New aspects of formation and progression of pancreatic fibrosis in pancreatitis
PDF (Русский)


pancreatitis, pancreatic stellate cells, pancreatic fibrogenesis, signal pathways, extracellular matrix

How to Cite

Akhmedov, V. A., & Gaus, O. V. (2019). New aspects of formation and progression of pancreatic fibrosis in pancreatitis. Herald of Pancreatic Club, 43(2), 20-24.

Abstract views: 89
PDF Downloads: 57 PDF Downloads: 31


Fibrosis formation is a dynamic process during which the formation of an extracellular matrix takes place in interstitial spaces and areas where the main components of exocrine pancreatic function (acinar cells) are damaged. According to studies, the biggest role in the formation of pancreatic fibrosis upon chronic pancreatitis is played by various types of effector cells, such as fibroblasts, myofibroblasts and fibrocytes, while fibroblasts and myofibroblasts are the key fibrosis cells responsible for the secretion of extracellular matrix. Activated pancreatic stellate cells become main components of fibrosis formation in patients with chronic pancreatitis, synthesizing transforming growth factor-β, fibroblast growth factor, which leads to enhanced synthesis of extracellular matrix.

The presented review highlights molecular mechanisms (Rho-kinase, mitogen-activating protein kinase, transforming growth factor-β, associated with the protein encoded by SMAD in humans, phosphatidylinositol-3 kinase), which play an important role in the activation of pancreatic stellate cells and launching the phenomenon of pancreatic fibrogenesis.

The presented data opens up prospects for the development of diagnostic areas with the search for new markers for the diagnosis of acute and chronic pancreatitis along with development of new therapeutic options for the pathogenetic therapy of patients with acute and chronic pancreatitis based on the results obtained.
PDF (Русский)


1. Andoh A., Bamba S., Fujino S. Fibroblast growth factor-2 stimulates interleukin-6 secretion in human pancreatic periacinar myofibroblasts. Pancreas. 2004. Vol. 29. Р. 278–283.
2. Aoki H., Ohnishi H., Hama K. Autocrine loop between TGF-beta1 and IL-1beta through Smad3- and ERKdependent pathways in rat pancreatic stellate cells. Am. J. Physiol. Cell Physiol. 2006. Vol. 290. Р.1100–1108.
3. Apte M. V., Wilson J. S., Lugea A., Pandol S. J. A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology. 2013. Vol. 144. Р. 1210–1219.
4. Awla D., Hartman H., Abdulla A. Rho-kinase signalling regulates trypsinogen activation and tissue damage in severe acute pancreatitis. Br. J. Pharmacol. 2011. Vol. 162. Р. 648–658.
5. Brenner D. A., Kisseleva T., Scholten D. Origin of myofibroblasts in liver fibrosis. Fibrogenesis Tissue Repair. 2012. Vol. 5. Р. 17.
6. Chen P., Huang L., Zhang Y., Qiao M. The antagonist of the JAK-1/STAT-1 signaling pathway improves the severity of cerulein-stimulated pancreatic injury via inhibition of NF-κB activity. Int. J. Mol. Med. 2011. Vol. 27. Р. 731–738.
7. Deng S., Zhu S., Wang B. Chronic pancreatitis and pancreatic cancer demonstrate active epithelial-mesenchymal transition profile, regulated by miR-217- SIRT1 pathway. Cancer Lett. 2014. Vol. 355. Р. 184–191.
8. Garcia-Carracedo D., Yu C. C., Akhavan N. Smad 4 loss synergizes with TGFα overexpression in promoting pancreatic metaplasia, PanIN development, and fibrosis. PLoS One. 2015. Vol. 10. P. e0120851.
9. Gukovsky I., Cheng J. H., Nam K. J. Phosphatidylinositide 3-kinase gamma regulates key pathologic responses to cholecystokinin in pancreatic acinar cells. Gastroenterology. 2004. Vol. 126. Р. 554–566.
10. Hansen M., Nielsen A. R., Vilsbøll T. Increased levels of YKL-40 and interleukin 6 in patients with chronic pancreatitis and secondary diabetes. Pancreas. 2012. Vol. 41. Р.1316–1318.
11. Huang Y., Xiao S., Jiang Q. Role of Rho kinase signal pathway in inflammatory bowel disease. Int. J. Clin. Exp. Med. 2015. Vol. 8. Р. 3089–3097.
12. Jura N., Archer H., Bar-Sagi D. Chronic pancreatitis, pancreatic adenocarcinoma and the black box in-between. Cell. Res. 2005. Vol. 15. Р. 72–77.
13. Lesina M., Wörmann S. M., Neuhöfer P. Interleukin-6 in inflammatory and malignant diseases of the pancreas. Semin. Immunol. 2014. Vol. 26. Р. 80–87.
14. Lupia E., Pigozzi L., Goffi A. Role of phosphoinositide 3-kinase in the pathogenesis of acute pancreatitis. World J. Gastroenterol. 2014. Vol. 20. Р. 15190–15199.
15. Masamune A., Kikuta K., Satoh M. Protease-activated receptor-2-mediated proliferation and collagen production of rat pancreatic stellate cells. J. Pharmacol. Exp. Ther. 2005. Vol. 312. Р. 651–658.
16. Masamune A., Kikuta K., Satoh M. Rho kinase inhibitors block activation of pancreatic stellate cells. Br. J. Pharmacol. 2003. Vol. 140. Р. 1292–1302.
17. Masamune A., Satoh M., Kikuta K. Inhibition of p38 mitogen-activated protein kinase blocks activation of rat pancreatic stellate cells. Pharmacol. Exp. Ther. 2003. Vol. 304. Р. 8–14.
18. Mazzon E., Impellizzeri D., Di Paola R. Effects of mitogen-activated protein kinase signaling pathway inhibition on the development of cerulein-induced acute pancreatitis in mice. Pancreas. 2012. Vol. 41. Р. 560–570.
19. McCarroll J. A., Phillips P. A., Park S. Pancreatic stellate cell activation by ethanol and acetaldehyde: is it mediated by the mitogen-activated protein kinase signaling pathway? Pancreas. 2003. Vol. 27. Р. 150–160.
20. Phillips P. A., McCarroll J. A., Park S. Rat pancreatic stellate cells secrete matrix metalloproteinases: implications for extracellular matrix turnover. Gut. 2003. Vol. 52. Р. 275–282.
21. Prud’homme G. J. Pathobiology of transforming growth factor beta in cancer, fibrosis and immunologic disease, and therapeutic considerations. Lab. Invest. 2007. Vol. 87. Р.1077–1091.
22. Rockey D. C., Bell P. D., Hill J. A. Fibrosis — a common pathway to organ injury and failure. N. Engl. J. Med. 2015. Vol. 372. Р.1138–1149.
23. Shek F. W., Benyon R. C., Walker F. M. Expression of transforming growth factor-beta 1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis. Am. J. Pathol. 2002. Vol. 160. Р. 1787–1798.
24. Siegel R. L., Miller K. D., Jemal A. Cancer statistics, 2015. CA Cancer. J. Clin. 2015. Vol. 65. Р. 5–29.
25. Singh V. P., Saluja A. K., Bhagat L. Phosphatidylinositol 3-kinasedependent activation of trypsinogen modulates the severity of acute pancreatitis. J. Clin. Invest. 2001. Vol. 108. Р. 1387–1395.
26. Tahara H., Sato K., Yamazaki Y. The antagonist of the JAK-1/STAT-1 signaling pathway improves the severity Transforming growth factor-α activates pancreatic stellate cells and may be involved in matrix metalloproteinase-1 upregulation. Lab. Invest. 2013. Vol. 93. Р. 720–732.
27. Whitcomb D. C. Inflammation and Cancer V. Chronic pancreatitis and pancreatic cancer. Am. J. Physiol. Gastrointest. Liver Physiol. 2004. Vol. 287. Р. 315–319.
28. Xu P., Wang J., Yang Z. W. Regulatory roles of the PI3K/Akt signaling pathway in rats with severe acute pancreatitis. PLoS One. 2013. Vol. 8. P. e81767.
29. Yu J. H., Kim K. H., Kim H. Suppression of IL-1beta expression by the Jak 2 inhibitor AG490 in cerulein-stimulated pancreatic acinar cells. Biochem. Pharmacol. 2006. Vol. 72. Р.1555–1562.