Abstract：
Intestinal barrier dysfunction usually occurred in acute pancreatitis (AP) but the mechanism remains unclear. In this study, RNA sequencing of ileum in L-arginine-induced AP mice demonstrated that phosphoenolpyruvate kinase 1 (Pck1) was significantly up-regulated. Increased Pck1 expression in intestinal epithelial cells (IECs) was further validated in ileum of AP mice and duodenum of AP patients. In AP mice, level of Pck1 was positively correlated with pancreatic and ileal histopathological scores, serum amylase activity, and intestinal permeability (serum diamine oxidase (DAO), D-lactate, and endotoxin). In AP patients, level of Pck1 had a positive correlation with Ranson scores, white blood cell count and C-reactive protein. Inhibition of Pck1 by 3-Mercaptopicolinic acid hydrochloride (3-MPA) alleviated pancreatic and ileal injuries in AP mice. AP + 3-MPA mice showed improved intestinal permeability, including less epithelial apoptosis, increased tight junction proteins (TJPs) expression, decreased serum DAO, D-lactate, endotoxin, and FITC-Dextran levels, and reduced bacteria translocation. Lysozyme secreted by Paneth cells and mucin2 (MUC2) secretion in goblet cells were also partly restored in AP + 3-MPA mice. Meanwhile, inhibition of Pck1 improved intestinal immune response during AP, including elevation of M2/M1 macrophages ratio and secretory immunoglobulin A (sIgA) and reduction in neutrophils infiltration. In vitro, administration of 3-MPA dramatically ameliorated inflammation and injuries of epithelial cells in enteroids treated by LPS. In conclusion, inhibition of Pck1 in IECs might alleviate AP via modulating intestinal homeostasis.
摘要：
肠屏障功能障碍通常发生在急性胰腺炎（AP），但机制尚不清楚。在这项研究中,L-精氨酸诱导的AP小鼠回肠的RNA测序表明磷酸烯醇丙酮酸激酶1(Pck1)显著上调。在AP小鼠的回肠和AP患者的十二指肠中进一步验证了肠上皮细胞（IECs）中Pck1表达的增加。在AP小鼠中,Pck1水平与胰腺和回肠组织病理学评分呈正相关,血清淀粉酶活性，和肠道通透性(血清二胺氧化酶(DAO)，D-乳酸,和内毒素）。在AP患者中，Pck1水平与Ranson评分呈正相关，白细胞计数和C反应蛋白。3-巯基吡啶甲酸盐酸盐（3-MPA）对Pck1的抑制作用减轻了AP小鼠的胰腺和回肠损伤。AP+3-MPA小鼠表现出改善的肠通透性，包括更少的上皮凋亡，紧密连接蛋白（TJPs）表达增加，降低血清DAO，D-乳酸,内毒素,和FITC-葡聚糖水平，减少细菌移位。在AP3-MPA小鼠中，潘氏细胞分泌的溶菌酶和杯状细胞中的粘蛋白2（MUC2）分泌也部分恢复。同时,抑制Pck1可改善AP期间的肠道免疫反应，包括M2/M1巨噬细胞比率和分泌性免疫球蛋白A（sIgA）的升高以及中性粒细胞浸润的减少。体外，3-MPA的给药可显着改善LPS处理的类肠的炎症和上皮细胞损伤。总之,抑制IECs中的Pck1可能通过调节肠道稳态来缓解AP。
