Department of General Surgery, Renmin Hospital of Wuhan University , Wuhan, Hubei , China.
Department of Pancreatic Surgery, Renmin Hospital of Wuhan University , Wuhan, Hubei , China.
Am J Physiol Gastrointest Liver Physiol. 2018 Nov 1;315(5):G838-G847. doi: 10.1152/ajpgi.00102.2018. Epub 2018 Aug 23.
This study was conducted to investigate the effect of 4-phenylbutyric acid (4-PBA) on vital organ injury following sodium taurocholate-induced acute pancreatitis (AP) in rats and the pertinent mechanism. The serum biochemical indicators and key inflammatory cytokines, histopathological damage and apoptosis of vital organs in rat AP, were evaluated in the presence or absence of 4-PBA. Moreover, mRNA and protein levels of endoplasmic reticulum stress (ERS) markers were assessed. 4-PBA significantly attenuated the structural and functional damage of vital organs, including serum pancreatic enzymes, hepatic enzymes, creatinine, and urea. The morphological changes and infiltration of neutrophils and macrophages were reduced as well. These effects were accompanied by decreased serum levels of proinflammatory TNF-α and IL-1β. Furthermore, 4-PBA diminished the expression of ERS markers (glucose-regulated protein 78, CCAAT/enhancer-binding protein homologous protein, protein kinase R-like ER kinase, activated transcription factor 6, and type-1 inositol requiring enzyme) in vital organs of AP rats. 4-PBA also reduced AP-induced apoptosis in lung, liver, and kidney tissues as shown by TUNEL assay. The present study demonstrated that 4-PBA protected pancreas, lung, liver, and kidney from injury in rat AP by regulating ERS and mitigating inflammatory response to restrain cell death and further suggested that 4-PBA may have potential therapeutic implications in the disease. NEW & NOTEWORTHY In this study, we suggest that endoplasmic reticulum stress (ERS) is an important player in the development of acute pancreatitis-induced multiorgan injury, providing additional evidence for the proinflammatory role of ERS. Because 4-phenylbutyric acid has been suggested to inhibit ERS in many pathological conditions, it is possible that this effect can be involved in alleviating inflammatory response and cell death to ameliorate vital organ damage following acute pancreatitis induced by sodium taurocholate in rats.
本研究旨在探讨 4- 苯基丁酸（4-PBA）对大鼠胆酸钠诱导的急性胰腺炎（AP）后重要器官损伤的影响及其相关机制。在存在或不存在 4-PBA 的情况下，评估了大鼠 AP 中血清生化指标和关键炎症细胞因子、重要器官的组织病理学损伤和细胞凋亡，以及内质网应激（ERS）标志物的 mRNA 和蛋白水平。4-PBA 显著减轻了重要器官的结构和功能损伤，包括血清胰腺酶、肝酶、肌酐和尿素。形态学变化和中性粒细胞及巨噬细胞浸润也减少了。这些作用伴随着促炎细胞因子 TNF-α 和 IL-1β 血清水平的降低。此外，4-PBA 还降低了 AP 大鼠重要器官中 ERS 标志物（葡萄糖调节蛋白 78、CCAAT/增强子结合蛋白同源蛋白、蛋白激酶 R 样内质网激酶、激活转录因子 6 和 1 型肌醇需求酶）的表达。TUNEL 检测显示，4-PBA 还减少了 AP 诱导的肺、肝和肾组织细胞凋亡。本研究表明，4-PBA 通过调节 ERS 减轻炎症反应，抑制细胞死亡，从而保护胰腺、肺、肝和肾免受大鼠 AP 损伤，进一步表明 4-PBA 可能在该疾病中具有潜在的治疗意义。
本研究提示内质网应激（ERS）在急性胰腺炎诱导的多器官损伤的发生发展中具有重要作用，为 ERS 的促炎作用提供了更多证据。由于 4- 苯基丁酸在许多病理条件下被认为能抑制 ERS，因此这种作用可能参与缓解炎症反应和细胞死亡，从而减轻大鼠胆酸钠诱导的急性胰腺炎后重要器官的损伤。
