急性胰腺炎胰酶异常活化和分泌的分子机制

崔恬玉; 刘瑞霞; 阴赪宏

doi:10.3969/j.issn.1001-5256.2022.05.047

急性胰腺炎胰酶异常活化和分泌的分子机制

DOI: 10.3969/j.issn.1001-5256.2022.05.047

a.
首都医科大学附属北京妇产医院内科，北京 100026
b.
首都医科大学附属北京妇产医院中心试验室，北京 100026

基金项目:

北京市教育委员会科技计划一般项目 (KM201910025007);

国家自然科学基金 (81571933)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：崔恬玉负责拟定写作思路，检索文献，撰写论文; 刘瑞霞、阴赪宏负责指导、修改论文并最终定稿。

详细信息

通信作者:
阴赪宏，yinchh@ccmu.edu.cn

计量
- 文章访问数: 574
- HTML全文浏览量: 206
- PDF下载量: 39
- 被引次数: 0
出版历程
- 收稿日期: 2021-08-31
- 录用日期: 2021-10-08
- 出版日期: 2022-05-20

Research advances in abnormal activation and secretion of pancreatic enzymes in acute pancreatitis

a.
Department of Internal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China
b.
Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China

Research funding:

Beijing Municipal Commission of Education (KM201910025007);

National Natural Science Foundation of China (81571933)

More Information

Corresponding author: YIN Chenghong, yinchh@ccmu.edu.cn(ORCID: 0000-0002-2503-3285)

摘要

摘要: 胰腺腺泡细胞内胰酶异常活化和分泌是急性胰腺炎(AP)的重要发病机制之一，可直接损伤胰腺组织加速疾病进程，诱发重症急性胰腺炎。目前临床抑制胰酶异常活化和分泌的药物效果欠佳，探寻新的治疗靶点十分重要。本文归纳了AP胰酶异常活化和分泌的病理事件(胞浆钙离子超载、溶酶体与酶原颗粒的共定位、细胞器损伤、胰酶顶端侧分泌受阻和基底侧分泌增加等)，搜集了相关事件的分子机制，讨论了胰酶异常活化和分泌在AP早期的作用过程，为未来靶向药物的研发提供思路。
- 胰腺炎 /
- 胰酶 /
- 分泌小泡
Abstract: Abnormal activation and secretion of pancreatic enzymes in pancreatic acinar cells is one of the important pathogeneses of acute pancreatitis (AP) and can directly damage the pancreatic tissue to accelerate disease progression and induce severe AP. At present, the drugs inhibiting the abnormal activation and secretion of pancreatic enzymes tend to have an unsatisfactory effect in clinical practice, and therefore, it is of great importance to search for new therapeutic targets. This article summarizes the pathological events of abnormal activation and secretion of pancreatic enzymes (cytoplasmic calcium overload, colocalization of lysosomes and zymogen granules, organelle injury, obstructed apical secretion of trypsin, and increased basal secretion of trypsin), collects the molecular mechanisms of related events, and discusses the role of abnormal activation and secretion of pancreatic enzymes in the early stage of AP, so as to provide ideas for the development of targeted drugs in the future.
- Pancreatitis /
- Pancreatin /
- Secretory Vesicles

HTML全文

图 1 VAMP8介导的顶端侧分泌受损和基底侧分泌增强示意图

Figure 1. Schematic illustration of VAMP8-mediated impaired apical secretion and enhanced basal secretion

下载: 全尺寸图片幻灯片

参考文献(37)

[1]	LEE PJ, PAPACHRISTOU GI. New insights into acute pancreatitis[J]. Nat Rev Gastroenterol Hepatol, 2019, 16(8): 479-496. DOI: 10.1038/s41575-019-0158-2.
[2]	ZHANG W, ZHANG M, KUANG Z, et al. The risk factors for acute respiratory distress syndrome in patients with severe acute pancreatitis: A retrospective analysis[J]. Medicine (Baltimore), 2021, 100(2): e23982. DOI: 10.1097/MD.0000000000023982.
[3]	LEPPÄNIEMI A, TOLONEN M, TARASCONI A, et al. 2019 WSES guidelines for the management of severe acute pancreatitis[J]. World J Emerg Surg, 2019, 14: 27. DOI: 10.1186/s13017-019-0247-0.
[4]	HAO S, DANG DS. Clinical observation of octreotide in the treatment of acute pancreatitis at different time of administration[J]. Chin J Med Offic, 2020, 48(7): 761-764. DOI: 10.16680/j.1671-3826.2020.07.04. 郝双, 党大胜. 奥曲肽不同给药时机治疗急性胰腺炎临床效果观察[J]. 临床军医杂志, 2020, 48(7): 761-764. DOI: 10.16680/j.1671-3826.2020.07.04.
[5]	QI H, CHEN G, WANG YW, et al. Effects of magnesium isoglycyrrhizinate combined with octreotide on acute pancreatitis and its effect on hs-CRP、IL-1β、IL-6 levels[J]. J Changchun Univ Chin Med, 2020, 36(3): 520-522. DOI: 10.13463/j.cnki.cczyy.2020.03.032. 齐宏, 陈广, 王渊文, 等. 异甘草酸镁联合奥曲肽治疗急性胰腺炎的临床疗效及对hs-CRP、IL-1β、IL-6水平的影响[J]. 长春中医药大学学报, 2020, 36(3): 520-522. DOI: 10.13463/j.cnki.cczyy.2020.03.032.
[6]	GUKOVSKAYA AS, GORELICK FS, GROBLEWSKI GE, et al. Recent insights into the pathogenic mechanism of pancreatitis: Role of acinar cell organelle disorders[J]. Pancreas, 2019, 48(4): 459-470. DOI: 10.1097/MPA.0000000000001298.
[7]	MAYERLE J, SENDLER M, HEGYI E, et al. Genetics, cell biology, and pathophysiology of pancreatitis[J]. Gastroenterology, 2019, 156(7): 1951-1968. e1. DOI: 10.1053/j.gastro.2018.11.081.
[8]	PALLAGI P, MADÁCSY T, VARGA Á, et al. Intracellular Ca²⁺ signalling in the pathogenesis of acute pancreatitis: Recent advances and translational perspectives[J]. Int J Mol Sci, 2020, 21(11): 4005. DOI: 10.3390/ijms21114005.
[9]	WENG N, BAUMLER MD, THOMAS DD, et al. Functional role of J domain of cysteine string protein in Ca²⁺-dependent secretion from acinar cells[J]. Am J Physiol Gastrointest Liver Physiol, 2009, 296(5): G1030-1039. DOI: 10.1152/ajpgi.90592.2008.
[10]	CRIDDLE DN, MCLAUGHLIN E, MURPHY JA, et al. The pancreas misled: Signals to pancreatitis[J]. Pancreatology, 2007, 7(5-6): 436-446. DOI: 10.1159/000108960.
[11]	LEE KP, YUAN JP, HONG JH, et al. An endoplasmic reticulum/plasma membrane junction: STIM1/Orai1/TRPCs[J]. FEBS Lett, 2010, 584(10): 2022-2027. DOI: 10.1016/j.febslet.2009.11.078.
[12]	MUKHERJEE R, MARENINOVA OA, ODINOKOVA IV, et al. Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: Inhibition prevents acute pancreatitis by protecting production of ATP[J]. Gut, 2016, 65(8): 1333-1346. DOI: 10.1136/gutjnl-2014-308553.
[13]	PETERSEN OH, GERASIMENKO JV, GERASIMENKO OV, et al. The roles of calcium and ATP in the physiology and pathology of the exocrine pancreas[J]. Physiol Rev, 2021, 101(4): 1691-1744. DOI: 10.1152/physrev.00003.2021.
[14]	ELMUNZER BJ, SERRANO J, CHAK A, et al. Rectal indomethacin alone versus indomethacin and prophylactic pancreatic stent placement for preventing pancreatitis after ERCP: Study protocol for a randomized controlled trial[J]. Trials, 2016, 17(1): 120. DOI: 10.1186/s13063-016-1251-2.
[15]	SHAH AU, SARWAR A, ORABI AI, et al. Protease activation during in vivo pancreatitis is dependent on calcineurin activation[J]. Am J Physiol Gastrointest Liver Physiol, 2009, 297(5): G967-973. DOI: 10.1152/ajpgi.00181.2009.
[16]	MITHÖFER K, FERNÁNDEZ-DEL CASTILLO C, FRICK TW, et al. Acute hypercalcemia causes acute pancreatitis and ectopic trypsinogen activation in the rat[J]. Gastroenterology, 1995, 109(1): 239-246. DOI: 10.1016/0016-5085(95)90290-2.
[17]	ORABI AI, SHAH AU, AHMAD MU, et al. Dantrolene mitigates caerulein-induced pancreatitis in vivo in mice[J]. Am J Physiol Gastrointest Liver Physiol, 2010, 299(1): G196-204. DOI: 10.1152/ajpgi.00498.2009.
[18]	HALANGK W, LERCH MM, BRANDT-NEDELEV B, et al. Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis[J]. J Clin Invest, 2000, 106(6): 773-781. DOI: 10.1172/JCI9411.
[19]	TALUKDAR R, SAREEN A, ZHU H, et al. Release of cathepsin B in cytosol causes cell death in acute pancreatitis[J]. Gastroenterology, 2016, 151(4): 747-758. e5. DOI: 10.1053/j.gastro.2016.06.042.
[20]	SALUJA A, DUDEJA V, DAWRA R, et al. Early intra-acinar events in pathogenesis of pancreatitis[J]. Gastroenterology, 2019, 156(7): 1979-1993. DOI: 10.1053/j.gastro.2019.01.268.
[21]	SENDLER M, WEISS FU, GOLCHERT J, et al. Cathepsin B-mediated activation of trypsinogen in endocytosing macrophages increases severity of pancreatitis in mice[J]. Gastroenterology, 2018, 154(3): 704-718. e10. DOI: 10.1053/j.gastro.2017.10.018.
[22]	CHENG L, HAN ST. Research Progress on the mechanism of endoplasmic reticulum stress response in acute pancreatitis[J]. Chin J Pancreatol, 2019, 19(1): 69-72. DOI: 10.3760/cma.j.issn.1674-1935.2019.01.018. 程璐, 韩树堂. 急性胰腺炎内质网应激反应机制研究进展[J]. 中华胰腺病杂志, 2019, 19(1): 69-72. DOI: 10.3760/cma.j.issn.1674-1935.2019.01.018.
[23]	SZMOLA R, SAHIN-TÓTH M. Pancreatitis-associated chymotrypsinogen C (CTRC) mutant elicits endoplasmic reticulum stress in pancreatic acinar cells[J]. Gut, 2010, 59(3): 365-372. DOI: 10.1136/gut.2009.198903.
[24]	ANTONUCCI L, FAGMAN JB, KIM JY, et al. Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress[J]. Proc Natl Acad Sci U S A, 2015, 112(45): E6166-6174. DOI: 10.1073/pnas.1519384112.
[25]	WARTMANN T, MAYERLE J, KÄHNE T, et al. Cathepsin L inactivates human trypsinogen, whereas cathepsin L-deletion reduces the severity of pancreatitis in mice[J]. Gastroenterology, 2010, 138(2): 726-737. DOI: 10.1053/j.gastro.2009.10.048.
[26]	BICZO G, VEGH ET, SHALBUEVA N, et al. Mitochondrial dysfunction, through impaired autophagy, leads to endoplasmic reticulum stress, deregulated lipid metabolism, and pancreatitis in animal models[J]. Gastroenterology, 2018, 154(3): 689-703. DOI: 10.1053/j.gastro.2017.10.012.
[27]	DENG SJ, ZOU WB, LIAO Z. Research progress on the mechanism of carboxyl ester lipase in the pathogenesis of pancreatic diseases[J]. Chin J Pancreatol, 2020, 20(1): 66-69. DOI: 10.3760/cma.j.issn.1674-1935.2020.01.014. 邓顺江, 邹文斌, 廖专. 羧基酯脂肪酶在胰腺疾病发病中的作用机制研究进展[J]. 中华胰腺病杂志, 2020, 20(1): 66-69. DOI: 10.3760/cma.j.issn.1674-1935.2020.01.014.
[28]	LUGEA A, GERLOFF A, SU HY, et al. The combination of alcohol and cigarette smoke induces endoplasmic reticulum stress and cell death in pancreatic acinar cells[J]. Gastroenterology, 2017, 153(6): 1674-1686. DOI: 10.1053/j.gastro.2017.08.036.
[29]	ZELIC M, RODERICK JE, O'DONNELL JA, et al. RIP kinase 1-dependent endothelial necroptosis underlies systemic inflammatory response syndrome[J]. J Clin Invest, 2018, 128(5): 2064-2075. DOI: 10.1172/JCI96147.
[30]	HASHIMOTO D, OHMURAYA M, HIROTA M, et al. Involvement of autophagy in trypsinogen activation within the pancreatic acinar cells[J]. J Cell Biol, 2008, 181(7): 1065-1072. DOI: 10.1083/jcb.200712156.
[31]	LI N, WU X, HOLZER RG, et al. Loss of acinar cell IKKα triggers spontaneous pancreatitis in mice[J]. J Clin Invest, 2013, 123(5): 2231-2243. DOI: 10.1172/JCI64498.
[32]	MESSENGER SW, JONES EK, HOLTHAUS CL, et al. Acute acinar pancreatitis blocks vesicle-associated membrane protein 8 (VAMP8)-dependent secretion, resulting in intracellular trypsin accumulation[J]. J Biol Chem, 2017, 292(19): 7828-7839. DOI: 10.1074/jbc.M117.781815.
[33]	MIZUNO-YAMASAKI E, RIVERA-MOLINA F, NOVICK P. GTPase networks in membrane traffic[J]. Annu Rev Biochem, 2012, 81: 637-659. DOI: 10.1146/annurev-biochem-052810-093700.
[34]	MESSENGER SW, FALKOWSKI MA, THOMAS DD, et al. Vesicle associated membrane protein 8 (VAMP8)-mediated zymogen granule exocytosis is dependent on endosomal trafficking via the constitutive-like secretory pathway[J]. J Biol Chem, 2014, 289(40): 28040-28053. DOI: 10.1074/jbc.M114.593913.
[35]	MESSENGER SW, THOMAS DD, COOLEY MM, et al. Early to late endosome trafficking controls secretion and zymogen activation in rodent and human pancreatic acinar cells[J]. Cell Mol Gastroenterol Hepatol, 2015, 1(6): 695-709. DOI: 10.1016/j.jcmgh.2015.08.002.
[36]	CHVANOV M, DE FAVERI F, MOORE D, et al. Intracellular rupture, exocytosis and actin interaction of endocytic vacuoles in pancreatic acinar cells: Initiating events in acute pancreatitis[J]. J Physiol, 2018, 596(13): 2547-2564. DOI: 10.1113/JP275879.
[37]	NEULAND K, FRICK M. Vesicular control of fusion pore expansion[J]. Commun Integr Biol, 2015, 8(2): e1018496. DOI: 10.1080/19420889.2015.1018496.