. Valproic acid (VPA), a well-known anti-epileptic drug, has been shown to have anti-oxidant and anti-inflammatory effects in various ischemia/reperfusion (I/R) models. The purpose of this study was to investigate whether VPA could affect survival and development of ALI in a rat model of intestinal I/R.
METHODS
Two experiments were performed. Experiment I: Male Sprague-Dawley rats (250-300 g) were subjected to intestinal ischemia (1h) and reperfusion (3h). They were randomized into 2 groups (n=7 per group) 3 min after ischemia: Vehicle (Veh) and VPA (300 mg/kg, IV). Primary end-point for this study was survival over 4h from the start of ischemia. Experiment II: The histological and biochemical effects of VPA treatment on lungs were examined 3h (1h ischemia+2h reperfusion) after intestinal I/R injury (Veh vs. VPA, n=9 per group). An objective histological score was used to grade the degree of ALI. Enzyme linked immunosorbent assay (ELISA) was performed to measure serum levels of interleukins (IL-6 and 10), and lung tissue of cytokine-induced neutrophil chemoattractant (CINC) and myeloperoxidase (MPO). In addition, the activity of 8-isoprostane was analyzed for pulmonary oxidative damage.
RESULTS
In Experiment I, 4-h survival rate was significantly higher in VPA treated animals compared to Veh animals (71.4% vs. 14.3%, p=0.006). In Experiment II, ALI was apparent in all of the Veh group animals. Treatment with VPA prevented the development of ALI, with a reduction in the histological score (3.4 ± 0.3 vs. 5.3 ± 0.6, p=0.025). Moreover, compared to the Veh control group the animals from the VPA group displayed decreased serum levels of IL-6 (952 ± 213 pg/ml vs. 7709 ± 1990 pg/ml, p=0.011), and lung tissue concentrations of CINC (1188 ± 28 pg/ml vs. 1298 ± 27 pg/ml, p<0.05), MPO activity (368 ± 23 ng/ml vs. 490 ± 29 ng/ml, p<0.05) and 8-isoprostane levels (1495 ± 221 pg/ml vs. 2191 ± 177 pg/ml, p<0.05).
CONCLUSION
VPA treatment improves survival and attenuates ALI in a rat model of intestinal I/R injury, at least in part, through its anti-oxidant and anti-inflammatory effects.
目的
急性肺损伤（ALI）可在许多临床情况下发展，并与显著的发病率和死亡率相关。丙戊酸（VPA），一种众所周知的抗癫痫药物，在各种缺血/再灌注（I / R）模型中已显示出抗氧化和抗炎作用。本研究的目的是研究 VPA 是否可以影响肠 I / R 大鼠模型中的 ALI 的存活和发展。
方法
进行了两项实验。实验 I：雄性 Sprague-Dawley 大鼠（250-300g）接受肠缺血（1h）和再灌注（3h）。在缺血后 3 分钟，他们被随机分为 2 组（每组 n=7）：载体（Veh）和 VPA（300mg/kg，IV）。本研究的主要终点是从缺血开始后的 4 小时内的存活。实验二：观察肠 I / R 损伤后 3 小时（1h 缺血+2h 再灌注）VPA 治疗对肺的组织学和生化影响（Veh 与 VPA，每组 n=9）。采用客观组织学评分来分级 ALI 的程度。通过酶联免疫吸附试验（ELISA）测量血清中白细胞介素（IL-6 和 10）水平，以及肺组织中细胞因子诱导的中性粒细胞趋化因子（CINC）和髓过氧化物酶（MPO）。此外，还分析了 8-异前列腺素的活性以评估肺的氧化损伤。
结果
在实验 I 中，与 Veh 处理的动物相比，VPA 处理的动物 4 小时的存活率显着更高（71.4%比 14.3%，p=0.006）。在实验 II 中，所有 Veh 组动物均出现 ALI。VPA 治疗可预防 ALI 的发展，组织学评分降低（3.4±0.3比 5.3±0.6，p=0.025）。此外，与 Veh 对照组相比，VPA 组动物的血清 IL-6 水平（952±213pg/ml 比 7709±1990pg/ml，p=0.011）和肺组织 CINC 浓度（1188±28pg/ml 比 1298±27pg/ml，p<0.05）、MPO 活性（368±23ng/ml 比 490±29ng/ml，p<0.05）和 8-异前列腺素水平（1495±221pg/ml 比 2191±177pg/ml，p<0.05）均降低。
结论
VPA 治疗可改善肠 I / R 损伤大鼠模型的存活率并减轻 ALI，至少部分是通过其抗氧化和抗炎作用。
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