Early activation of endoplasmic reticulum stress is associated with arginine-induced acute pancreatitis
Early activation of endoplasmic reticulum stress is associated with arginine-induced acute pancreatitis
复制标题
DOI：
10.1152/ajpgi.00471.2005
复制
发表时间：
2006-08-01
影响因子：
4.5
通讯作者：
Logsdon, Craig D.
中科院分区：
文献类型：
--
作者：
Kubisch, Constanze H.;Sans, Maria Dolors;Logsdon, Craig D.
内质网(ER)应激机制在糖尿病和阿尔茨海默病等多种疾病状态中起关键作用，但它们是否参与急性胰腺炎尚不清楚。在这里，我们第一次展示了所有主要的内质网应激感知和信号机制都存在于外分泌腺泡中，并在实验性急性胰腺炎的精氨酸模型中被激活。以4.0g/kg体重体重的精氨酸腹腔注射诱导大鼠胰腺炎。通过分析血清淀粉酶、胰腺胰酶活性、水分含量和组织学来评估胰腺炎的严重程度。分析内质网应激相关分子PERK、eIF2α、ATF6、XBP-1、Bip、CHOP和caspase-12。精氨酸处理可诱导快速重症胰腺炎，表现为4h内血清淀粉酶升高、胰腺组织水肿和腺泡细胞损伤。精氨酸处理还可导致ER应激的早期激活，表现为PERK及其下游靶分子eIF2α的磷酸化、ATF6移位到细胞核(1h内)和Bip的上调(4h内)。24 h后，内质网应激相关促凋亡分子caspase-12活性增强，caspase-3活性增强，TdT(末端脱氧核苷酸转移酶)介导的dUDP缺口末端标记(TUNEL)染色增强。这些结果表明，内质网应激是一个重要的早期腺泡细胞事件，可能有助于在精氨酸模型中发生急性胰腺炎。
Endoplasmic reticulum (ER) stress mechanisms have been found to play critical roles in a number of diseases states, such as diabetes mellitus and Alzheimer disease, but whether they are involved in acute pancreatitis is unknown. Here we show for the first time that all major ER stress sensing and signaling mechanisms are present in exocrine acini and are activated early in the arginine model of experimental acute pancreatitis. Pancreatitis was induced in rats by intraperitoneal injection of 4.0 g/kg body wt arginine. Pancreatitis severity was assessed by analysis of serum amylase, pancreatic trypsin activity, water content, and histology. ER stress-related molecules PERK, eIF2 alpha, ATF6, XBP-1, BiP, CHOP, and caspase-12 were analyzed. Arginine treatment induced rapid and severe pancreatitis, as indicated by increased serum amylase, pancreatic tissue edema, and acinar cell damage within 4 h. Arginine treatment also caused an early activation of ER stress, as indicated by phosphorylation of PERK and its downstream target eIF2 alpha, ATF6 translocation into the nucleus (within 1 h), and upregulation of BiP (within 4 h). XBP-1 splicing and CHOP expression were observed within 8 h. After 24 h, increased activation of the ER stress-related proapoptotic molecule caspase-12 was observed along with an increase in caspase-3 activity and TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labeling (TUNEL) staining in exocrine acini. These results indicate that ER stress is an important early acinar cell event that likely contributes to the development of acute pancreatitis in the arginine model.