Механизмы повреждения ацинарных клеток поджелудочной железы при остром алкогольном панкреатите
В обзоре представлен анализ современных сведений об основных механизмах токсичного воздействия алкоголя и его метаболитов на ацинарные клетки поджелудочной железы при остром панкреатите. Показано, что механизмы клеточного повреждения многокомпонентны и тесно взаимосвязаны регуляторными факторами молекулярного уровня. На ранней стадии заболевания они приводят к следующим структурно-функциональным изменениям ацинарных клеток, способствующим преждевременной внутриклеточной активации трипсиногена и аутоагрессии: устойчивому подъему цитозольного Ca2+ и избытку митохондриального Cа2+, дестабилизации лизосом и зимогенных гранул, нарушению аутофагии, деполяризации митохондрий, снижению выработки АТФ и некрозу.
1. Острый панкреатит. Дифференцированная лечебно-диагностическая тактика / М. В. Лысенко [и др.]. – М. : Литтерра, 2010. – 165 с.
2. Маев, И. В. Болезни поджелудочной железы : в 2 т. / И. В. Маев, Ю. А. Кучерявый. – М. : Медицина, 2008. – Т. 2. – 558 с.
3. Lankisch, P. G. Acute pancreatitis / P. G. Lankisch, M. Apte, P. A. Banks // Гастроэнтерология Санкт-Петербурга. – 2017. – № 2. – P. 3–13.
4. Acute pancreatitis in fve european countries: etiology and mortality / L. Gullo [et al.] // Pancreas. – 2002. – Vol. 24, N 3. – P. 223–227. https://doi.org/10.1097/00006676-200204000-00003
5. Singh, P. Pathophysiological mechanisms in acute pancreatitis: current understanding / P. Singh, P. K. Garg // Indian J. Gastroenterol. – 2016. –Vol. 35, N 3. – Р. 153–166. https://doi.org/10.1007/s12664-016-0647-y
6. Calcium signalling in the acinar environment of the exocrine pancreas: physiology and pathophysiology / O. Gryshchenko [et al.] // J. Physiol. – 2018. – Vol. 596, N 14. – P. 2663–2678. https://doi.org/10.1113/jp275395
7. Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevent acute pancreatitis by protecting production of ATP / R. Mukherjee [et al.] // Gut. – 2015. – Vol. 65, N 8. – Р. 1333–1346. https://doi.org/10.1136/gutjnl-2014-308553
8. Gukovsky, I. Organellar dysfunction in the pathogenesis of pancreatitis / I. Gukovsky, S. J. Pandol, A. S. Gukovskaya // Antioxid. Redox Signal. – 2011. – Vol. 15, N 10. – Р. 2699–2710. https://doi.org/10.1089/ars.2011.4068
9. Caerulein-induced in vitro activation of trypsinogen in rat pancreatic aciniis mediated by cathepsin B / A. K. Saluja [et al.] // Gastroenterology. – 1997. – Vol. 113, N 1. – Р. 304–310. https://doi.org/10.1016/s0016-5085(97)70108-2
10. Activation of trypsinogen in large endocytic vacuoles of pancreatic acinar cells / M. W. Sherwood [et al.] // Proc. Natl. Acad. Sci. USA. – 2007. – Vol. 104, N 13. – P. 5674–5679. https://doi.org/10.1073/pnas.0700951104
11. Effects of ethanol and protein defciency on pancreatic digestive and lysosomal enzymes / M. V. Apte [et al.] // Gut. – 1995. – Vol. 36, N 2. – P. 287–293. https://doi.org/10.1136/gut.36.2.287
12. Impaired autophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitis / O. A. Mareninova [et al.] // J. Clin. Invest. – 2009. – Vol. 119, N 11. – P. 3340–3355. https://doi.org/10.1172/jci38674
13. MiR-352 participates in the regulation of trypsinogen activation in pancreatic acinar cells by influencing the function of autophagic lysosomes / Z. Song [et al.] // Oncotarget. – 2018. – Vol. 9, N 13. – P. 10868–10879. https://doi.org/10.18632/oncotarget.24220
14. Parzych, K. R. An overview of autophagy: morphology, mechanism, and regulation / K. R. Parzych, D. J. Klionsky // Antioxid. Redox Signal. – 2014. – Vol. 20, N 3. – P. 460–473. https://doi.org/10.1089/ars.2013.5371
15. Pancreatic acinar ultrastructure in human acute pancreatitis/ H. Helin [et al.] // Virchows. Arch. A Pathol. Anat. Histol. – 1980. – Vol. 387, N 3. – P. 259–270. https://doi.org/10.1007/bf00454829
16. Niederau, C. Intracellular vacuoles in experimental acute pancreatitis in rats and mice are an acidifd compartment / C. Niederau, J. H. Grendell // J. Clin. Invest. – 1988. – Vol. 81, N 1. – P. 229–236. https://doi.org/10.1172/jci113300
17. Calcium dependent enzyme activation and vacuole formation in the apical granular region of pancreatic acinar cells / M. Raraty [et al.] // Proc. Natl. Acad. Sci. USA. – 2000. – Vol. 97, N 24. – Р. 13126–13131. https://doi.org/10.1073/pnas.97.24.13126
18. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes / D. J. Klionsky [et al.] // Autophagy. – 2008. – Vol. 4. – P. 151–175.
19. Nixon, R. A. Neurodegenerative lysosomal disorders: a continuum from development to late age / R. A. Nixon, D.-S. Yang, J.-H. Lee // Autophagy. – 2008. – Vol. 4, N 5. – P. 590–599. https://doi.org/10.4161/auto.6259
20. Role of LAMP-2 in lysosome biogenesis and autophagy / E.-L. Eskelinen [et al.] // Mol. Biol. Cell. – 2002. – Vol. 13, N 9. – P. 3355–3368. https://doi.org/10.1091/mbc.e02-02-0114
21. LAMP proteins are required for fusion of lysosomes with phagosomes / K. K. Huynh [et al.] // EMBO J. – 2007. – Vol. 26, N 2. – P. 313–324. https://doi.org/10.1038/sj.emboj.7601511
22. Levine, B. Autophagy in the pathogenesis of disease / B. Levine, G. Kroemer // Cell. – 2008. – Vol. 132, N 1. – P. 27–42. https://doi.org/10.1016/j.cell.2007.12.018
23. Impaired autolysosome formation correlates with Lamp-2 depletion: role of apoptosis, autophagy, and necrosis in pancreatitis / F. Fortunato [et al.] // Gastroenterology. – 2009. – Vol. 137, N 1. – P. 350–360.e5. https://doi.org/10.1053/j.gastro.2009.04.003
24. Gukovskaya, A. S. Autophagy and pancreatitis / A. S. Gukovskaya, I. Gukovsky // Am. J. Physiol. Gastrointest. Liver Physiol. – 2012. – Vol. 303, N 9. – P. 993–1003. https://doi.org/10.1152/ajpgi.00122.2012
25. Inflammation, autophagy, and obesity: common features in the pathogenesis of pancreatitis and pancreatic cancer / I. Gukovsky [et al.] // Gastroenterology. – 2013. – Vol. 144, N 6. – P. 1199–1209.e4. https://doi.org/10.1053/j.gastro.2013.02.007
26. Vacuolar ATPase regulates zymogen activation in pancreatic acini / S. D. Waterford [et al.] / J. Biol. Chem. – 2004. – Vol. 280, N 7. – P. 5430–5434. https://doi.org/10.1074/jbc.m413513200
27. Czaja, M. J. Functions of autophagy in hepatic and pancreatic physiology and disease / M. J. Czaja // Gastroenterology. – 2011. – Vol. 140, N 7. – P. 1895–1908. https://doi.org/10.1053/j.gastro.2011.04.038
28. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene / D. C. Whitcomb [et al.] // Nat. Genet. – 1996. – Vol. 14, N 2. – P. 141–145. https://doi.org/10.1038/ng1096-141
29. Petersen, O. H. Polarized calcium signaling in exocrine gland cells / O. H. Petersen, A. V. Tepikin // Annu. Rev. Physiol. – 2008. – Vol. 70, N 1. – Р. 273–299. https://doi.org/10.1146/annurev.physiol.70.113006.100618
30. Ex vivo human pancreatic slice preparations offer a valuable model for studying pancreatic exocrine biology / T. Liang [et al.] // J. Biol. Chem. – 2017. – Vol. 292, N 14. – P. 5957–5969. https://doi.org/10.1074/jbc.m117.777433
31. Long-distance communication between muscarinic receptors and Ca2+ release channels revealed by carbachol uncaging in cell-attached patch pipette / M. C. Ashby [et al.] // J. Biol. Chem. – 2003. – Vol. 278, N 23. – P. 20860–20864. https://doi.org/10.1074/jbc.m302599200
32. Berridge, M. J. Inositol trisphosphate and calcium signaling / M. J. Berridge // Nature. – 1993. – Vol. 361. – P. 315–325.
33. The distribution of the endoplasmic reticulum in living pancreatic acinar cells / O. V. Gerasimenko [et al.] // Cell. Calcium. – 2002. – Vol. 32, N 5–6. – P. 261–268. https://doi.org/10.1016/s0143416002001938
34. Polarized expression of Ca2+ channels in pancreatic and salivary gland cells – correlation with initiation and propagation of [Ca2+] I waves / M. G. Lee [et al.] // J. Biol. Chem. – 1997. – Vol. 272, N 25. – P. 15765–15770. https://doi.org/10.1074/jbc.272.25.15765
35. Dynamic changes in cytosolic and mitochondrial ATP levels in pancreatic acinar cells / S. G. Voronina [et al.] // Gastroenterology. – 2010 – Vol. 138, N 5. – P. 1976–1987.e5. https://doi.org/10.1053/j.gastro.2010.01.037
36. Pancreatic protease activation by alcohol metabolite depends on Ca2+ release via acid store IP3 receptors / J. V. Gerasimenko [et al.] // Proc. Natl. Acad. Sci. USA. – 2009. – Vol. 106, N 26. – P. 10758–10763. https://doi.org/10.1073/pnas.0904818106
37. Petersen, O. H. Ca2+ tunneling through the ER lumen as a mechanism for delivering Ca2+ entering via store-operated Ca2+ channels to specifc target sites / O. H. Petersen, R. Courjaret, K. Machaca // J. Physiol. – 2017. – Vol. 595, N 10. – P. 2999–3014. https://doi.org/10.1113/jp272772
38. Fatty acid ethyl ester synthase inhibition ameliorates ethanol-induced Ca2+-dependent mitochondrial dysfunction and acute pancreatitis / W. Huang [et al.] // Gut. – 2013. – Vol. 63, N 8. – P. 1313–1324. https://doi.org/10.1136/gutjnl-2012-304058
39. Gukovskaya, A. S. Cell death pathways in pancreatitis and pancreatic cancer / A. S. Gukovskaya, S. J. Pandol // Pancreatology. – 2004. – Vol. 4, N 6. – P. 567–586. https://doi.org/10.1159/000082182
40. Острый панкреатит: морфологические аспекты течения заболевания / В. Г. Фирсова [и др.] // Анналы хирург. гепатологии. – 2014. – Т. 19, №1. – С. 86–95.
41. Thrower, E. C. Molecular and cellular mechanisms of pancreatic injury / E. C. Thrower, F. S. Gorelick, S. Z. Husainb // Curr. Opin. Gastroenterol. – 2010. – Vol. 26, N 5. – P. 484–489. https://doi.org/10.1097/mog.0b013e32833d119e
42. Gerasimenko, J. V. The role of Ca2 + in the pathophysiology of pancreatitis / J. V. Gerasimenko, O. V. Gerasimenko, O. H. Petersen // J. Physiol. – 2013. – Vol. 592, N 2. – P. 269–280. https://doi.org/10.1113/jphysiol.2013.261784
43. The role of NF-kappa B activation in the pathogenesis of acute pancreatitis / Z. Rakonczay [et al.] // Gut. – 2007. – Vol. 57, N 2. – Р. 259–267. https://doi.org/10.1136/gut.2007.124115