Department of Anaesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
Chin Med J (Engl). 2010 Oct;123(19):2682-7.
Valproic acid (VPA) improves early survival and organ function in a highly lethal poly-trauma and hemorrhagic shock model or other severe insults. We assessed whether VPA could improve organ function in a rat model of septic shock and illustrated the possible mechanisms.
Forty Sprague-Dawley rats were randomly assigned to four groups (n = 10): control group, VPA group, LPS group, and LPS + VPA group. Lipopolysaccharide (LPS) (10 mg/kg) was injected intravenously to replicate the experimental model of septic shock. Rats were treated with VPA (300 mg/kg, i.v.) or saline. Six hours after LPS injection, blood was sampled for gas analysis, measurement of serum alanine aminotransferase, aspartate aminotransferase, urine nitrogen, creatinine and tumor necrosis factor-alpha. Lung, liver and kidney were collected for histopathological assessment. In addition, myeloperoxidase activity and tumor necrosis factor-a in pulmonary tissue were measured. Acetylation of histone H3 in lung was also evaluated by Western blotting.
LPS resulted in a significant decrease in PaO2, which was increased by VPA administration followed LPS injection. In addition, LPS also induced an increase in the serum levels of alanine aminotransferase, aspartate aminotransferase, urine nitrogen, creatinine, and tumor necrosis factor-alpha. However, these increases were attenuated in the LPS + VPA group. The lungs, liver and kidneys from the LPS group were significantly damaged compared with the control group. However, the damage was attenuated in the LPS + VPA group. Myeloperoxidase activity and tumor necrosis factor-alpha levels in pulmonary tissue increased significantly in the LPS group compared with the control group. These increases were significantly inhibited in the LPS + VPA group. Acetylation of histone H3 in lung tissue in the LPS group was inhibited compared with the control. However, the level of acetylation of histone H3 in the LPS + VPA group was markedly elevated in contrast to the LPS group.
Treatment with VPA can attenuate multiple organ damage caused by LPS induced septic shock. Our data also suggest that the beneficial effects are in part due to the decrease in inflammatory cytokines and restoration of normal acetylation homeostasis.
丙戊酸（VPA）可改善高度致命性的多发伤伴失血性休克模型或其他严重损伤患者的早期存活率和器官功能。我们评估了 VPA 是否可改善脓毒性休克大鼠模型的器官功能，并阐述了可能的机制。
40 只 Sprague-Dawley 大鼠被随机分配到 4 个组（n=10）：对照组、VPA 组、LPS 组和 LPS+VPA 组。静脉内注射脂多糖（LPS，10mg/kg）以复制脓毒性休克的实验模型。大鼠给予 VPA（300mg/kg，静脉内）或生理盐水。LPS 注射后 6 小时，采集血样进行气体分析，测定血清丙氨酸氨基转移酶、天冬氨酸氨基转移酶、尿氮、肌酐和肿瘤坏死因子-α。收集肺、肝和肾进行组织病理学评估。此外，还测定肺组织髓过氧化物酶活性和肿瘤坏死因子-α。通过 Western 印迹法评估肺组织中组蛋白 H3 的乙酰化。
LPS 导致 PaO2 显著降低，给予 VPA 后 LPS 注射可使 PaO2 升高。此外，LPS 还导致血清丙氨酸氨基转移酶、天冬氨酸氨基转移酶、尿氮、肌酐和肿瘤坏死因子-α水平升高。但 LPS+VPA 组这些升高被减弱。与对照组相比，LPS 组的肺、肝和肾明显受损，但 LPS+VPA 组受损被减弱。与对照组相比，LPS 组肺组织中髓过氧化物酶活性和肿瘤坏死因子-α水平显著升高，LPS+VPA 组显著抑制了这些升高。与对照组相比，LPS 组肺组织中组蛋白 H3 的乙酰化受到抑制，但 LPS+VPA 组组蛋白 H3 的乙酰化水平明显升高。
VPA 治疗可减轻 LPS 诱导的脓毒性休克引起的多器官损伤。我们的数据还表明，这些有益作用部分是由于炎症细胞因子减少和正常乙酰化平衡恢复所致。
