Mechanisms of mechanically-induced acute pancreatitis

机械性急性胰腺炎的机制

• 批准号: 10538561
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10538561
• 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; Lysosomes; Mechanical Stimulation; Mechanical Stress; Mechanics; Mitochondria; Modeling; Mus; Obstruction; Operative Surgical Procedures; Pancreas; Pancreatic duct; Pancreatitis; Pathologic; Pattern; Piezo 1 ion channel; Process; Production; Protein Biosynthesis; Proteins; Regulation; Role; Series; Site; Sorting; Trauma; Trypsin; Zymogen Granules; acute pancreatitis; antagonist; clinically relevant; design; extracellular; insight; mechanical force; novel; pharmacologic; 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.

摘要 胰腺对机械损伤极为敏感。对胰腺的物理操作可以引发 导致酶原过早激活并最终导致胰腺炎的一系列细胞事件。为什么 胰腺对机械应力和机械力引起的机制非常敏感。 在我们发现胰腺腺泡细胞表达机械激活的离子之前，胰腺炎是未知的。 频道。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，在类似于胰腺管的情况下，增加胰管内的压力 内窥镜逆行胰胆管造影术(ERCP)所致小鼠胰腺炎和胰腺炎的临床研究 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基因缺失对压力诱导的胰腺炎小鼠的保护作用。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。作为一名 通过激活阳离子通道，Piezo1可使细胞外钙迅速流入细胞内。异常 胰腺腺泡细胞内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 通过扰乱正常的钙稳态而导致胰腺炎。我们的初步数据还表明，机械设备 胰腺腺泡细胞激活破坏线粒体功能并刺激细胞内胰酶 激活。因此，为了评估Piezo1在胰腺中的病理生理作用，我们将(1)建立 胰腺腺泡细胞机械激活与钙信号的关系，(2)确定 机械激活对线粒体功能和能量代谢的影响 机械敏感离子通道激活在酶原过早激活和生成中的作用 胰腺腺泡细胞中的炎性介质。我们将使用动物、细胞生物学和 用于表征胰腺腺泡细胞机械激活的免费遗传和药理学工具。 这些研究将揭示当压力施加到胰腺炎时导致胰腺炎的基本机制。 与临床情况相关，如外科操作、腹部创伤、ERCP和 胆结石引起的胆管梗阻，可能为预防胰腺炎提供一个新的靶点 对腺体的操控是可以预见的。

项目成果

Piezo1-mediated stellate cell activation causes pressure-induced pancreatic fibrosis in mice.

• DOI: 10.1172/jci.insight.158288
• 发表时间: 2022-04-22
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Swain, Sandip M.;Romac, Joelle M-J;Vigna, Steven R.;Liddle, Rodger A.
• 通讯作者: Liddle, Rodger A.