Sutton Robert, Criddle David, Raraty Michael G T, Tepikin Alexei, Neoptolemos John P, Petersen Ole H
Department of Surgery, University of Liverpool, 5th Floor UCD Block, Royal Liverpool University Hospital, Daulby Street, Liverpool L69 3GA, UK.
Pancreatology. 2003;3(6):497-505. doi: 10.1159/000075581. Epub 2003 Dec 11.
Evidence consistently suggests that the earliest changes of acute pancreatitis are intracellular, the hallmark of which is premature intracellular activation of digestive zymogens, accompanied by disruption of normal signal transduction and secretion. Principal components of physiological signal transduction include secretagogue-induced activation of G-protein-linked receptors, followed by generation of inositol 1,4,5-trisphosphate, nicotinic acid adenine dinucleotide phosphate and cyclic ADP-ribose. In response, calcium is released from endoplasmic reticulum terminals within the apical, granular pole of the cell, where calcium signals are usually contained by perigranular mitochondria, in turn responding by increased metabolism. When all three intracellular messengers are administered together, even at threshold concentrations, dramatic potentiation results in sustained, global, cytosolic calcium elevation. Prolonged, global elevation of cytosolic calcium is also induced by hyperstimulation, bile salts, alcohol and fatty acid ethyl esters, and depends on continued calcium entry into the cell. Such abnormal calcium signals induce intracellular activation of digestive enzymes, and of nuclear factor kappaB, as well as the morphological changes of acute pancreatitis. Depletion of endoplasmic reticulum calcium and mitochondrial membrane potential may contribute to further cell injury. This review outlines current understanding of signal transduction in the pancreas, and its application to the pathophysiology of acute pancreatitis.
证据一直表明，急性胰腺炎最早的变化发生在细胞内，其标志是消化酶原在细胞内过早激活，同时伴有正常信号转导和分泌的破坏。生理信号转导的主要成分包括促分泌剂诱导的G蛋白偶联受体激活，随后生成肌醇1,4,5-三磷酸、烟酰胺腺嘌呤二核苷酸磷酸和环ADP-核糖。作为响应，钙从细胞顶端颗粒极的内质网终末释放，钙信号通常由颗粒周围的线粒体控制，线粒体进而通过增加代谢做出反应。当三种细胞内信使一起给药时，即使在阈值浓度下，也会产生显著的增强作用，导致细胞质钙持续、整体升高。过度刺激、胆汁盐、酒精和脂肪酸乙酯也会诱导细胞质钙长时间整体升高，并且这依赖于钙持续进入细胞。这种异常的钙信号会诱导消化酶和核因子κB在细胞内激活，以及急性胰腺炎的形态学变化。内质网钙的消耗和线粒体膜电位可能会导致进一步的细胞损伤。本综述概述了目前对胰腺信号转导的理解及其在急性胰腺炎病理生理学中的应用。
