Gryshchenko Oleksiy, Gerasimenko Julia V, Gerasimenko Oleg V, Petersen Ole H
Medical Research Council Group, Cardiff School of Biosciences, Cardiff University, Cardiff, CF10 3AX, Wales, UK.
Bogomoletz Institute of Physiology, Kiev, 01024, Ukraine.
J Physiol. 2016 Jan 15;594(2):281-93. doi: 10.1113/JP271468. Epub 2015 Nov 8.
Bradykinin may play a role in the autodigestive disease acute pancreatitis, but little is known about its pancreatic actions. In this study, we have investigated bradykinin-elicited Ca(2+) signal generation in normal mouse pancreatic lobules. We found complete separation of Ca(2+) signalling between pancreatic acinar (PACs) and stellate cells (PSCs). Pathophysiologically relevant bradykinin concentrations consistently evoked Ca(2+) signals, via B2 receptors, in PSCs but never in neighbouring PACs, whereas cholecystokinin, consistently evoking Ca(2+) signals in PACs, never elicited Ca(2+) signals in PSCs. The bradykinin-elicited Ca(2+) signals were due to initial Ca(2+) release from inositol trisphosphate-sensitive stores followed by Ca(2+) entry through Ca(2+) release-activated channels (CRACs). The Ca(2+) entry phase was effectively inhibited by a CRAC blocker. B2 receptor blockade reduced the extent of PAC necrosis evoked by pancreatitis-promoting agents and we therefore conclude that bradykinin plays a role in acute pancreatitis via specific actions on PSCs.
Normal pancreatic stellate cells (PSCs) are regarded as quiescent, only to become activated in chronic pancreatitis and pancreatic cancer. However, we now report that these cells in their normal microenvironment are far from quiescent, but are capable of generating substantial Ca(2+) signals. We have compared Ca(2+) signalling in PSCs and their better studied neighbouring acinar cells (PACs) and found complete separation of Ca(2+) signalling in even closely neighbouring PACs and PSCs. Bradykinin (BK), at concentrations corresponding to the slightly elevated plasma BK levels that have been shown to occur in the auto-digestive disease acute pancreatitis in vivo, consistently elicited substantial Ca(2+) signals in PSCs, but never in neighbouring PACs, whereas the physiological PAC stimulant cholecystokinin failed to evoke Ca(2+) signals in PSCs. The BK-induced Ca(2+) signals were mediated by B2 receptors and B2 receptor blockade protected against PAC necrosis evoked by agents causing acute pancreatitis. The initial Ca(2+) rise in PSCs was due to inositol trisphosphate receptor-mediated release from internal stores, whereas the sustained phase depended on external Ca(2+) entry through Ca(2+) release-activated Ca(2+) (CRAC) channels. CRAC channel inhibitors, which have been shown to protect PACs against damage caused by agents inducing pancreatitis, therefore also inhibit Ca(2+) signal generation in PSCs and this may be helpful in treating acute pancreatitis.
缓激肽可能在自身消化性疾病急性胰腺炎中发挥作用，但其对胰腺的作用知之甚少。在本研究中，我们调查了正常小鼠胰腺小叶中缓激肽引发的Ca(2+)信号产生情况。我们发现胰腺腺泡细胞（PACs）和星状细胞（PSCs）之间的Ca(2+)信号传导完全分离。生理病理相关浓度的缓激肽通过B2受体在PSCs中持续引发Ca(2+)信号，但在相邻的PACs中从未引发，而胆囊收缩素在PACs中持续引发Ca(2+)信号，在PSCs中从未引发。缓激肽引发的Ca(2+)信号是由于肌醇三磷酸敏感储存库最初释放Ca(2+)，随后Ca(2+)通过Ca(2+)释放激活通道（CRACs）进入细胞。Ca(2+)进入阶段被CRAC阻滞剂有效抑制。B2受体阻断减少了促胰腺炎药物诱发的PAC坏死程度，因此我们得出结论，缓激肽通过对PSCs的特定作用在急性胰腺炎中发挥作用。
正常胰腺星状细胞（PSCs）被认为是静止的，仅在慢性胰腺炎和胰腺癌中被激活。然而，我们现在报告，这些细胞在其正常微环境中远非静止，而是能够产生大量Ca(2+)信号。我们比较了PSCs及其研究较多的相邻腺泡细胞（PACs）中的Ca(2+)信号传导，发现即使相邻的PACs和PSCs之间的Ca(2+)信号传导也完全分离。缓激肽（BK）在体内自身消化性疾病急性胰腺炎中出现的血浆BK水平略有升高时的浓度，在PSCs中持续引发大量Ca(2+)信号，但在相邻的PACs中从未引发，而生理性PAC刺激物胆囊收缩素未能在PSCs中引发Ca(2+)信号。BK诱导的Ca(2+)信号由B2受体介导，B2受体阻断可防止由引起急性胰腺炎的药物诱发的PAC坏死。PSCs中最初的Ca(2+)升高是由于肌醇三磷酸受体介导的内部储存库释放，而持续阶段依赖于通过Ca(2+)释放激活的Ca(2+)（CRAC）通道的外部Ca(2+)进入。CRAC通道抑制剂已被证明可保护PACs免受诱导胰腺炎的药物造成的损伤，因此也抑制PSCs中的Ca(2+)信号产生，这可能有助于治疗急性胰腺炎。
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