4-Phenylbutyrate Benefits Traumatic Hemorrhagic Shock in Rats by Attenuating Oxidative Stress, Not by Attenuating Endoplasmic Reticulum Stress
4-Phenylbutyrate Benefits Traumatic Hemorrhagic Shock in Rats by Attenuating Oxidative Stress, Not by Attenuating Endoplasmic Reticulum Stress
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DOI：
10.1097/ccm.0000000000001469
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发表时间：
2016-07-01
影响因子：
8.8
通讯作者：
Liu, Liangming
中科院分区：
文献类型：
--
作者：
Yang, Guangming;Peng, Xiaoyong;Liu, Liangming
目的：严重创伤和休克后的血管功能障碍，如血管低反应性是创伤患者死亡的主要原因。氧化应激和内质网应激在血管功能障碍中起重要作用。本研究的目的是确定4-苯基丁酸盐是否可以通过抑制氧化应激和内质网应激来改善血管功能障碍并引起抗休克作用。设计：前瞻性、随机、对照实验室实验。设置：创伤、烧伤和复合伤国家重点实验室。受试者：552只Sprague-Dawley大鼠。干预措施：将大鼠麻醉后，通过左侧股骨骨折并出血建立创伤失血性休克模型。4-苯基丁酸的作用（5、20、50、100、200和300 mg/kg）对创伤失血性休克大鼠和培养的血管平滑肌细胞的血管反应性、动物存活率、血流动力学和重要器官功能的影响，以及与氧化应激和内质网应激的关系。小剂量4-苯丁酸酯可明显改善创伤失血性休克大鼠的血管功能，稳定血流动力学，增加组织血流量，改善重要器官功能，明显改善生存结局。在本研究中观察到的所有剂量中，20 mg/kg的4-苯基丁酸酯具有最佳效果。进一步的结果表明，4-苯丁酸酯显着抑制氧化应激，减少休克诱导的氧化应激指标，如活性氧的产生，增加抗氧化酶，如超氧化物歧化酶，过氧化氢酶，谷胱甘肽水平，并通过抑制线粒体通透性转换孔在大鼠动脉和血管平滑肌细胞的开放，改善线粒体功能。相比之下，4-苯基丁酸并不影响创伤失血性休克后内质网应激标志物的变化。结论：4-苯丁酸对创伤失血性休克动物具有保护器官功能和提高动物存活率的作用。4-苯丁酸酯在创伤失血性休克中的这些有益作用是通过减轻氧化应激和线粒体通透性转换孔开放来保护血管功能的结果。核因子-E2相关因子2和核因子-κ B B可能参与4-苯丁酸酯介导的氧化应激抑制。
Objective: Vascular dysfunction such as vascular hyporeactivity following severe trauma and shock is a major cause of death in injured patients. Oxidative stress and endoplasmic reticulum stress play an important role in vascular dysfunction. The objective of the present study was to determine whether or not 4-phenylbutyrate can improve vascular dysfunction and elicit antishock effects by inhibiting oxidative and endoplasmic reticulum stress.Design: Prospective, randomized, controlled laboratory experiment.Setting: State key laboratory of trauma, burns, and combined injury.Subjects: Five hundred and fifty-two Sprague-Dawley rats.Interventions: Rats were anesthetized, and a model of traumatic hemorrhagic shock was established by left femur fracture and hemorrhage. The effects of 4-phenylbutyrate (5, 20, 50, 100, 200, and 300 mg/kg) on vascular reactivity, animal survival, hemodynamics, and vital organ function in traumatic hemorrhagic shock rats and cultured vascular smooth muscle cells, and the relationship to oxidative stress and endoplasmic reticulum stress was observed.Measurements and Main Results: Lower doses of 4-phenylbutyrate significantly improved the vascular function, stabilized the hemodynamics, and increased the tissue blood flow and vital organ function in traumatic hemorrhagic shock rats, and markedly improved the survival outcomes. Among all dosages observed in the present study, 20 mg/kg of 4-phenylbutyrate had the best effect. Further results indicated that 4-phenylbutyrate significantly inhibited the oxidative stress, decreased shock-induced oxidative stress index such as the production of reactive oxygen species, increased the antioxidant enzyme levels such as superoxide dismutase, catalase, and glutathione, and improved the mitochondrial function by inhibiting the opening of the mitochondrial permeability transition pore in rat artery and vascular smooth muscle cells. In contrast, 4-phenylbutyrate did not affect the changes of endoplasmic reticulum stress markers following traumatic hemorrhagic shock. Furthermore, 4-phenylbutyrate increased the nuclear levels of nuclear factor-E2-related factor 2, and decreased the nuclear levels of nuclear factor kappa B in hypoxic vascular smooth muscle cells.Conclusions: 4-phenylbutyrate has beneficial effects for traumatic hemorrhagic shock including improving animal survival and protecting organ function. These beneficial effects of 4-phenylbutyrate in traumatic hemorrhagic shock result from its vascular function protection via attenuation of the oxidative stress and mitochondrial permeability transition pore opening. Nuclear factor-E2-related factor 2 and nuclear factor-kappa B may be involved in 4-phenylbutyrate-mediated inhibition of oxidative stress.