Calcium signalling in the acinar environment of the exocrine pancreas: physiology and pathophysiology.
Calcium signalling in the acinar environment of the exocrine pancreas: physiology and pathophysiology.
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DOI：
10.1113/jp275395
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发表时间：
2018-07
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：
Gryshchenko O;Gerasimenko JV;Peng S;Gerasimenko OV;Petersen OH
同时监测外分泌胰腺小叶中不同细胞类型的Ca 2+信号，并直接比较对各种刺激的信号反应。从胰腺神经细胞中记录了K+诱导的去极化诱发的Ca 2+信号。神经细胞刺激诱发的Ca 2+信号在腺泡，但不是在星状细胞。星状细胞是不电兴奋的，因为它们，像腺泡细胞，不产生Ca 2+信号响应膜去极化。在实验性酒精相关急性胰腺炎中，星状细胞对缓激肽的反应性显著降低，但它们对胰蛋白酶的刺激变得敏感。我们的研究结果为星状细胞在急性胰腺炎中的重要作用提供了新的证据。它们似乎是促进坏死腺泡细胞死亡的恶性循环中的关键因素。从一些垂死的腺泡细胞中释放的初始胰蛋白酶在星状细胞中产生Ca 2+信号，其继而损伤更多的腺泡细胞，引起进一步的胰蛋白酶释放。胰腺腺泡细胞中的生理性Ca 2+信号控制液体和酶分泌，而病理性试剂诱导的过量Ca 2+信号诱导导致急性胰腺炎的破坏性过程。胰腺-腺泡星状细胞中的Ca 2+信号也可能在急性胰腺炎的发展中发挥作用。在这项研究中，我们探讨了Ca 2+信号在胰腺组织的腺泡环境中的不同类型的细胞。我们首次记录了胰腺神经中去极化诱发的Ca 2+信号，并表明腺泡细胞接受功能性胆碱能神经支配，而星状细胞没有功能性神经支配的证据。星状细胞，像腺泡，细胞是不电兴奋的，因为它们不产生Ca 2+信号响应膜去极化。在星状细胞中引起Ca 2+信号的主要试剂是缓激肽，但在实验性酒精相关急性胰腺炎中，这些细胞对缓激肽的反应性降低，然后获得对胰蛋白酶的敏感性。我们的新发现对我们了解急性胰腺炎的发展具有影响，我们提出了一种方案，其中星状细胞中的Ca 2+信号提供了促进腺泡细胞死亡的放大循环。从垂死的腺泡细胞中最初释放的蛋白酶激肽释放酶和胰蛋白酶可以通过缓激肽生成和蛋白酶激活受体诱导星状细胞中的Ca 2+信号，然后可能通过一氧化氮生成，损伤更多的腺泡细胞，从而导致蛋白酶的额外释放，产生恶性循环。同时监测外分泌胰腺小叶中不同细胞类型的Ca 2+信号，并直接比较对各种刺激的信号反应。从胰腺神经细胞记录由K+诱导的去极化诱发的Ca 2+信号。神经细胞刺激诱发的Ca 2+信号在腺泡，但不是在星状细胞。星状细胞是不电兴奋的，因为它们，像腺泡细胞，不产生Ca 2+信号响应膜去极化。在实验性酒精相关急性胰腺炎中，星状细胞对缓激肽的反应性显著降低，但它们对胰蛋白酶的刺激变得敏感。我们的研究结果为星状细胞在急性胰腺炎中的重要作用提供了新的证据。它们似乎是促进坏死腺泡细胞死亡的恶性循环中的关键因素。从一些垂死的腺泡细胞中释放的初始胰蛋白酶在星状细胞中产生Ca 2+信号，其继而损伤更多的腺泡细胞，引起进一步的胰蛋白酶释放。
Ca2+ signalling in different cell types in exocrine pancreatic lobules was monitored simultaneously and signalling responses to various stimuli were directly compared. Ca2+ signals evoked by K+‐induced depolarization were recorded from pancreatic nerve cells. Nerve cell stimulation evoked Ca2+ signals in acinar but not in stellate cells. Stellate cells are not electrically excitable as they, like acinar cells, did not generate Ca2+ signals in response to membrane depolarization. The responsiveness of the stellate cells to bradykinin was markedly reduced in experimental alcohol‐related acute pancreatitis, but they became sensitive to stimulation with trypsin. Our results provide fresh evidence for an important role of stellate cells in acute pancreatitis. They seem to be a critical element in a vicious circle promoting necrotic acinar cell death. Initial trypsin release from a few dying acinar cells generates Ca2+ signals in the stellate cells, which then in turn damage more acinar cells causing further trypsin liberation. Physiological Ca2+ signals in pancreatic acinar cells control fluid and enzyme secretion, whereas excessive Ca2+ signals induced by pathological agents induce destructive processes leading to acute pancreatitis. Ca2+ signals in the peri‐acinar stellate cells may also play a role in the development of acute pancreatitis. In this study, we explored Ca2+ signalling in the different cell types in the acinar environment of the pancreatic tissue. We have, for the first time, recorded depolarization‐evoked Ca2+ signals in pancreatic nerves and shown that whereas acinar cells receive a functional cholinergic innervation, there is no evidence for functional innervation of the stellate cells. The stellate, like the acinar, cells are not electrically excitable as they do not generate Ca2+ signals in response to membrane depolarization. The principal agent evoking Ca2+ signals in the stellate cells is bradykinin, but in experimental alcohol‐related acute pancreatitis, these cells become much less responsive to bradykinin and then acquire sensitivity to trypsin. Our new findings have implications for our understanding of the development of acute pancreatitis and we propose a scheme in which Ca2+ signals in stellate cells provide an amplification loop promoting acinar cell death. Initial release of the proteases kallikrein and trypsin from dying acinar cells can, via bradykinin generation and protease‐activated receptors, induce Ca2+ signals in stellate cells which can then, possibly via nitric oxide generation, damage more acinar cells and thereby cause additional release of proteases, generating a vicious circle. Ca2+ signalling in different cell types in exocrine pancreatic lobules was monitored simultaneously and signalling responses to various stimuli were directly compared. Ca2+ signals evoked by K+‐induced depolarization were recorded from pancreatic nerve cells. Nerve cell stimulation evoked Ca2+ signals in acinar but not in stellate cells. Stellate cells are not electrically excitable as they, like acinar cells, did not generate Ca2+ signals in response to membrane depolarization. The responsiveness of the stellate cells to bradykinin was markedly reduced in experimental alcohol‐related acute pancreatitis, but they became sensitive to stimulation with trypsin. Our results provide fresh evidence for an important role of stellate cells in acute pancreatitis. They seem to be a critical element in a vicious circle promoting necrotic acinar cell death. Initial trypsin release from a few dying acinar cells generates Ca2+ signals in the stellate cells, which then in turn damage more acinar cells causing further trypsin liberation.