All authors: State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, P.R. China.
Crit Care Med. 2016 Aug;44(8):e689-701. doi: 10.1097/CCM.0000000000001662.
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.
Laboratory investigation.
State Key Laboratory of Trauma, Burns and Combined Injury.
Sprague-Dawley rats.
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.
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 stress-mediated cytokine release, apoptosis, and oxidative stress via inhibition of nuclear factor-κB, caspase-3 and caspase-9, and increasing glutathione peroxidase and superoxide dismutase expression, respectively.
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.
脓毒症和感染性休克是 ICU 中常见的并发症。严重脓毒症或感染性休克后，重要器官功能障碍是导致高死亡率的关键因素，其中内质网应激起着重要作用。用 4-苯丁酸抗内质网应激是否对脓毒症有益，其潜在机制尚不清楚。
实验室研究。
创伤、烧伤与复合伤国家重点实验室。
Sprague-Dawley 大鼠。
采用盲肠结扎穿孔诱导脓毒性休克大鼠、脂多糖处理的血管平滑肌细胞和心肌细胞，观察 4-苯丁酸对重要器官功能的影响及其与内质网应激的关系，以及内质网应激介导的炎症、凋亡和氧化应激。
常规治疗（包括液体复苏、血管加压素和抗生素）仅能轻微改善血流动力学参数，如平均动脉压和心输出量，也能轻微改善脓毒性休克大鼠的重要器官功能和动物存活率。补充 4-苯丁酸（5mg/kg；抗内质网应激），特别是在早期使用，可显著改善血流动力学参数、重要器官功能，如肝、肾和肠道屏障功能，以及脓毒性休克大鼠的动物存活率。4-苯丁酸的应用抑制了内质网应激和内质网应激相关蛋白，如心脏和肠系膜上动脉等重要器官中的 CCAAT/增强子结合蛋白同源蛋白。进一步的研究表明，4-苯丁酸通过抑制核因子-κB、半胱天冬酶-3 和半胱天冬酶-9，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、凋亡和氧化应激。
用 4-苯丁酸抗内质网应激对感染性休克有益。4-苯丁酸的这种有益作用与抑制内质网应激介导的氧化应激、凋亡和细胞因子释放密切相关。这一发现为严重脓毒症等临床危急情况提供了一种潜在的治疗措施。
