Mechanisms of mechanically-induced acute pancreatitis

摘要 胰腺对机械损伤非常敏感。对胰腺的物理操作可以启动一个 一系列细胞事件导致过早的酶原激活并最终导致胰腺炎。为什么 胰腺对机械应力非常敏感，机械力引起胰腺损伤的机制 胰腺炎是未知的，直到我们发现胰腺腺泡细胞表达机械激活离子， 渠道胰腺中主要的机械激活通道是阳离子通道Piezo 1。我们 最近证明，在类似于胰腺炎的情况下， 内窥镜逆行胰胆管造影术（ERCP）的临床状况，引起小鼠胰腺炎， 这些作用可被Piezo 1拮抗剂GsMTx 4阻断。此外，选择性腺泡细胞特异性 Piezo1基因缺失保护小鼠免受压力诱导的胰腺炎。因此，激活 胰腺腺泡细胞中的机械敏感性离子通道是先前未认识到的导致胰腺炎的原因。 然而，Piezo1激活引起胰腺炎的机制尚不清楚。作为 阳离子通道，Piezo1激活产生细胞外钙快速流入细胞。异常 胰腺腺泡细胞内的钙调节扰乱酶原颗粒和溶酶体功能， 被认为是胰腺炎发展的早期过程。Piezo1有可能诱导 胰腺炎是由于扰乱了正常的钙稳态。我们的初步数据还表明， 胰腺腺泡细胞的活化破坏线粒体功能并刺激细胞内胰蛋白酶 activation.因此，为了评估Piezo 1在胰腺中的病理生理作用，我们将（1）建立 胰腺腺泡细胞中机械激活和钙信号传导之间的关系，（2）确定 机械活化对线粒体功能和能量代谢的影响，以及（3）表征机械活化对线粒体功能和能量代谢的影响。 机械敏感离子通道激活对酶原过早激活和产生的贡献 胰腺腺泡细胞中的炎症介质。我们将使用动物，细胞生物学， 互补的遗传和药理学工具来表征胰腺腺泡细胞的机械活化。 这些研究将揭示当压力施加到胰腺时引起胰腺炎的基本机制。 腺体，并与临床条件，如手术操作，腹部创伤，ERCP， 胆结石引起的胆管梗阻，并可能提供一个新的目标，预防胰腺炎，其中 对腺体的操作是预期的。

Abstract The pancreas is extremely sensitive to mechanical injury. Physical manipulation of the pancreas can initiate a series of cellular events leading to premature zymogen activation and eventually pancreatitis. Why the pancreas is so sensitive to mechanical stress and the mechanism by which mechanical force causes pancreatitis were unknown until we discovered that pancreatic acinar cells express mechanically-activated ion channels. The dominant mechanically-activated channel in the pancreas is the cation channel Piezo1. We recently demonstrated that increasing pressure within the pancreatic duct, under conditions that resemble the clinical condition of endoscopic retrograde cholangiopancreatography (ERCP), caused pancreatitis in mice and these effects could be blocked by the Piezo1 antagonist, GsMTx4. Moreover, selective acinar cell-specific genetic deletion of Piezo1 protected mice against pressure-induced pancreatitis. Thus, activation of mechanically sensitive ion channels in pancreatic acinar cells is a previously unrecognized cause of pancreatitis, however, the mechanisms by which Piezo1 activation causes pancreatitis is unknown. As a cation channel, Piezo1 activation produces a rapid influx of extracellular calcium into the cell. Abnormal calcium regulation within the pancreatic acinar cell perturbs zymogen granule and lysosome function and is thought to be an early process in the development of pancreatitis. It is possible that Piezo1 induces pancreatitis by disturbing normal calcium homeostasis. Our preliminary data also indicate that mechanical activation of pancreatic acinar cells disrupts mitochondrial function and stimulates intracellular trypsin activation. Therefore, to assess the pathophysiological role of Piezo1 in the pancreas we will (1) establish the relationship between mechanoactivation and calcium signaling in pancreatic acinar cells, (2) determine the effects of mechanical activation on mitochondrial function and energy metabolism and (3) characterize the contribution of mechanically sensitive ion channel activation to premature zymogen activation and generation of inflammatory mediators in pancreatic acinar cells. We will use a combination of animal, cell biological, and complimentary genetic and pharmacological tools to characterize mechanoactivation of pancreatic acinar cells. These studies will unveil the fundamental mechanisms that cause pancreatitis when pressure is applied to the gland and are relevant to clinical conditions such as surgical manipulation, abdominal trauma, ERCP, and gallstone induced duct obstruction and may provide a novel target for preventing pancreatitis in which manipulation of the gland is anticipated.