4-Phenylbutyric Acid Reveals Good Beneficial Effects on Vital Organ Function via Anti-Endoplasmic Reticulum Stress in Septic Rats
4-Phenylbutyric Acid Reveals Good Beneficial Effects on Vital Organ Function via Anti-Endoplasmic Reticulum Stress in Septic Rats
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DOI：
10.1097/ccm.0000000000001662
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发表时间：
2016-08-01
影响因子：
8.8
通讯作者：
Li, Tao
中科院分区：
文献类型：
--
作者：
Liu, Liangming;Wu, Huiling;Li, Tao
目的：脓毒症和脓毒性休克是ICU常见的并发症。重要器官功能障碍是导致严重脓毒症或脓毒性休克后高死亡率的关键因素，其中内质网应激起重要作用。4-苯基丁酸抗内质网应激是否对脓毒症有益及其潜在机制尚不清楚。设计：实验室调查。单位：创伤、烧伤及复合伤国家重点实验室。受试者：Sprague-Dawley大鼠。干预措施：使用盲肠结扎和穿孔诱导的脓毒性休克大鼠，脂多糖处理的血管平滑肌细胞和心肌细胞，观察4-苯基丁酸对重要器官功能的影响以及与内质网应激和内质网应激介导的炎症、凋亡和氧化应激的关系。常规治疗，包括液体复苏、加压素和抗生素，仅轻微改善血流动力学变量，如平均动脉血压和心输出量，并略有改善脓毒性休克大鼠的重要器官功能和动物生存。补充4-苯基丁酸（5 mg/kg;抗内质网应激），特别是在早期给药，显着改善血流动力学变量，重要器官功能，如肝，肾，肠屏障功能，和动物存活率在感染性休克大鼠。4-应用苯丁酸可抑制严重脓毒症后重要器官（如心脏和上级肠系膜动脉）的内质网应激和内质网应激相关蛋白（如CCAAT/增强子结合蛋白同源蛋白）。进一步的研究表明，4-苯基丁酸通过抑制核因子-κ B、caspase-3和caspase-9，以及增加谷胱甘肽过氧化物酶和超氧化物歧化酶的表达，抑制内质网应激介导的细胞因子释放、细胞凋亡和氧化应激。4-苯基丁酸的这种有益作用与抑制内质网应激介导的氧化应激、细胞凋亡和细胞因子释放密切相关。这一发现为临床危重疾病（如严重脓毒症）提供了潜在的治疗措施。
Objectives: Sepsis and septic shock are the common complications in ICUs. Vital organ function disorder contributes a critical role in high mortality after severe sepsis or septic shock, in which endoplasmic reticulum stress plays an important role. Whether anti-endoplasmic reticulum stress with 4-phenylbutyric acid is beneficial to sepsis and the underlying mechanisms are not known.Design: Laboratory investigation.Setting: State Key Laboratory of Trauma, Burns and Combined Injury.Subjects: Sprague-Dawley rats.Interventions: Using cecal ligation and puncture-induced septic shock rats, lipopolysaccharide-treated vascular smooth muscle cells, and cardiomyocytes, effects of 4-phenylbutyric acid on vital organ function and the relationship with endoplasmic reticulum stress and endoplasmic reticulum stress-mediated inflammation, apoptosis, and oxidative stress were observed.Measurements and Main Results: Conventional treatment, including fluid resuscitation, vasopressin, and antibiotic, only slightly improved the hemodynamic variable, such as mean arterial blood pressure and cardiac output, and slightly improved the vital organ function and the animal survival of septic shock rats. Supplementation of 4-phenylbutyric acid (5 mg/kg; anti-endoplasmic reticulum stress), especially administered at early stage, significantly improved the hemodynamic variables, vital organ function, such as liver, renal, and intestinal barrier function, and animal survival in septic shock rats. 4-Phenylbutyric acid application inhibited the endoplasmic reticulum stress and endoplasmic reticulum stress-related proteins, such as CCAAT/enhancer-binding protein homologous protein in vital organs, such as heart and superior mesenteric artery after severe sepsis. Further studies showed that 4-phenylbutyric acid inhibited endoplasmic reticulum stressmediated cytokine release, apoptosis, and oxidative stress via inhibition of nuclear factor-kappa B, caspase-3 and caspase-9, and increasing glutathione peroxidase and superoxide dismutase expression, respectively.Conclusions: Anti-endoplasmic reticulum stress with 4-phenylbutyric acid is beneficial to septic shock. This beneficial effect of 4-phenylbutyric acid is closely related to the inhibition of endoplasmic reticulum stress-mediated oxidative stress, apoptosis, and cytokine release. This finding provides a potential therapeutic measure for clinical critical conditions, such as severe sepsis.