Mechanisms of mechanically-induced acute pancreatitis

机械性急性胰腺炎的机制

• 批准号: 10320376
• 负责人: Rodger A. Liddle
• 金额: $ 36.23万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320376
• 关键词: Abdomen; Acinar Cell; Animals; Biological; Calcium; Calcium Signaling; Cations; Cells; Cholelithiasis; Clinical; Data; Development; Duct (organ) structure; Endoscopic Retrograde Cholangiopancreatography; Energy Metabolism; Enzyme Precursors; Enzymes; Event; Generations; Genetic; Gland; Homeostasis; Human; Impairment; Inflammation Mediators; Injury; Interruption; Ion Channel; Lead; Lysosomes; Mechanical Stimulation; Mechanical Stress; Mechanics; Mitochondria; Modeling; Mus; Obstruction; Operative Surgical Procedures; Pancreas; Pancreatic duct; Pancreatitis; Pathologic; Pattern; Pharmacology; Piezo 1 ion channel; Process; Production; Protein Biosynthesis; Proteins; Regulation; Role; Series; Site; Sorting - Cell Movement; Trauma; Trypsin; Zymogen Granules; acute pancreatitis; antagonist; base; clinically relevant; design; extracellular; insight; mechanical force; novel; premature; pressure; prevent; tool

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.

抽象的 胰腺对机械损伤极其敏感。对胰腺的物理操作可以启动 一系列细胞事件导致酶原过早激活并最终引发胰腺炎。为什么 胰腺对机械应力以及机械力引起的机制非常敏感 直到我们发现胰腺腺泡细胞表达机械激活离子之前，胰腺炎还是未知的 渠道。胰腺中主要的机械激活通道是阳离子通道 Piezo1。我们 最近证明，在类似于胰管的条件下，胰管内的压力增加 内镜逆行胰胆管造影（ERCP）引起小鼠胰腺炎的临床状况 这些效应可以被 Piezo1 拮抗剂 GsMTx4 阻断。此外，选择性腺泡细胞特异性 Piezo1 基因缺失可保护小鼠免受压力诱发的胰腺炎。因此，激活 胰腺腺泡细胞中机械敏感的离子通道是以前未被认识到的原因 然而，Piezo1 激活导致胰腺炎的机制尚不清楚。作为一个 在阳离子通道中，Piezo1 激活会导致细胞外钙快速流入细胞内。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，并且是 被认为是胰腺炎发展的早期过程。 Piezo1 可能会诱导 通过扰乱正常的钙稳态来引发胰腺炎。我们的初步数据还表明，机械 胰腺腺泡细胞的激活会破坏线粒体功能并刺激细胞内胰蛋白酶 激活。因此，为了评估 Piezo1 在胰腺中的病理生理学作用，我们将 (1) 建立 胰腺腺泡细胞机械激活和钙信号传导之间的关系，（2）确定 机械激活对线粒体功能和能量代谢的影响以及（3）表征 机械敏感离子通道激活对过早酶原激活和生成的贡献 胰腺腺泡细胞中炎症介质的影响。我们将结合动物、细胞生物学和 互补的遗传和药理学工具来表征胰腺腺泡细胞的机械激活。 这些研究将揭示当压力施加到胰腺时导致胰腺炎的基本机制。 腺体，与临床状况相关，例如手术操作、腹部创伤、ERCP 和 胆结石引起的导管阻塞可能为预防胰腺炎提供新的靶点 预期会对腺体进行操纵。