Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium-driven bile uptake.
Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium-driven bile uptake.
复制标题
胆汁酸会诱导胰腺星状细胞坏死，依赖于钙进入和钠驱动的胆汁摄取。
DOI：
10.1113/jp272774
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发表时间：
2016-11-01
期刊：
影响因子：
--
通讯作者：
Petersen OH
中科院分区：
文献类型：
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作者：
Ferdek PE;Jakubowska MA;Gerasimenko JV;Gerasimenko OV;Petersen OH
急性胆源性胰腺炎是由胆汁返流进入胰腺引起的一种突然而严重的疾病。已知胆汁酸可在分离的胰腺腺泡细胞中诱导钙信号和坏死，但胆汁酸对星状细胞的影响尚不清楚。与邻近的胰腺小叶腺泡细胞相比，胆酸盐和牛磺胆酸在星状细胞中引起更明显的钙信号和坏死；而牛磺胆酸3-硫酸盐主要影响腺泡细胞。Ca~(2+)信号和坏死强烈依赖于细胞外的Ca~(2+)和Na~+，Na~+依赖的转运在胰星状细胞胆汁酸摄取中起重要作用。胆汁酸介导的胰腺损伤可被缓激肽诱导的星状细胞信号进一步加重，因此胆汁酸对星状细胞的杀伤可能在急性胆源性胰腺炎中具有重要意义。急性胆源性胰腺炎是由胆汁回流到胰腺引起的一种严重疾病，其特征是腺泡细胞内的消化酶过早激活，继而出现坏死和炎症。胆汁酸可以引起腺泡细胞的病理性钙信号和坏死。然而，胆汁酸在星状细胞中诱导的信号事件仍未被探索。这是首次在体外(小鼠胰腺小叶)和体外(人细胞)两种实验模型上证实胆汁酸对星状细胞的病理生理影响。胆酸钠和牛磺胆酸盐可诱导星状细胞胞浆内钙离子升高，其幅度大于邻近腺泡细胞同时引起的钙升高。相反，牛磺胆石酸-3-硫酸酯(TLC-S)对小叶星状细胞的作用很小，它能引起腺泡细胞的钙振荡。钙信号对胞外Na+的依赖性和牛磺胆酸钠共转运多肽(NTCP)的存在表明星状细胞摄取胆汁酸的机制依赖于Na+。胆汁酸处理主要引起星状细胞的坏死，这种坏死可被细胞外钙离子清除而取消，并在没有Na+的情况下显著减少，表明胆汁依赖性细胞死亡是钙信号的下游事件。TLC-S与炎症介质缓激肽联合应用时，星状细胞和腺泡细胞的广泛坏死程度均高于单用TLC-S。我们的发现为胆汁酸促进胰腺病理的机制提供了新的线索。这不仅涉及腺泡细胞中的信号传递，也涉及星状细胞中的信号传递。急性胆源性胰腺炎是由胆汁返流进入胰腺引起的一种突然而严重的疾病。已知胆汁酸可在分离的胰腺腺泡细胞中诱导钙信号和坏死，但胆汁酸对星状细胞的影响尚不清楚。与邻近的胰腺小叶腺泡细胞相比，胆酸盐和牛磺胆酸在星状细胞中引起更明显的钙信号和坏死；而牛磺胆酸3-硫酸盐主要影响腺泡细胞。Ca~(2+)信号和坏死强烈依赖于细胞外的Ca~(2+)和Na~+，Na~+依赖的转运在胰星状细胞胆汁酸摄取中起重要作用。胆汁酸介导的胰腺损伤可被缓激肽诱导的星状细胞信号进一步加重，因此胆汁酸对星状细胞的杀伤可能在急性胆源性胰腺炎中具有重要意义。
Acute biliary pancreatitis is a sudden and severe condition initiated by bile reflux into the pancreas. Bile acids are known to induce Ca2+ signals and necrosis in isolated pancreatic acinar cells but the effects of bile acids on stellate cells are unexplored. Here we show that cholate and taurocholate elicit more dramatic Ca2+ signals and necrosis in stellate cells compared to the adjacent acinar cells in pancreatic lobules; whereas taurolithocholic acid 3‐sulfate primarily affects acinar cells. Ca2+ signals and necrosis are strongly dependent on extracellular Ca2+ as well as Na+; and Na+‐dependent transport plays an important role in the overall bile acid uptake in pancreatic stellate cells. Bile acid‐mediated pancreatic damage can be further escalated by bradykinin‐induced signals in stellate cells and thus killing of stellate cells by bile acids might have important implications in acute biliary pancreatitis. Acute biliary pancreatitis, caused by bile reflux into the pancreas, is a serious condition characterised by premature activation of digestive enzymes within acinar cells, followed by necrosis and inflammation. Bile acids are known to induce pathological Ca2+ signals and necrosis in acinar cells. However, bile acid‐elicited signalling events in stellate cells remain unexplored. This is the first study to demonstrate the pathophysiological effects of bile acids on stellate cells in two experimental models: ex vivo (mouse pancreatic lobules) and in vitro (human cells). Sodium cholate and taurocholate induced cytosolic Ca2+ elevations in stellate cells, larger than those elicited simultaneously in the neighbouring acinar cells. In contrast, taurolithocholic acid 3‐sulfate (TLC‐S), known to induce Ca2+ oscillations in acinar cells, had only minor effects on stellate cells in lobules. The dependence of the Ca2+ signals on extracellular Na+ and the presence of sodium–taurocholate cotransporting polypeptide (NTCP) indicate a Na+‐dependent bile acid uptake mechanism in stellate cells. Bile acid treatment caused necrosis predominantly in stellate cells, which was abolished by removal of extracellular Ca2+ and significantly reduced in the absence of Na+, showing that bile‐dependent cell death was a downstream event of Ca2+ signals. Finally, combined application of TLC‐S and the inflammatory mediator bradykinin caused more extensive necrosis in both stellate and acinar cells than TLC‐S alone. Our findings shed new light on the mechanism by which bile acids promote pancreatic pathology. This involves not only signalling in acinar cells but also in stellate cells. Acute biliary pancreatitis is a sudden and severe condition initiated by bile reflux into the pancreas. Bile acids are known to induce Ca2+ signals and necrosis in isolated pancreatic acinar cells but the effects of bile acids on stellate cells are unexplored. Here we show that cholate and taurocholate elicit more dramatic Ca2+ signals and necrosis in stellate cells compared to the adjacent acinar cells in pancreatic lobules; whereas taurolithocholic acid 3‐sulfate primarily affects acinar cells. Ca2+ signals and necrosis are strongly dependent on extracellular Ca2+ as well as Na+; and Na+‐dependent transport plays an important role in the overall bile acid uptake in pancreatic stellate cells. Bile acid‐mediated pancreatic damage can be further escalated by bradykinin‐induced signals in stellate cells and thus killing of stellate cells by bile acids might have important implications in acute biliary pancreatitis.