Early changes in pancreatic acinar cell calcium signaling after pancreatic duct obstruction
Early changes in pancreatic acinar cell calcium signaling after pancreatic duct obstruction
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DOI：
10.1074/jbc.m207454200
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发表时间：
2003-03-14
影响因子：
4.8
通讯作者：
Lerch, MM
中科院分区：
文献类型：
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作者：
Mooren, FC;Hlouschek, V;Lerch, MM
细胞内Ca ~（2+）变化不仅参与重要的信号通路，而且还与包括急性胰腺炎在内的许多疾病状态有关。为了研究模拟人胆结石诱导的胰腺炎的实验模型中的潜在机制，我们将Sprague-Dawley大鼠和NMRI小鼠的胰管结扎长达6小时，并研究胰腺内的变化，包括分离腺泡中[Ca 2 +]（i）的动力学。与胆管结扎相反，胰管梗阻诱导胰腺内胰蛋白酶原活化、白细胞增多、高淀粉酶血症和胰腺水肿，并增加肺髓过氧化物酶活性。尽管离体腺泡静息[Ca 2 +]（i）升高45%至205 +/- 7 nmol，乙酰胆碱和胆囊收缩素（CCK）刺激的钙峰以及淀粉酶分泌下降，但胰管结扎既不损害[Ca 2 +]（i）信号模式，也不损害对Ca 2 +-ATP酶抑制剂毒胡萝卜素的淀粉酶输出，也不损害分泌素刺激的淀粉酶释放。在单细胞水平上，胰管结扎降低了次最大促分泌素刺激后出现生理反应（即Ca 2+振荡）的细胞百分比，并增加了出现病理反应（即峰值平台或无Ca 2+信号）的细胞百分比。此外，它还降低了促分泌素刺激引起的Ca 2+振荡的频率和幅度以及容量性Ca 2+内流。用钙螯合剂BAPTA-AM预处理动物，可显著降低血清胰腺酶升高和胰蛋白酶原活化。这些实验表明，胰管梗阻迅速改变了外分泌胰腺的生理反应的Ca 2+信号模式，已与过早的消化酶激活和胰腺炎的发病，这两者都可以通过管理的细胞内钙螯合剂预防。
Intracellular Ca2+-changes not only participate in important signaling pathways but have also been implicated in a number of disease states including acute pancreatitis. To investigate the underlying mechanisms in an experimental model mimicking human gallstone-induced pancreatitis, we ligated the pancreatic duct of Sprague-Dawley rats and NMRI mice for up to 6 h and studied intrapancreatic changes including the dynamics of [Ca2+](i) in isolated acini. In contrast to bile duct ligation, pancreatic duct obstruction induced intra-pancreatic trypsinogen activation, leukocytosis, hyperamylasemia, and pancreatic edema and increased lung myeloperoxidase activity. Although resting [Ca2+](i) in isolated acini rose by 45% to 205 +/- 7 nmol, the acetylcholine- and cholecystokinin (CCK)-stimulated calcium peaks as well as the amylase secretion declined, but neither the [Ca2+](i)-signaling pattern nor the amylase output in response to the Ca2+-ATPase inhibitor thapsigargin nor the secretin-stimulated amylase release were impaired by pancreatic duct ligation. On the single cell level pancreatic duct ligation reduced the percentage of cells in which submaximal secretagogue stimulation was followed by a physiological response (i.e. Ca2+ oscillations) and increased the percentage of cells with a pathological response (i.e. peak plateau or absent Ca2+ signal). Moreover, it reduced the frequency and amplitude of Ca2+ oscillation as well as the capacitative Ca2+ influx in response to secretagogue stimulation. Serum pancreatic enzyme elevation as well as trypsinogen activation was significantly reduced by pretreatment of animals with the calcium chelator BAPTA-AM. These experiments suggest that pancreatic duct obstruction rapidly changes the physiological response of the exocrine pancreas to a Ca2+-signaling pattern that has been associated with premature digestive enzyme activation and the onset of pancreatitis, both of which can be prevented by administration of an intracellular calcium chelator.