Keywords
pancreas, stellate cells, fibrosis, extracellular matrix, signaling pathways, prospects for antifibrotic therapy.
How to Cite
Gubergrits, N. B., & Bieliaieva, N. V. (2025). DEVELOPMENT AND PROGRESSION OF PANCREATIC FIBROSIS: CURRENT CONCEPTS. Herald of Pancreatic Club, 67(2), 22-37. https://doi.org/10.33149/vkp.2025.02.04
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Abstract
Pancreatic stellate cells (PSCs) are pluripotent cells located between the pancreatic lobules and the surrounding acinus. In the resting (inactivated state), PSCs store a supply of vitamin A (retinoids) in their cytoplasm, contain intermediate filaments, desmin, gliofibrillar acidic protein, nestin, neuroectodermal proteins, nerve cell adhesion molecules, and nerve growth factor. Once activated, PSCs can transform into myofibroblast-like cells. They lose lipid droplets containing vitamin A, they have decreased content of vimentin, desmin, increased proliferation, migration, and increased synthesis of intracellular matrix. Convincing evidence suggests that activated PSCs are a major source of extracellular matrix protein accumulation in pathological conditions that lead to pancreatic fibrosis in chronic pancreatitis and pancreatic cancer. The article contains a detailed analysis of current literature data on the mechanisms of pancreatic fibrosis and the role of stellate cells in fibrogenesis. The results of the research on the functions of PSCs in norm and pathology: in acute and chronic pancreatitis, and pancreatic cancer are presented. Variants of pancreatic fibrosis and mechanisms of its development in aging are described.
In order to develop new strategies for treating pancreatic diseases, this article summarises the results of recent studies on the biological properties of PSCs, including their involvement in exosome synthesis, cellular senescence processes, epithelial-mesenchymal transformation, and metabolism. The development of antifibrotic therapy based on available theoretical knowledge and experimental results is particularly important, and evidence-based studies are being conducted. The possibility of using enzyme replacement therapy in the prevention and progression of fibrogenesis in the pancreas is considered; the results of clinical trials revealing the antifibrotic potential of enzyme preparations are presented.
References
1. Ахмедов А., Гаус О. В. Новые аспекты формирования и прогрессирования фиброза поджелудочной железы при панкреатите. Вестник Клуба панкреатологов. 2019; 2: 20−24.
2. Корочанская Н. В., Рогаль М. Л., Гришина И. Ю. Хирургическая и медикаментозная профилактика раковой трансформации хронического панкреатита. Гастро News. 2008; 5: 46−50.
3. Маев И. В., Кучерявый Ю. А. Дозозависимая терапия полиферментными препаратами. Врач. 2003; 12: 1–4.
4. Andoh A., Takaya H., Saotome T. et al. Cytokine regulation of chemokine (IL-8, MCP-1, and RANTES) gene expression in human pancreatic periacinar myofibroblasts. Gastroenterology. 2000; 119(1): 211–9. http://doi.org/10.1053/gast.2000.8538.
5. Apte M., Pirola R., Wilson J. The fibrosis of chronic pancreatitis: new insights into the role of pancreatic stellate cells. Antioxid. Redox Signal. 2011; 15(10): 2711–22. http://doi.org/10.1089/ars.2011.4079.
6. Apte M., Pirola R. C., Wilson J. S. Pancreatic stellate cell: physiologic role, role in fibrosis and cancer. Curr. Opin. Gastroenterol. 2015; 31(5): 416–23. http://doi.org/10.1097/MOG.0000000000000196.
7. Apte M., Haber P., Applegate T. et al. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut. 1998; 43(1): 128–33. http://doi.org/10.1136/gut.43.1.128.
8. Apte M., Park S., Phillips P. et al. Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas. 2004; 29(3): 179–87. http://doi.org/10.1097/00006676-200410000-00002.
9. Apte M., Wilson J., Lugea A. et al. A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology. 2013; 144(6): 1210–9. http://doi.org/10.1053/j.gastro.2012.11.037.
10. Apte M., Wilson J. Dangerous liaisons: pancreatic stellate cells and pancreatic cancer cells. J Gastroenterol. Hepatol. 2012; 27(2): 69–74. http://doi.org/10.1111/j.1440-1746.2011.07000.x.
11. Apte M., Xu Z., Pothula S. et al. Pancreatic cancer: The microenvironment needs attention too! Pancreatology. 2015; 15(4): S32–8. http://doi.org/10.1016/j.pan.2015.02.013.
12. Arumugam T., Brandt W., Ramachandran V. et al. Trefoil factor 1 stimulates both pancreatic cancer and stellate cells and increases metastasis. Pancreas. 2011; 40(6): 815–22. http://doi.org/ 10.1097/MPA.0b013e31821f6927.
13. Bachem M., Schneider E., Gross H. et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology. 1998; 115(2): 421–32. http://doi.org/10.1016/s0016-5085(98)70209-4.
14. Bachem M., Schünemann M., Ramadani M. et al. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology. 2005; 128(4): 907–21. http://doi.org/10.1053/j.gastro.2004.12.036.
15. Omary M., Lugea A., Lowe A. et al. The pancreatic stellate cell: a star on the rise in pancreatic diseases. J. Clin. Invest. 2007; 117(1): 50–9. http://doi.org/10.1172/JCI30082.
16. Blaine S., Ray K., Branch K. et al. Epidermal growth factor receptor regulates pancreatic fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 2009; 297(3): G434–41. http://doi.org/10.1152/ajpgi.00152.2009.
17. Brizzi M., Tarone G., Defilippi P. Extracellular matrix, integrins, and growth factors as tailors of the stem cell niche. Curr. Opin. Cell Biol. 2012; 24(5): 645–51. http://doi.org/10.1016/j.ceb.2012.07.001.
18. Bynigeri R., Jakkampudi A. Jangala R. et al. Pancreatic stellate cell: Pandoraʼs box for pancreatic disease biology. World J. Gastroenterol. 2017; 23(3): 382–405. http://doi.org/10.3748/wjg.v23.i3.382.
19. Cabrera M., Tilahun E. Nakles R. et al. Human pancreatic cancer-associated stellate cells remain activated after in vivo chemoradiation. Front. Oncol. 2014; 4: 102. http://doi.org/10.3389/fonc.2014.00102.
20. Charrier A., Chen R., Chen L. et al. Connective tissue growth factor (CCN2) and microRNA-21 are components of a positive feedback loop in pancreatic stellate cells (PSC) during chronic pancreatitis and are exported in PSC-derived exosomes. J. Cell Commun. Signal. 2014; 8(2): 147–56. http://doi.org/10.1007/s12079-014-0220-3.
21. Chen H., Mrazek A., Wang X. et al. Design, synthesis, and characterization of novel apigenin analogues that suppress pancreatic stellate cell proliferation in vitro and associated pancreatic fibrosis in vivo. Bioorg. Med. Chem. 2014; 22(13): 3393–404. http://doi.org/10.1016/j.bmc.2014.04.043.
22. de la Iglesia-Garcia D., Vallejo-Senra N., Iglesias-Garcia J. et al. Increased risk of mortality associated with pancreatic exocrine insufficiency in patients with chronic pancreatitis. J. Clin. Gastroenterol. 2018; 52(8): e63–e72. http://doi.org/10.1097/MCG.0000000000000917.
23. Detlefsen S., Sipos B., Feyerabend B. et al. Fibrogenesis in alcoholic chronic pancreatitis: the role of tissue necrosis, macrophages, myofibroblasts and cytokines. Mod. Pathol. 2006; 19(8): 1019–26. http://doi.org/10.1038/modpathol.3800613.
24. Detlefsen S., Sipos B., Feyerabend B. et al. Pancreatic fibrosis associated with age and ductal papillary hyperplasia. Virchows Arch. 2005; 447(5): 800–5. http://doi.org/10.1007/s00428-005-0032-1.
25. Detlefsen S., Sipos B., Zhao J. et al. Autoimmune pancreatitis: expression and cellular source of profibrotic cytokines and their receptors. Am. J. Surg. Pathol. 2008; 32(7): 986–95. http://doi.org/10.1097/PAS.0b013e31815d2583.
26. Clinical pancreatology for practicing gastroenterologists and surgeons. Dominguez-Munoz J. E. Ed. A Blackwell Publishing Company; 2021. 698 p.
27. Elsner A., Lange F., Fitzner B. et al. Distinct antifibrogenic effects of erlotinib, sunitinib and sorafenib on rat pancreatic stellate cells. World J. Gastroenterol. 2014; 20(24): 7914–25. http://doi.org/10.3748/wjg.v20.i24.7914.
28. Elsässer H., Adler G., Kern H. Time course and cellular source of pancreatic regeneration following acute pancreatitis in the rat. Pancreas. 1986; 1(5): 421–9. http://doi.org/10.1097/00006676-198609000-00006.
29. Emmrich J., Weber I., Sparmann G. et al. Activation of pancreatic stellate cells in experimental chronic pancreatitis in rats. Gastroenterology. 2000; 118: A166.
30. Erkan M., Michalski C. W., Rieder S. et al. The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma. Clin. Gastroenterol. Hepatol. 200; 6(10): 1155–61. http://doi.org/10.1016/j.cgh.2008.05.006.
31. Fitzner B., Müller S., Walther M. et al. Senescence determines the fate of activated rat pancreatic stellate cells. J. Cell Mol. Med. 2012; 16(11): 2620–30. http://doi.org/10.1111/j.1582-4934.2012.01573.x.
32. Friess H., Zhu Z., di Mola F. et al. Nerve growth factor and its high-affinity receptor in chronic pancreatitis. Ann. Surg. 1999; 230(5): 615–24. http://doi.org/10.1097/00000658-199911000-00002.
33. Fukui H., Brauner B., Bode J. et al. Plasma endotoxin concentrations in patients with alcoholic and non-alcoholic liver disease: reevaluation with an improved chromogenic assay. J. Hepatol. 1991; 12(2): 162–9. http://doi.org/10.1016/0168-8278(91)90933-3.
34. Gao X., Cao Y., Staloch D. et al. Bone morphogenetic protein signaling protects against cerulein-induced pancreatic fibrosis. PLoS One. 2014; 9(2): e89114. http://doi.org/10.1371/journal.pone.0089114.
35. Gibo J., Ito T., Kawabe K. et al. Camostat mesilate attenuates pancreatic fibrosis via inhibition of monocytes and pancreatic stellate cells activity. Lab Invest. 2005; 85(1): 75–89. http://doi.org/10.1038/labinvest.3700203.
36. Gómez J., Molero X., Vaquero E. et al. Vitamin E attenuates biochemical and morphological features associated with development of chronic pancreatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 2004; 287(1): G162–9. http://doi.org/10.1152/ajpgi.00333.2003.
37. Gryshchenko O., Gerasimenko J., Gerasimenko O. et al. Ca(2+) signals mediated by bradykinin type 2 receptors in normal pancreatic stellate cells can be inhibited by specific Ca(2+) channel blockade. J. Physiol. 2016; 594(2): 281–93. http://doi.org/10.1113/JP271468.
38. Gukovskaya A., Mouria M., Gukovsky I. et al. Ethanol metabolism and transcription factor activation in pancreatic acinar cells in rats. Gastroenterology. 2002; 122: 106–118.
39. Gukovsky I., Lugea A., Shahsahebi M. et al. A rat model reproducing key pathological responses of alcoholic chronic pancreatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 2008; 294(1): G68–79. http://doi.org/10.1152/ajpgi.00006.2007.
40. Haber P., Keogh G., Apte M. et al. Activation of pancreatic stellate cells in human and experimental pancreatic fibrosis. Am. J. Pathol. 1999; 155(4): 1087–95. http://doi.org/10.1016/S0002-9440(10)65211-X.
41. Hamada S., Masamune A., Takikawa T. et al. Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells. Biochem. Biophys. Res. Commun. 2012; 421(2): 349–54. http://doi.org/10.1016/j.bbrc.2012.04.014.
42. Hennigs J., Seiz O., Spiro J. et al. Molecular basis of P2-receptor-mediated calcium signaling in activated pancreatic stellate cells. Pancreas. 2011; 40(5): 740–6. http://doi.org/10.1097/MPA.0b013e31821b5b68.
43. Hu Y., Wan R., Yu G. et al. Imbalance of Wnt/Dkk negative feedback promotes persistent activation of pancreatic stellate cells in chronic pancreatitis. PLoS One. 2014; 9(4): e95145. http://doi.org/10.1371/journal.pone.0095145.
44. Hughes C., Gaber L., Mohey el-Din A. et al. Inhibition of TNF alpha improves survival in an experimental model of acute pancreatitis. Am. Surg. 1996; 62(1): 8–13.
45. Ikejiri N. The vitamin A-storing cells in the human and rat pancreas. Kurume Med. J. 1990; 37(2): 67–81. http://doi.org/10.2739/kurumemedj.37.67.
46. Ikenaga N., Ohuchida K., Mizumoto K. et al. CD10+ pancreatic stellate cells enhance the progression of pancreatic cancer. Gastroenterology. 2010; 139(3): 1041–51. http://doi.org/10.1053/j.gastro.2010.05.084.
47. Ishiwatari H., Sato Y., Murase K. et al. Treatment of pancreatic fibrosis with siRNA against a collagen-specific chaperone in vitamin A-coupled liposomes. Gut. 2013; 62(9): 1328–39. http://doi.org/10.1136/gutjnl-2011-301746
48. Jaster R., Sparmann G., Emmrich J. et al. Extracellular signal regulated kinases are key mediators of mitogenic signals in rat pancreatic stellate cells. Gut. 2002; 51(4): 579–84. http://doi.org/10.1136/gut.51.4.579.
49. Jaster R. Molecular regulation of pancreatic stellate cell function. Mol. Cancer. 2004; 3: 26. http://doi.org/10.1186/1476-4598-3-26.
50. Karger A., Fitzner B., Brock P. et al. Molecular insights into connective tissue growth factor action in rat pancreatic stellate cells. Cell Signal. 2008; 20(10): 1865–72. http://doi.org/10.1016/j.cellsig.2008.06.016.
51. Kikuta К., Masamune A., Hamada S. et al. Pancreatic stellate cells reduce insulin expression and induce apoptosis in pancreatic beta-cells. Biochem. Biophys. Res. Commun. 2013; 433: 292–297.
52. Kikuta К., Masamune A., Watanabe T. et al. Pancreatic stellate cells promote epithelial-mesenchymal transition in pancreatic cancer cells. Biochem. Biophys. Res. Commun. 2010; 403: 380–384.
53. Kloppel G. Pathology of chronic pancreatitis and pancreatic pain. Acta Chir. Scand. 1990; 156: 261–265.
54. Kon A., Tando Y., Yanagimachi M. et al. The study on the treatment of pancreatic steatorrhea and pancreatic diabetes for patients with pancreatic insufficiency. Abstracts of papers submitted to the Joint 40th anniversary meeting of American Pancreatic Association and Japan Pancreas Society, Honolulu (Hawaii). Pancreas. 2009; 38(8): 1019.
55. Kordes C., Sawitza I., Haussinger D. Hepatic and pancreatic stellate cells in focus. Biol. Chem. 2009; 390: 1003–1012.
56. Kuno A., Yamada T., Masuda K. et al. Angiotensin-converting enzyme inhibitor attenuates pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori rats. Gastroenterology. 2003; 124(4): 1010–9.
57. Lu X., Dong X., Fu Y. et al. Protective effect of salvianolic acid В on chronic pancreatitis induced by trinitrobenzene sulfonie acid solution in rats. Pancreas. 2009; 38: 71–77.
58. Marrache F., Tu S., Bhagat G. et al. Overexpression of interleukin-lbeta in the murine pancreas results in chronic pancreatitis. Gastroenterology. 2008; 135: 1277–1287.
59. Masamune A., Kikuta K., Satoh M, et al. Rho kinase inhibitors block activation of pancreatic stellate cells. Br. J. Pharmacol. 2003; 140: 1292–1302.
60. Masamune A., Kikuta K., Watanabe T. et al. Pancreatic stellate cells express Toll-like receptors. J. Gastroenterol. 2008; 43: 352–362.
61. Masamune A., Nakano E., Hamada S. et al. Alteration of the microRNA expression profile during the activation of pancreatic stellate cells. Scand J. Gastroenterol. 2014; 49: 323–331.
62. Masamune A., Satoh M., Kikuta К. et al. Activation of JAK-STAT pathway is required for platelet-derived growth factor-induced proliferation of pancreatic stellate cells. World J. Gastroenterol. 2005; 11: 3385–3391.
63. Masamune A., Shimosegawa T. Signal transduction in pancreatic stellate cells. J. Gastroenterol. 2009; 44: 249–260.
64. Masamune A., Suzuki N., Kikuta К. et al. Curcumin blocks activation of pancreatic stellate cells. J. Cell Biochem. 2006; 97: 1080–1093.
65. Mato E., Lucas M., Petriz J. et al. Identification of a pancreatic stellate cell population with properties of progenitor cells: new role for stellate cells in the pancreas. Biochem. J. 2009; 421: 181–191.
66. Matsumura N., Ochi K., Ichimura M. et al. Study on free radicals and pancreatic fibrosis — pancreatic fibrosis induced by repeated injections of superoxide dismutase inhibitor. Pancreas. 2001; 22: 53–57.
67. McCarroll J., Phillips P., Santucci N. et al. Alcoholic pancreatic fibrosis: role of the phosphatidylinositol-3 kinase (PI3-K) and protein kinase С (PKC) pathways in pancreatic stellate cells. J. Gastroenterol. Hepatol. 2004; 29: 347.
68. McCarroll J., Phillips P., Kumar R. et al. Pancreatic stellate cell migration: role of the phosphatidylinositol 3-kinase (РІЗ-kinase) pathway. Biochem. Pharmacol. 2004; 67: 1215–1225.
69. McCarroll J., Phillips P., Park S. et al. Pancreatic stellate cell activation by ethanol and acetaldehyde: is it mediated by the mitogen-activated protein kinase signaling pathway? Pancreas. 2003; 27: 150–160.
70. McCarroll J., Phillips P., Santucci N. et al. Vitamin A induces quiescence in culture-activated pancreatic stellate cells — potential as an anti-fibrotic agent? Pancreas. 2003; 27: 396.
71. Menke A., Yamaguchi H., Gress T. et al. Extracellular matrix is reduced by inhibition of transforming growth factor betal in pancreatitis in the rat. Gastroenterology. 1997; 113: 295–303.
72. Michalski C. W., Maier M., Erkan M. et al. Cannabinoids Reduce Markers of Inflammation and Fibrosis in Pancreatic Stellate Cells. PLoS One. 2008; 3(2): e1701.
73. Motoo Y. Antiproteases in the treatment of chronic pancreatitis. JOP. 2007; 8(4): 533–7.
74. Nagashio Y., Ueno H., Imamura M. et al. Inhibition of transforming growth factor beta decreases pancreatic fibrosis and protects the pancreas against chronic injury in mice. Lab. Invest. 2004; 84(12): 1610–8.
75. Neuschwander-Tetri B., Burton F., Presti M. et al. Repetitive self-limited acute pancreatitis induces pancreatic fibrogenesis in the mouse. Dig. Dis. Sci. 2000; 45: 665–674.
76. Niina Y., Ito T., Oono T. et al. A sustained prostacyclin analog, ONO-1301, attenuates pancreatic fibrosis in experimental chronic pancreatitis induced by dibutyltin dichloride in rats. Pancreatology. 2014; 14: 201–210.
77. Ohashi K., Kim J., Нага H. et al. WBN/Kob rats. A new spontaneously occurring model of chronic pancreatitis. Int. J. Pancreatol. 1990; 6: 231–247.
78. Ohnishi H., Miyata T., Yasuda H. et al. Distinct roles of Smad2-, Smad3-, and ERK-dependent pathways in transforming growth factor-beta 1 regulation of pancreatic stellate cellular functions. J. Biol. Chem. 2004; 279: 8873–8878.
79. Ozdemir В., Pentcheva-Hoang T., Carstens J. et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014; 25: 719–734.
80. Pancreas — pathological practice and research. Ed. K. Suda. Basel et al.: Karger. 2007. 318 p.
81. Pancreatitis: medical and surgical management. Eds.: D. B. Adams et al. Chichester: Wiley Blackwell. 2017. 326 p.
82. Pancreatology: a clinical casebook. Eds.: T. B. Gardner, K. D. Smith. Cham (Switzerland): Springer International Publishing AG. 2017. 193 p.
83. Patel M., Collins J., Benyon C. et al. Pancreatic stellate cells express IGF-1 and insulin receptors: implications for treatment of pancreatic fibrosis / 42nd European Pancreatic Club (EPC) meeting. Pancreatology. 2010; 10: 272.
84. Pereda J., Sabater L., Cassinello N. et al. Effect of simultaneous inhibition of TNF-alpha production and xanthine oxidase in experimental acute pancreatitis: the role of mitogen activated protein kinases. Ann. Surg. 2004; 240: 108–116.
85. Phillips P., McCarroll J., Park S. et al. Pancreatic stellate cells secrete matrix metalloproteinases — implications for extracellular matrix turnover. Gut. 2003; 52: 275–282.
86. Phillips P., Yang L., Shulkes A. et al. Pancreatic stellate cells produce acetylcholine and may play a role in pancreatic exocrine secretion. Proc. Natl. Acad. Sci. USA. 2010;107: 17397–17402.
87. Pothula S., Xu Z., Goldstein D. et al. Hepatocyte growth factor inhibition: a novel therapeutic approach in pancreatic cancer. Br. J. Cancer. 2016; 114: 269–280.
88. Pothula S., Xu Z., Goldstein D. et al. Key role of pancreatic stellate cells in pancreatic cancer. Cancer Lett. 2016; 381: 194–200.
89. Reding T., Bimmler D., Perren A. et al. A selective COX-2 inhibitor suppresses chronic pancreatitis in an animal model (WBN/Kob rats): significant reduction of macrophage infiltration and fibrosis. Gut. 2006; 55(8): 1165–73.
90. Rhim A., Oberstein P., Thomas D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014; 25: 735–747.
91. Riopel M., Li J., Liu S. et al. pi integrin-extracellular matrix interactions are essential for maintaining exocrine pancreas architecture and function. Lab. Invest. 2012; 93: 31–40.
92. Schneider E., Schmid-Kotsas A., Zhao J. et al. Identification of mediators stimulating proliferation and matrix synthesis of rat pancreatic stellate cells. Am. J. Physiol. Cell Physiol. 2001; 281: C532–543.
93. Shek F., Benyon R., Walker F. et al. Expression of transforming growth factor-β1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis. Am. J. Pathol. 2002; 160: 1787–1798.
94. Shen J., Wan R., Hu G. et al. miR-15b and miR-16 induce the apoptosis of rat activated pancreatic stellate cells by targeting Bcl-2 in vitro. Pancreatology. 2012; 12: 91–99.
95. Sherman M., Yu R., Engle D. et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell. 2014; 159: 80–93.
96. Shimizu K., Kobayashi M., Tahara J. et al. Cytokines and peroxisome proliferator-activated receptor gamma ligand regulate phagocytosis by pancreatic stellate cells. Gastroenterology. 2005; 128: 2105–2118.
97. Shimizu K., Shiratori K., Kobayashi M. et al. Troglitazone inhibits the progression of chronic pancreatitis and the profibrogenic activity of pancreatic stellate cells via a PPARgamma-independent mechanism. Pancreas. 2004; 29: 67–74.
98. Shinozaki S., Ohnishi H., Hama К. et al. Indian hedgehog promotes the migration of rat activated pancreatic stellate cells by increasing membrane type-1 matrix metalloproteinase on the plasma membrane. J. Cell Physiol. 2008; 216: 38–46.
99. Sparmann G., Kruse M., Hofmeister-Mielke N. et al. Bone marrow-derived pancreatic stellate cells in rats. Cell Res. 2010; 20: 288–298.
100. Suzuki N., Masamune A., Kikuta К. et al. Ellagic acid inhibits pancreatic fibrosis in male Wistar Bonn/Kobori rats. Dig. Dis. Sci. 2009; 54: 802–810.
101. The Pancreas: An Integrated Textbook of Basic Science, Medicine and Surgery. Ed. H. G. Beger, A. L. Warshaw, R. H. Hruban et al. Oxford: Willey Blackwell. 2018. 1173 p.
102. Tsang S., Bian Z. Anti-fibrotic and anti-tumorigenic effects of rhein, a natural anthraquinone derivative, in mammalian stellate and carcinoma cells. Phytother. Res. 2015; 29: 407–414.
103. Tsukamoto H., Towner S., Yu G. et al. Potentiation of ethanol-induced pancreatic injury by dietary fat. Induction of chronic pancreatitis by alcohol in rats. Am. J. Pathol. 1988; 131: 246–257.
104. Uchida M., Ito T., Nakamura T. et al. Pancreatic stellate cells and CX3CR1: occurrence in normal pancreas and acute and chronic pancreatitis and effect of their activation by a CX3CR1 agonist. Pancreas. 2014; 43: 708–719.
105. Uesugi T., Froh M., Gabele E. et al. Contribution of angiotensin II to alcohol-induced pancreatic fibrosis in rats. J. Pharmacol. Exp. Ther. 2004; 311: 921–928.
106. van Westerloo D., Florquin S., de Boer A. et al. Therapeutic effects of troglitazone in experimental chronic pancreatitis in mice. Am. J. Pathol. 2005; 166(3): 721–8.
107. Vonlaufen A., Phillips P., Xu Z. et al. Alcohol withdrawal promotes regression of pancreatic fibrosis via induction of pancreatic stellate cell (PSC apoptosis). Gut. 2011; 60: 238–246.
108. Vonlaufen A., Phillips P., Xu Z. et al. Isolation of quiescent human pancreatic stellate cells; a useful in vitro tool to study hPSC biology. Pancreatology. 2010; 10: 434–443.
109. Vonlaufen A., Xu Z., Joshi S. et al. Bacterial endotoxin — a trigger factor for alcoholic pancreatitis? Findings of a novel physiologically relevant model. Gastroenterology. 2007; 133: 1293–1303.
110. Wake K. Perisinusoidal stellate cells (fat-storing cells, interstitial cells, lipocytes), their related structure in and around the liver sinusoids, and vitamin A-storing cells in extrahepatic organs. Int. Rev. Cytol. 1980; 66: 303–353.
111. Wang L., Silva M., DʼCosta Z. et al. The prognostic role of desmoplastic stroma in pancreatic ductal adenocarcinoma. Oncotarget. 2016; 7: 4183–4194.
112. Wang Z., Dong S., Zhou W. Pancreatic stellate cells: Key players in pancreatic health and diseases (Review). Mol. Med. Rep. 2024; 30(1): 109. http://doi.org/10.3892/mmr.2024.13233.
113. Watanabe T., Masamune A., Kikuta К. et al. Bone marrow contributes to the population of pancreatic stellate cells in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 2009; 297: G1138–G1146.
114. Watari N., Hotta Y., Mabuchi Y. Morphological studies on a vitamin А-storing cell and its complex with macrophage observed in mouse pancreatic tissues following excess vitamin A administration. Okajimas Folia Anatpn. 1982; 58: 837–858.
115. Witteck L., Jaster R. Trametinib and dactolisib but not regorafenib exert antiproliferative effects on rat pancreatic stellate cells. Hepatobil. Pancreat. Dis. Int. 2015; 14: 642–650.
116. Won J., Zhang Y., Ji В. et al. Phenotypic changes in mouse pancreatic stellate cell Ca2+ signaling events following activation in culture and in a disease model of pancreatitis. Mol. Biol. Cell. 2011; 22: 421–436.
117. Xiao W., Jiang W., Shen J. et al. Retinoic acid ameliorates pancreatic fibrosis and inhibits the activation of pancreatic stellate cells in mice with experimental chronic pancreatitis via suppressing the Wnt/beta- catenin signaling pathway. PLoS ONE. 2015; 10: e0141462.
118. Xu W., Li W., Wang Y. et al. Regenerating islet-derived protein 1 inhibits the activation of islet stellate cells isolated from diabetic mice. Oncotarget. 2015; 6: 37054–37065.
119. Xu Z., Vonlaufen A., Phillips P.et al. Role of pancreatic stellate cells in pancreatic cancer metastasis. Am. J. Pathol. 2010; 177: 2585–2596.
120. Xue R., Jia K., Wang J. et al. A Rising Star in Pancreatic Diseases: Pancreatic Stellate Cells. Front. Physiol. 2018; 9: 754. http://doi.org/10.3389/fphys.2018.00754.
121. Yamada T., Kuno A., Masuda K. et al. Candesartan, an angiotensin II receptor antagonist, suppresses pancreatic inflammation and fibrosis in rats. J. Pharmacol. Exp. Ther. 2003; 307(1): 17–23.
122. Yasuma T., Gabazza E. Cell Death in Acute Organ Injury and Fibrosis. Int. J. Mol. Sci. 2024; 25(7): 3930. http://doi.org/10.3390/ijms25073930.
123. Yoshida S., Ujiki M., Ding X. et al. Pancreatic stellate cells (PSCs) express cyclooxygenase-2 (COX-2) and pancreatic cancer stimulates COX-2 in PSCs. Mol. Cancer. 2005; 4: 27.
124. Zechner D., Knapp N., Bobrowski A. et al. Diabetes increases pancreatic fibrosis during chronic inflammation. Exp. Biol. Med. (Maywood, NJ). 2014; 239: 670–676.
125. Zha M., Xu W., Jones P. et al. Isolation and characterization of human islet stellate cells. Exp. Cell Res. 2016; 314: 61–66.
126. Zhang H., Wu H., Guan J. et al. Paracrine SDF-lalpha signaling mediates the effects of PSCs on GEM chemoresistance through an IL-6 autocrine loop in pancreatic cancer cells. Oncotarget. 2015; 6: 3085–3097.
127. Zhang X., Cui Y., Fang L. et al. Chronic high-fat diets induce oxide injuries and fibrogenesis of pancreatic cells in rats. Pancreas. 2008; 37(3): e31-8. http://doi.org/10.1097/MPA.0b013e3181744b50.
128. Zheng M., Gao R. Vitamin D: a potential star for treating chronic pancreatitis. Front. Pharmacol. 2022; 13: 902639. http://doi.org/10.3389/fphar.2022.902639.
129. Zheng M., Li H., Gao Y. et al. Vitamin D3 analogue calcipotriol inhibits the profibrotic effects of transforming growth factor- β1 on pancreatic stellate cells. Eur. J. Pharmacol. 2023; 957: 176000. http://doi.org/10.1016/j.ejphar.2023.176000.
130. Zhou Z.., Zhang L, Wei X. et al. 1,25(OH)2D3 inhibits pancreatic stellate cells activation and promotes insulin secretion in T2DM. Endocrine. 2024; 85(3): 1193–1205. http://doi.org/10.1007/s12020-024-03833-0.
131. Zhu Y., Yang M., Xu W. et al. The collagen matrix regulates the survival and function of pancreatic islets. Endocrine. 2024; 83(3): 537–547. http://doi.org/10.1007/s12020-023-03592-4.
132. Zimmermann A., Gloor B., Kappeler A. et al. Pancreatic stellate cells contribute to regeneration early after acute necrotising pancreatitis in humans. Gut. 2002; 51: 574–578.
2. Корочанская Н. В., Рогаль М. Л., Гришина И. Ю. Хирургическая и медикаментозная профилактика раковой трансформации хронического панкреатита. Гастро News. 2008; 5: 46−50.
3. Маев И. В., Кучерявый Ю. А. Дозозависимая терапия полиферментными препаратами. Врач. 2003; 12: 1–4.
4. Andoh A., Takaya H., Saotome T. et al. Cytokine regulation of chemokine (IL-8, MCP-1, and RANTES) gene expression in human pancreatic periacinar myofibroblasts. Gastroenterology. 2000; 119(1): 211–9. http://doi.org/10.1053/gast.2000.8538.
5. Apte M., Pirola R., Wilson J. The fibrosis of chronic pancreatitis: new insights into the role of pancreatic stellate cells. Antioxid. Redox Signal. 2011; 15(10): 2711–22. http://doi.org/10.1089/ars.2011.4079.
6. Apte M., Pirola R. C., Wilson J. S. Pancreatic stellate cell: physiologic role, role in fibrosis and cancer. Curr. Opin. Gastroenterol. 2015; 31(5): 416–23. http://doi.org/10.1097/MOG.0000000000000196.
7. Apte M., Haber P., Applegate T. et al. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut. 1998; 43(1): 128–33. http://doi.org/10.1136/gut.43.1.128.
8. Apte M., Park S., Phillips P. et al. Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas. 2004; 29(3): 179–87. http://doi.org/10.1097/00006676-200410000-00002.
9. Apte M., Wilson J., Lugea A. et al. A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology. 2013; 144(6): 1210–9. http://doi.org/10.1053/j.gastro.2012.11.037.
10. Apte M., Wilson J. Dangerous liaisons: pancreatic stellate cells and pancreatic cancer cells. J Gastroenterol. Hepatol. 2012; 27(2): 69–74. http://doi.org/10.1111/j.1440-1746.2011.07000.x.
11. Apte M., Xu Z., Pothula S. et al. Pancreatic cancer: The microenvironment needs attention too! Pancreatology. 2015; 15(4): S32–8. http://doi.org/10.1016/j.pan.2015.02.013.
12. Arumugam T., Brandt W., Ramachandran V. et al. Trefoil factor 1 stimulates both pancreatic cancer and stellate cells and increases metastasis. Pancreas. 2011; 40(6): 815–22. http://doi.org/ 10.1097/MPA.0b013e31821f6927.
13. Bachem M., Schneider E., Gross H. et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology. 1998; 115(2): 421–32. http://doi.org/10.1016/s0016-5085(98)70209-4.
14. Bachem M., Schünemann M., Ramadani M. et al. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology. 2005; 128(4): 907–21. http://doi.org/10.1053/j.gastro.2004.12.036.
15. Omary M., Lugea A., Lowe A. et al. The pancreatic stellate cell: a star on the rise in pancreatic diseases. J. Clin. Invest. 2007; 117(1): 50–9. http://doi.org/10.1172/JCI30082.
16. Blaine S., Ray K., Branch K. et al. Epidermal growth factor receptor regulates pancreatic fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 2009; 297(3): G434–41. http://doi.org/10.1152/ajpgi.00152.2009.
17. Brizzi M., Tarone G., Defilippi P. Extracellular matrix, integrins, and growth factors as tailors of the stem cell niche. Curr. Opin. Cell Biol. 2012; 24(5): 645–51. http://doi.org/10.1016/j.ceb.2012.07.001.
18. Bynigeri R., Jakkampudi A. Jangala R. et al. Pancreatic stellate cell: Pandoraʼs box for pancreatic disease biology. World J. Gastroenterol. 2017; 23(3): 382–405. http://doi.org/10.3748/wjg.v23.i3.382.
19. Cabrera M., Tilahun E. Nakles R. et al. Human pancreatic cancer-associated stellate cells remain activated after in vivo chemoradiation. Front. Oncol. 2014; 4: 102. http://doi.org/10.3389/fonc.2014.00102.
20. Charrier A., Chen R., Chen L. et al. Connective tissue growth factor (CCN2) and microRNA-21 are components of a positive feedback loop in pancreatic stellate cells (PSC) during chronic pancreatitis and are exported in PSC-derived exosomes. J. Cell Commun. Signal. 2014; 8(2): 147–56. http://doi.org/10.1007/s12079-014-0220-3.
21. Chen H., Mrazek A., Wang X. et al. Design, synthesis, and characterization of novel apigenin analogues that suppress pancreatic stellate cell proliferation in vitro and associated pancreatic fibrosis in vivo. Bioorg. Med. Chem. 2014; 22(13): 3393–404. http://doi.org/10.1016/j.bmc.2014.04.043.
22. de la Iglesia-Garcia D., Vallejo-Senra N., Iglesias-Garcia J. et al. Increased risk of mortality associated with pancreatic exocrine insufficiency in patients with chronic pancreatitis. J. Clin. Gastroenterol. 2018; 52(8): e63–e72. http://doi.org/10.1097/MCG.0000000000000917.
23. Detlefsen S., Sipos B., Feyerabend B. et al. Fibrogenesis in alcoholic chronic pancreatitis: the role of tissue necrosis, macrophages, myofibroblasts and cytokines. Mod. Pathol. 2006; 19(8): 1019–26. http://doi.org/10.1038/modpathol.3800613.
24. Detlefsen S., Sipos B., Feyerabend B. et al. Pancreatic fibrosis associated with age and ductal papillary hyperplasia. Virchows Arch. 2005; 447(5): 800–5. http://doi.org/10.1007/s00428-005-0032-1.
25. Detlefsen S., Sipos B., Zhao J. et al. Autoimmune pancreatitis: expression and cellular source of profibrotic cytokines and their receptors. Am. J. Surg. Pathol. 2008; 32(7): 986–95. http://doi.org/10.1097/PAS.0b013e31815d2583.
26. Clinical pancreatology for practicing gastroenterologists and surgeons. Dominguez-Munoz J. E. Ed. A Blackwell Publishing Company; 2021. 698 p.
27. Elsner A., Lange F., Fitzner B. et al. Distinct antifibrogenic effects of erlotinib, sunitinib and sorafenib on rat pancreatic stellate cells. World J. Gastroenterol. 2014; 20(24): 7914–25. http://doi.org/10.3748/wjg.v20.i24.7914.
28. Elsässer H., Adler G., Kern H. Time course and cellular source of pancreatic regeneration following acute pancreatitis in the rat. Pancreas. 1986; 1(5): 421–9. http://doi.org/10.1097/00006676-198609000-00006.
29. Emmrich J., Weber I., Sparmann G. et al. Activation of pancreatic stellate cells in experimental chronic pancreatitis in rats. Gastroenterology. 2000; 118: A166.
30. Erkan M., Michalski C. W., Rieder S. et al. The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma. Clin. Gastroenterol. Hepatol. 200; 6(10): 1155–61. http://doi.org/10.1016/j.cgh.2008.05.006.
31. Fitzner B., Müller S., Walther M. et al. Senescence determines the fate of activated rat pancreatic stellate cells. J. Cell Mol. Med. 2012; 16(11): 2620–30. http://doi.org/10.1111/j.1582-4934.2012.01573.x.
32. Friess H., Zhu Z., di Mola F. et al. Nerve growth factor and its high-affinity receptor in chronic pancreatitis. Ann. Surg. 1999; 230(5): 615–24. http://doi.org/10.1097/00000658-199911000-00002.
33. Fukui H., Brauner B., Bode J. et al. Plasma endotoxin concentrations in patients with alcoholic and non-alcoholic liver disease: reevaluation with an improved chromogenic assay. J. Hepatol. 1991; 12(2): 162–9. http://doi.org/10.1016/0168-8278(91)90933-3.
34. Gao X., Cao Y., Staloch D. et al. Bone morphogenetic protein signaling protects against cerulein-induced pancreatic fibrosis. PLoS One. 2014; 9(2): e89114. http://doi.org/10.1371/journal.pone.0089114.
35. Gibo J., Ito T., Kawabe K. et al. Camostat mesilate attenuates pancreatic fibrosis via inhibition of monocytes and pancreatic stellate cells activity. Lab Invest. 2005; 85(1): 75–89. http://doi.org/10.1038/labinvest.3700203.
36. Gómez J., Molero X., Vaquero E. et al. Vitamin E attenuates biochemical and morphological features associated with development of chronic pancreatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 2004; 287(1): G162–9. http://doi.org/10.1152/ajpgi.00333.2003.
37. Gryshchenko O., Gerasimenko J., Gerasimenko O. et al. Ca(2+) signals mediated by bradykinin type 2 receptors in normal pancreatic stellate cells can be inhibited by specific Ca(2+) channel blockade. J. Physiol. 2016; 594(2): 281–93. http://doi.org/10.1113/JP271468.
38. Gukovskaya A., Mouria M., Gukovsky I. et al. Ethanol metabolism and transcription factor activation in pancreatic acinar cells in rats. Gastroenterology. 2002; 122: 106–118.
39. Gukovsky I., Lugea A., Shahsahebi M. et al. A rat model reproducing key pathological responses of alcoholic chronic pancreatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 2008; 294(1): G68–79. http://doi.org/10.1152/ajpgi.00006.2007.
40. Haber P., Keogh G., Apte M. et al. Activation of pancreatic stellate cells in human and experimental pancreatic fibrosis. Am. J. Pathol. 1999; 155(4): 1087–95. http://doi.org/10.1016/S0002-9440(10)65211-X.
41. Hamada S., Masamune A., Takikawa T. et al. Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells. Biochem. Biophys. Res. Commun. 2012; 421(2): 349–54. http://doi.org/10.1016/j.bbrc.2012.04.014.
42. Hennigs J., Seiz O., Spiro J. et al. Molecular basis of P2-receptor-mediated calcium signaling in activated pancreatic stellate cells. Pancreas. 2011; 40(5): 740–6. http://doi.org/10.1097/MPA.0b013e31821b5b68.
43. Hu Y., Wan R., Yu G. et al. Imbalance of Wnt/Dkk negative feedback promotes persistent activation of pancreatic stellate cells in chronic pancreatitis. PLoS One. 2014; 9(4): e95145. http://doi.org/10.1371/journal.pone.0095145.
44. Hughes C., Gaber L., Mohey el-Din A. et al. Inhibition of TNF alpha improves survival in an experimental model of acute pancreatitis. Am. Surg. 1996; 62(1): 8–13.
45. Ikejiri N. The vitamin A-storing cells in the human and rat pancreas. Kurume Med. J. 1990; 37(2): 67–81. http://doi.org/10.2739/kurumemedj.37.67.
46. Ikenaga N., Ohuchida K., Mizumoto K. et al. CD10+ pancreatic stellate cells enhance the progression of pancreatic cancer. Gastroenterology. 2010; 139(3): 1041–51. http://doi.org/10.1053/j.gastro.2010.05.084.
47. Ishiwatari H., Sato Y., Murase K. et al. Treatment of pancreatic fibrosis with siRNA against a collagen-specific chaperone in vitamin A-coupled liposomes. Gut. 2013; 62(9): 1328–39. http://doi.org/10.1136/gutjnl-2011-301746
48. Jaster R., Sparmann G., Emmrich J. et al. Extracellular signal regulated kinases are key mediators of mitogenic signals in rat pancreatic stellate cells. Gut. 2002; 51(4): 579–84. http://doi.org/10.1136/gut.51.4.579.
49. Jaster R. Molecular regulation of pancreatic stellate cell function. Mol. Cancer. 2004; 3: 26. http://doi.org/10.1186/1476-4598-3-26.
50. Karger A., Fitzner B., Brock P. et al. Molecular insights into connective tissue growth factor action in rat pancreatic stellate cells. Cell Signal. 2008; 20(10): 1865–72. http://doi.org/10.1016/j.cellsig.2008.06.016.
51. Kikuta К., Masamune A., Hamada S. et al. Pancreatic stellate cells reduce insulin expression and induce apoptosis in pancreatic beta-cells. Biochem. Biophys. Res. Commun. 2013; 433: 292–297.
52. Kikuta К., Masamune A., Watanabe T. et al. Pancreatic stellate cells promote epithelial-mesenchymal transition in pancreatic cancer cells. Biochem. Biophys. Res. Commun. 2010; 403: 380–384.
53. Kloppel G. Pathology of chronic pancreatitis and pancreatic pain. Acta Chir. Scand. 1990; 156: 261–265.
54. Kon A., Tando Y., Yanagimachi M. et al. The study on the treatment of pancreatic steatorrhea and pancreatic diabetes for patients with pancreatic insufficiency. Abstracts of papers submitted to the Joint 40th anniversary meeting of American Pancreatic Association and Japan Pancreas Society, Honolulu (Hawaii). Pancreas. 2009; 38(8): 1019.
55. Kordes C., Sawitza I., Haussinger D. Hepatic and pancreatic stellate cells in focus. Biol. Chem. 2009; 390: 1003–1012.
56. Kuno A., Yamada T., Masuda K. et al. Angiotensin-converting enzyme inhibitor attenuates pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori rats. Gastroenterology. 2003; 124(4): 1010–9.
57. Lu X., Dong X., Fu Y. et al. Protective effect of salvianolic acid В on chronic pancreatitis induced by trinitrobenzene sulfonie acid solution in rats. Pancreas. 2009; 38: 71–77.
58. Marrache F., Tu S., Bhagat G. et al. Overexpression of interleukin-lbeta in the murine pancreas results in chronic pancreatitis. Gastroenterology. 2008; 135: 1277–1287.
59. Masamune A., Kikuta K., Satoh M, et al. Rho kinase inhibitors block activation of pancreatic stellate cells. Br. J. Pharmacol. 2003; 140: 1292–1302.
60. Masamune A., Kikuta K., Watanabe T. et al. Pancreatic stellate cells express Toll-like receptors. J. Gastroenterol. 2008; 43: 352–362.
61. Masamune A., Nakano E., Hamada S. et al. Alteration of the microRNA expression profile during the activation of pancreatic stellate cells. Scand J. Gastroenterol. 2014; 49: 323–331.
62. Masamune A., Satoh M., Kikuta К. et al. Activation of JAK-STAT pathway is required for platelet-derived growth factor-induced proliferation of pancreatic stellate cells. World J. Gastroenterol. 2005; 11: 3385–3391.
63. Masamune A., Shimosegawa T. Signal transduction in pancreatic stellate cells. J. Gastroenterol. 2009; 44: 249–260.
64. Masamune A., Suzuki N., Kikuta К. et al. Curcumin blocks activation of pancreatic stellate cells. J. Cell Biochem. 2006; 97: 1080–1093.
65. Mato E., Lucas M., Petriz J. et al. Identification of a pancreatic stellate cell population with properties of progenitor cells: new role for stellate cells in the pancreas. Biochem. J. 2009; 421: 181–191.
66. Matsumura N., Ochi K., Ichimura M. et al. Study on free radicals and pancreatic fibrosis — pancreatic fibrosis induced by repeated injections of superoxide dismutase inhibitor. Pancreas. 2001; 22: 53–57.
67. McCarroll J., Phillips P., Santucci N. et al. Alcoholic pancreatic fibrosis: role of the phosphatidylinositol-3 kinase (PI3-K) and protein kinase С (PKC) pathways in pancreatic stellate cells. J. Gastroenterol. Hepatol. 2004; 29: 347.
68. McCarroll J., Phillips P., Kumar R. et al. Pancreatic stellate cell migration: role of the phosphatidylinositol 3-kinase (РІЗ-kinase) pathway. Biochem. Pharmacol. 2004; 67: 1215–1225.
69. McCarroll J., Phillips P., Park S. et al. Pancreatic stellate cell activation by ethanol and acetaldehyde: is it mediated by the mitogen-activated protein kinase signaling pathway? Pancreas. 2003; 27: 150–160.
70. McCarroll J., Phillips P., Santucci N. et al. Vitamin A induces quiescence in culture-activated pancreatic stellate cells — potential as an anti-fibrotic agent? Pancreas. 2003; 27: 396.
71. Menke A., Yamaguchi H., Gress T. et al. Extracellular matrix is reduced by inhibition of transforming growth factor betal in pancreatitis in the rat. Gastroenterology. 1997; 113: 295–303.
72. Michalski C. W., Maier M., Erkan M. et al. Cannabinoids Reduce Markers of Inflammation and Fibrosis in Pancreatic Stellate Cells. PLoS One. 2008; 3(2): e1701.
73. Motoo Y. Antiproteases in the treatment of chronic pancreatitis. JOP. 2007; 8(4): 533–7.
74. Nagashio Y., Ueno H., Imamura M. et al. Inhibition of transforming growth factor beta decreases pancreatic fibrosis and protects the pancreas against chronic injury in mice. Lab. Invest. 2004; 84(12): 1610–8.
75. Neuschwander-Tetri B., Burton F., Presti M. et al. Repetitive self-limited acute pancreatitis induces pancreatic fibrogenesis in the mouse. Dig. Dis. Sci. 2000; 45: 665–674.
76. Niina Y., Ito T., Oono T. et al. A sustained prostacyclin analog, ONO-1301, attenuates pancreatic fibrosis in experimental chronic pancreatitis induced by dibutyltin dichloride in rats. Pancreatology. 2014; 14: 201–210.
77. Ohashi K., Kim J., Нага H. et al. WBN/Kob rats. A new spontaneously occurring model of chronic pancreatitis. Int. J. Pancreatol. 1990; 6: 231–247.
78. Ohnishi H., Miyata T., Yasuda H. et al. Distinct roles of Smad2-, Smad3-, and ERK-dependent pathways in transforming growth factor-beta 1 regulation of pancreatic stellate cellular functions. J. Biol. Chem. 2004; 279: 8873–8878.
79. Ozdemir В., Pentcheva-Hoang T., Carstens J. et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014; 25: 719–734.
80. Pancreas — pathological practice and research. Ed. K. Suda. Basel et al.: Karger. 2007. 318 p.
81. Pancreatitis: medical and surgical management. Eds.: D. B. Adams et al. Chichester: Wiley Blackwell. 2017. 326 p.
82. Pancreatology: a clinical casebook. Eds.: T. B. Gardner, K. D. Smith. Cham (Switzerland): Springer International Publishing AG. 2017. 193 p.
83. Patel M., Collins J., Benyon C. et al. Pancreatic stellate cells express IGF-1 and insulin receptors: implications for treatment of pancreatic fibrosis / 42nd European Pancreatic Club (EPC) meeting. Pancreatology. 2010; 10: 272.
84. Pereda J., Sabater L., Cassinello N. et al. Effect of simultaneous inhibition of TNF-alpha production and xanthine oxidase in experimental acute pancreatitis: the role of mitogen activated protein kinases. Ann. Surg. 2004; 240: 108–116.
85. Phillips P., McCarroll J., Park S. et al. Pancreatic stellate cells secrete matrix metalloproteinases — implications for extracellular matrix turnover. Gut. 2003; 52: 275–282.
86. Phillips P., Yang L., Shulkes A. et al. Pancreatic stellate cells produce acetylcholine and may play a role in pancreatic exocrine secretion. Proc. Natl. Acad. Sci. USA. 2010;107: 17397–17402.
87. Pothula S., Xu Z., Goldstein D. et al. Hepatocyte growth factor inhibition: a novel therapeutic approach in pancreatic cancer. Br. J. Cancer. 2016; 114: 269–280.
88. Pothula S., Xu Z., Goldstein D. et al. Key role of pancreatic stellate cells in pancreatic cancer. Cancer Lett. 2016; 381: 194–200.
89. Reding T., Bimmler D., Perren A. et al. A selective COX-2 inhibitor suppresses chronic pancreatitis in an animal model (WBN/Kob rats): significant reduction of macrophage infiltration and fibrosis. Gut. 2006; 55(8): 1165–73.
90. Rhim A., Oberstein P., Thomas D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014; 25: 735–747.
91. Riopel M., Li J., Liu S. et al. pi integrin-extracellular matrix interactions are essential for maintaining exocrine pancreas architecture and function. Lab. Invest. 2012; 93: 31–40.
92. Schneider E., Schmid-Kotsas A., Zhao J. et al. Identification of mediators stimulating proliferation and matrix synthesis of rat pancreatic stellate cells. Am. J. Physiol. Cell Physiol. 2001; 281: C532–543.
93. Shek F., Benyon R., Walker F. et al. Expression of transforming growth factor-β1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis. Am. J. Pathol. 2002; 160: 1787–1798.
94. Shen J., Wan R., Hu G. et al. miR-15b and miR-16 induce the apoptosis of rat activated pancreatic stellate cells by targeting Bcl-2 in vitro. Pancreatology. 2012; 12: 91–99.
95. Sherman M., Yu R., Engle D. et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell. 2014; 159: 80–93.
96. Shimizu K., Kobayashi M., Tahara J. et al. Cytokines and peroxisome proliferator-activated receptor gamma ligand regulate phagocytosis by pancreatic stellate cells. Gastroenterology. 2005; 128: 2105–2118.
97. Shimizu K., Shiratori K., Kobayashi M. et al. Troglitazone inhibits the progression of chronic pancreatitis and the profibrogenic activity of pancreatic stellate cells via a PPARgamma-independent mechanism. Pancreas. 2004; 29: 67–74.
98. Shinozaki S., Ohnishi H., Hama К. et al. Indian hedgehog promotes the migration of rat activated pancreatic stellate cells by increasing membrane type-1 matrix metalloproteinase on the plasma membrane. J. Cell Physiol. 2008; 216: 38–46.
99. Sparmann G., Kruse M., Hofmeister-Mielke N. et al. Bone marrow-derived pancreatic stellate cells in rats. Cell Res. 2010; 20: 288–298.
100. Suzuki N., Masamune A., Kikuta К. et al. Ellagic acid inhibits pancreatic fibrosis in male Wistar Bonn/Kobori rats. Dig. Dis. Sci. 2009; 54: 802–810.
101. The Pancreas: An Integrated Textbook of Basic Science, Medicine and Surgery. Ed. H. G. Beger, A. L. Warshaw, R. H. Hruban et al. Oxford: Willey Blackwell. 2018. 1173 p.
102. Tsang S., Bian Z. Anti-fibrotic and anti-tumorigenic effects of rhein, a natural anthraquinone derivative, in mammalian stellate and carcinoma cells. Phytother. Res. 2015; 29: 407–414.
103. Tsukamoto H., Towner S., Yu G. et al. Potentiation of ethanol-induced pancreatic injury by dietary fat. Induction of chronic pancreatitis by alcohol in rats. Am. J. Pathol. 1988; 131: 246–257.
104. Uchida M., Ito T., Nakamura T. et al. Pancreatic stellate cells and CX3CR1: occurrence in normal pancreas and acute and chronic pancreatitis and effect of their activation by a CX3CR1 agonist. Pancreas. 2014; 43: 708–719.
105. Uesugi T., Froh M., Gabele E. et al. Contribution of angiotensin II to alcohol-induced pancreatic fibrosis in rats. J. Pharmacol. Exp. Ther. 2004; 311: 921–928.
106. van Westerloo D., Florquin S., de Boer A. et al. Therapeutic effects of troglitazone in experimental chronic pancreatitis in mice. Am. J. Pathol. 2005; 166(3): 721–8.
107. Vonlaufen A., Phillips P., Xu Z. et al. Alcohol withdrawal promotes regression of pancreatic fibrosis via induction of pancreatic stellate cell (PSC apoptosis). Gut. 2011; 60: 238–246.
108. Vonlaufen A., Phillips P., Xu Z. et al. Isolation of quiescent human pancreatic stellate cells; a useful in vitro tool to study hPSC biology. Pancreatology. 2010; 10: 434–443.
109. Vonlaufen A., Xu Z., Joshi S. et al. Bacterial endotoxin — a trigger factor for alcoholic pancreatitis? Findings of a novel physiologically relevant model. Gastroenterology. 2007; 133: 1293–1303.
110. Wake K. Perisinusoidal stellate cells (fat-storing cells, interstitial cells, lipocytes), their related structure in and around the liver sinusoids, and vitamin A-storing cells in extrahepatic organs. Int. Rev. Cytol. 1980; 66: 303–353.
111. Wang L., Silva M., DʼCosta Z. et al. The prognostic role of desmoplastic stroma in pancreatic ductal adenocarcinoma. Oncotarget. 2016; 7: 4183–4194.
112. Wang Z., Dong S., Zhou W. Pancreatic stellate cells: Key players in pancreatic health and diseases (Review). Mol. Med. Rep. 2024; 30(1): 109. http://doi.org/10.3892/mmr.2024.13233.
113. Watanabe T., Masamune A., Kikuta К. et al. Bone marrow contributes to the population of pancreatic stellate cells in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 2009; 297: G1138–G1146.
114. Watari N., Hotta Y., Mabuchi Y. Morphological studies on a vitamin А-storing cell and its complex with macrophage observed in mouse pancreatic tissues following excess vitamin A administration. Okajimas Folia Anatpn. 1982; 58: 837–858.
115. Witteck L., Jaster R. Trametinib and dactolisib but not regorafenib exert antiproliferative effects on rat pancreatic stellate cells. Hepatobil. Pancreat. Dis. Int. 2015; 14: 642–650.
116. Won J., Zhang Y., Ji В. et al. Phenotypic changes in mouse pancreatic stellate cell Ca2+ signaling events following activation in culture and in a disease model of pancreatitis. Mol. Biol. Cell. 2011; 22: 421–436.
117. Xiao W., Jiang W., Shen J. et al. Retinoic acid ameliorates pancreatic fibrosis and inhibits the activation of pancreatic stellate cells in mice with experimental chronic pancreatitis via suppressing the Wnt/beta- catenin signaling pathway. PLoS ONE. 2015; 10: e0141462.
118. Xu W., Li W., Wang Y. et al. Regenerating islet-derived protein 1 inhibits the activation of islet stellate cells isolated from diabetic mice. Oncotarget. 2015; 6: 37054–37065.
119. Xu Z., Vonlaufen A., Phillips P.et al. Role of pancreatic stellate cells in pancreatic cancer metastasis. Am. J. Pathol. 2010; 177: 2585–2596.
120. Xue R., Jia K., Wang J. et al. A Rising Star in Pancreatic Diseases: Pancreatic Stellate Cells. Front. Physiol. 2018; 9: 754. http://doi.org/10.3389/fphys.2018.00754.
121. Yamada T., Kuno A., Masuda K. et al. Candesartan, an angiotensin II receptor antagonist, suppresses pancreatic inflammation and fibrosis in rats. J. Pharmacol. Exp. Ther. 2003; 307(1): 17–23.
122. Yasuma T., Gabazza E. Cell Death in Acute Organ Injury and Fibrosis. Int. J. Mol. Sci. 2024; 25(7): 3930. http://doi.org/10.3390/ijms25073930.
123. Yoshida S., Ujiki M., Ding X. et al. Pancreatic stellate cells (PSCs) express cyclooxygenase-2 (COX-2) and pancreatic cancer stimulates COX-2 in PSCs. Mol. Cancer. 2005; 4: 27.
124. Zechner D., Knapp N., Bobrowski A. et al. Diabetes increases pancreatic fibrosis during chronic inflammation. Exp. Biol. Med. (Maywood, NJ). 2014; 239: 670–676.
125. Zha M., Xu W., Jones P. et al. Isolation and characterization of human islet stellate cells. Exp. Cell Res. 2016; 314: 61–66.
126. Zhang H., Wu H., Guan J. et al. Paracrine SDF-lalpha signaling mediates the effects of PSCs on GEM chemoresistance through an IL-6 autocrine loop in pancreatic cancer cells. Oncotarget. 2015; 6: 3085–3097.
127. Zhang X., Cui Y., Fang L. et al. Chronic high-fat diets induce oxide injuries and fibrogenesis of pancreatic cells in rats. Pancreas. 2008; 37(3): e31-8. http://doi.org/10.1097/MPA.0b013e3181744b50.
128. Zheng M., Gao R. Vitamin D: a potential star for treating chronic pancreatitis. Front. Pharmacol. 2022; 13: 902639. http://doi.org/10.3389/fphar.2022.902639.
129. Zheng M., Li H., Gao Y. et al. Vitamin D3 analogue calcipotriol inhibits the profibrotic effects of transforming growth factor- β1 on pancreatic stellate cells. Eur. J. Pharmacol. 2023; 957: 176000. http://doi.org/10.1016/j.ejphar.2023.176000.
130. Zhou Z.., Zhang L, Wei X. et al. 1,25(OH)2D3 inhibits pancreatic stellate cells activation and promotes insulin secretion in T2DM. Endocrine. 2024; 85(3): 1193–1205. http://doi.org/10.1007/s12020-024-03833-0.
131. Zhu Y., Yang M., Xu W. et al. The collagen matrix regulates the survival and function of pancreatic islets. Endocrine. 2024; 83(3): 537–547. http://doi.org/10.1007/s12020-023-03592-4.
132. Zimmermann A., Gloor B., Kappeler A. et al. Pancreatic stellate cells contribute to regeneration early after acute necrotising pancreatitis in humans. Gut. 2002; 51: 574–578.