Skip to main content

Novel and Experimental Therapies in Chronic Pancreatitis

Digestive Diseases and Sciences volume 62, pages 1751–1761 (2017)Cite this article

Abstract

Chronic pancreatitis (CP) is a progressive inflammatory disease of the pancreas. The currently available treatment of CP is aimed at controlling symptoms and managing complications. Unfortunately, no specific treatment is available to halt the progression of the disease process because the pathophysiological perturbations in CP are not well understood. In this review, we discuss various therapeutic targets and investigational agents acting on these targets. Among these, therapies modulating immune cells and those acting on pancreatic stellate cells appear promising and may translate into clinical benefit in near future. However, these experimental therapies are mostly in animal models and they do not recapitulate all aspects of human disease. Still they may be beneficial in developing effective therapeutic modalities to curb inflammation in chronic pancreatitis.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Whitcomb DC, Frulloni L, Garg P, Greer JB, et al. Chronic pancreatitis: an international draft consensus proposal for a new mechanistic definition. Pancreatology. 2016;16:218–224.

    Article  PubMed  Google Scholar 

  2. The Copenhagen Pancreatic Study Group. An interim report from a prospective epidemiological multicentre study. Scand J Gastroenterol. 1981;16:305–312.

    Article  Google Scholar 

  3. Robles-Diaz G, Vargas F, Uscanga L, Fernandez-del Castillo C. Chronic pancreatitis in Mexico City. Pancreas. 1990;5:479–483.

    Article  CAS  PubMed  Google Scholar 

  4. Garg PK, Tandon RK. Survey on chronic pancreatitis in the Asia-Pacific region. J Gastroenterol Hepatol. 2004;19:998–1004.

    Article  PubMed  Google Scholar 

  5. Lin Y, Tamakoshi A, Matsuno S, Takeda K, et al. Nationwide epidemiological survey of chronic pancreatitis in Japan. J Gastroenterol. 2000;35:136–141.

    Article  CAS  PubMed  Google Scholar 

  6. Balaji LN, Tandon RK, Tandon BN, Banks A. Prevalence and clinical features of chronic pancreatitis in southern India. Int J Pancreatol. 1994;15:29–34.

    CAS  PubMed  Google Scholar 

  7. Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology. 2001;120:682–707.

    Article  CAS  PubMed  Google Scholar 

  8. Tandon RK, Sato N, Garg PK. Chronic pancreatitis: Asia-Pacific consensus report. J Gastroenterol Hepatol. 2002;17:508–518.

    Article  PubMed  Google Scholar 

  9. Rösch T, Daniel S, Scholz M, Huibregtse K, European Society of Gastrointestinal Endoscopy Research Group. Endoscopic treatment of chronic pancreatitis: a multicenter study of 1000 patients with long-term follow-up. Endoscopy. 2002;34:765–771.

    Article  PubMed  Google Scholar 

  10. Cahen DL, Gouma DJ, Nio Y, Rauws EJ, et al. Endoscopic versus surgical drainage of the pancreatic duct in chronic pancreatitis. N Engl J Med. 2007;356:676–684.

    Article  CAS  PubMed  Google Scholar 

  11. Xue J, Sharma V, Habtezion A. Immune cells and immune-based therapy in pancreatitis. Immunol Res. 2014;58:378–386.

    Article  CAS  PubMed  Google Scholar 

  12. Zimnoch L, Szynaka B, Puchalski Z. Mast cells and pancreatic stellate cells in chronic pancreatitis with differently intensified fibrosis. Hepatogastroenterology. 2002;49:1135–1138.

    PubMed  Google Scholar 

  13. Schmitz-Winnenthal H, Pietsch DH, Schimmack S, Bonertz A, et al. Chronic pancreatitis is associated with disease-specific regulatory T-cell responses. Gastroenterology. 2010;138:1178–1188.

    Article  PubMed  Google Scholar 

  14. Grundsten M, Liu GZ, Permert J, Hjeilmstrom P, Tsai JA. Increased central memory T cells in patients with chronic pancreatitis. Pancreatology. 2005;5:177–182.

    Article  PubMed  Google Scholar 

  15. Marrache F, Pendyala S, Bhagal G, Betz KS, Song Z, Wang TC. Role of bone marrow derived cells in experimental chronic pancreatitis. Gut. 2008;57:1113–1120.

    Article  CAS  PubMed  Google Scholar 

  16. Lardon J, Rooman I, Bouwens L. Nestin expression in pancreatic stellate cells and angiogenic endothelial cells. Histochem Cell Biol. 2002;117:535–540.

    Article  CAS  PubMed  Google Scholar 

  17. Omary MB, Lugea A, Lowe AW, Pandol SJ. The pancreatic stellate cell: a star on the rise in pancreatic diseases. J Clin Invest. 2007;117:50–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Xue J, Sharma V, Hsieh MH, Chawla M, et al. Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis. Nature communications. 2015;6:7158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Baumert J-T, Sparmann G, Emmrich J, Stefan L, Jaster R. Inhibitory effect of interferons on pancreatic stellate cell activation. World J Gastroenterol. 2006;12:896–901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhao HF, Ito T, Gibo J, Kawabe K, et al. Anti-monocyte chemoattractant protein 1 gene therapy attenuates experimental chronic pancreatitis induced by dibutyltin dichloride in rats. Gut. 2005;54:1759–1767.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Su SB, Xie MJ, Sawabu N, Motoo Y. Supressive effect of herbal medicine Saiko-Keishi-to on acinar cell apoptosis in rat spontaneous chronic pancreatitis. Pancreotology. 2007;7:28–36.

    Article  Google Scholar 

  22. Su SB, Motoo Y, Xie MJ, Taga H, Sawabu N. Antifibrotic effect of herbal medicine Saiko-Keishi-to (TJ-10) on chronic pancreatitis in the WBN/KOB rat. Pancreas. 2001;22:8–17.

    Article  CAS  PubMed  Google Scholar 

  23. Masamune A, Suzuki N, Kikuta K, Satoh M, Satoh K, Shimosewaga T. Curcumin blocks activation of pancreatic stellate cells. J Cell Biochem. 2006;95:1080–1093.

    Article  Google Scholar 

  24. Wei L, Yamamoto M, Harada M, Otsuki M. Treatment with pravastatin attenuates progression of chronic pancreatitis in rat. Lab Invest. 2011;91:872–884.

    Article  CAS  PubMed  Google Scholar 

  25. Jaster R, Brock P, Sparmann G, Emmrich J, Liebe S. Inhibition of pancreatic stellate cell activation by the hydroxymethylglutaryl coenzyme A reductase inhibitor Lovastatin. Biochem Pharmacol. 2003;65:1295–1303.

    Article  CAS  PubMed  Google Scholar 

  26. Lin WR, Yen TH, Lim SN, Perng MD, et al. Granulocyte colony-stimulating factor reduces fibrosis in a mouse model of chronic pancreatitis. PLoS ONE. 2014;9:e116229. doi:10.1371/journal.pone.0116229.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Kuno A, Yamada T, Masuda K, Ogawa K, et al. Angiotensin-converting enzyme inhibitor attenuates pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori rats. Gastroenterology. 2003;124:1010–1019.

    Article  CAS  PubMed  Google Scholar 

  28. Skipworth JR, Nijmeijer RM, van Santvoort HC, Besselink MG, et al. The effect of renin angiotensin system genetic variants in acute pancreatitis. Ann Surg. 2015;261:180–188.

    Article  PubMed  Google Scholar 

  29. Madro A, Kurzepa J, Celinski K, Slomka M, et al. Effects of renin-angiotensin system inhibitors on fibrosis in patients with alcoholic chronic pancreatitis. J Physiol Pharmacol. 2016;67:103–110.

    CAS  PubMed  Google Scholar 

  30. Tamura Y, Hirado M, Okamura K, Minato Y, Fujii S. Synthetic inhibitors of trypsin, plasmin, kallikrein, thrombin, C1r, and C1 esterase. Biochim Biophys Acta Enzymol. 1977;484:417–422.

    Article  CAS  Google Scholar 

  31. Gibo J, Ito T, Kawabe K, Hisano T, et al. Camostat mesilate attenuates pancreatic fibrosis via inhibition of monocytes and pancreatic stellate cells activity. Lab Inv. 2005;85:75–89.

    Article  CAS  Google Scholar 

  32. Otsuki M, Okhi A, Okabayashi Y, Suehiro I, Baba S. Effect of synthetic protease inhibitor camostat on pancreatic exocrine function in rats. Pancreas. 1987;2:164–169.

    Article  CAS  PubMed  Google Scholar 

  33. Kisfalvi K, Papp M, Friess H, Buchler M, Goracz UG. Beneficial effects of oral administration of camostat on cerulein-induced pancreatitis in rats. Dig Dis Sci. 1995;40:546–547.

    Article  CAS  PubMed  Google Scholar 

  34. Ito T, Otsuki M, Itoi T, Shimosegawa T, et al. Pancreatic diabetes in a follow-up survey of chronic pancreatitis in Japan. J Gastroenterol. 2007;42:291–297.

    Article  PubMed  Google Scholar 

  35. Jaster R, Hilgendorf I, Fitzner B, Brock P, et al. Regulation of pancreatic stellate cell function in vitro: biological and molecular effects of all-trans retinoic acid. Biochem Pharmacol. 2003;66:633–641.

    Article  CAS  PubMed  Google Scholar 

  36. Li XC, Lu XL, Chen HH. α-Tocopherol treatment ameliorates chronic pancreatitis in an experimental rat model induced by trinitrobenzene sulfonic acid. Pancreatology. 2011;11:5–11.

    Article  CAS  PubMed  Google Scholar 

  37. Yoo BM, Oh TY, Kim YB, Yeo Y, et al. Novel antioxidant ameliorates the fibrosis and inflammation of cerulein-induced chronic pancreatitis in a mouse model. Pancreatology. 2005;5:165–176.

    Article  CAS  PubMed  Google Scholar 

  38. Mrazek AA, Porro LJ, Bhatia V, Falzon M, et al. Apigenin inhibits pancreatic stellate cell activity in pancreatitis. J Surg Res. 2015;196:8–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Suzuki N, Masamune A, Kikuta K, Watanabe T, Satoh K, Shimosegawa K. Ellagic acid inhibits pancreatic fibrosis in male Wistar Bonn/Kobori rats. Dig Dis Sci. 2009;54:802–810.

    Article  CAS  PubMed  Google Scholar 

  40. Masamune A, Kikuta K, Satoh M, Suzuki N, Shimosewaga T. Green tea polyphenol epigallocatechin-3-gallate blocks PDGF-induced proliferation and migration of rat pancreatic stellate cells. World J Gastroenterol. 2005;11:3368–3374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Asaumi H, Wantabe S, Taguchi M, et al. Green tea polyphenol (-) -epigallocatechin-3-gallate inhibits ethanol induced activation of pancreatic stellate cells. Eur J Clin Invest. 2006;36:113–122.

    Article  CAS  PubMed  Google Scholar 

  42. Jaster R, Sparmann G, Emmrich J, Liebe S. Extracellular signal regulated kinases are key mediators of mitogenic signals in rat pancreatic stellate cells. Gut. 2002;51:579–584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lin Z, Zheng LC, Zhang HZ, Tsang SW, Bian ZX. Antifibrotic effects of phenolic compounds on pancreatic stellate cells. BMC Complement Altern Med. 2015;15:259.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Zion O, Genin O, Kawada N, Yoshizato K, et al. Inhibition of transforming growth factor beta signaling by halofuginone as a modality for pancreas fibrosis prevention. Pancreas. 2009;38:427–435.

    Article  CAS  PubMed  Google Scholar 

  45. Niina Y, Ito T, Oono T, Nakamura T, Fujimori N, 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.

    Article  CAS  PubMed  Google Scholar 

  46. Reding T, Bimler D, Perren A, Sun LK, 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;55:1165–1173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wei L, Yamamoto M, Harada M, Otsuki M. Treatment with pravastatin attenuates progression of chronic pancreatitis in rat. Lab Inv. 2011;91:872–884.

    Article  CAS  Google Scholar 

  48. Zhou CH, Lin-Li, Zhu XY, Wen-Tang, et al. Protective effects of edaravone on experimental chronic pancreatitis induced by dibutyltin dichloride in rats. Pancreatology. 2013;13:125–132.

    Article  CAS  PubMed  Google Scholar 

  49. Yang T, Liang Y, Lin Q, Liu J, et al. miR-29 mediates TGF β1-induced extracellular matrix synthesis through activation of PI3K-AKT pathway in human lung fibroblasts. J Cell Biochem. 2013;114:1336–1342.

    Article  CAS  PubMed  Google Scholar 

  50. Xiong M, Jiang L, Zhou Y, Qiu W, et al. The miR- 200 family regulates TGF-b1-induced renal tubular epithelial to mesenchymal transition through Smad pathway by targeting ZEB1 and ZEB2 expression. Am J Physiol Renal Physiol. 2012;302:F369–F379.

    Article  CAS  PubMed  Google Scholar 

  51. Zhu H, Luo H, Li Y, Zhou Y, et al. MicroRNA-21 in scleroderma fibrosis and its function in TGF-beta-regulated fibrosis-related genes expression. J Clin Immunol. 2013;33:1100–1109.

    Article  CAS  PubMed  Google Scholar 

  52. Zarjou A, Yang S, Abraham E, Agarwal A, Liu G. Identification of a micro RNA signature in renal fibrosis: role of miR-21. Am J Physiol Renal Physiol. 2011;301:F793–F801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chan LK, Gerstenlauer M, Konukiewitz B, Steiger K, et al. Epithelial NEMO/IKKγ limits fibrosis and promotes regeneration during pancreatitis. Gut 2016. doi:10.1136/gutjnl-2015-311028.

  54. Midha S, Hasan A, Dhingra R, Garg PK. Long-term pain relief with optimized medical including antioxidants and step-up interventional therapy in patients with chronic pancreatitis. J Gastroenterol Hepatol. 2016;32:270–277. doi:10.1111/jgh.13410.

    Google Scholar 

  55. Garg PK. Antioxidants for chronic pancreatitis: reasons for disappointing results despite sound principles. Gastroenterology. 2013;144:e19–e20.

    Article  PubMed  Google Scholar 

  56. Tang Y, Laio Y, Kawaguchi-Sakita N, Raut V, et al. Sinisan, a traditional Chinese medicine, attenuates experimental chronic pancreatitis induced by trinitrobenzene sulfonic acid in rats. J Hepatobiliary Pancreat Sci. 2011;18:551–558.

    Article  PubMed  Google Scholar 

  57. Shiratori K, Takeuchi T, Satake K, Matsuno S. Clinical evaluation of oral administration of a cholecystokinin A receptor antagonist (loxiglumide) to patients with acute, painful attacks of chronic pancreatitis: a multicenter dose response study in Japan. Pancreas. 2002;25:e15.

    Article  Google Scholar 

  58. Levenick JM, Andrews CL, Purich ED, Gordon SR, Gardner TB. A phase II trial of human secretin infusion for refractory type B pain in chronic pancreatitis. Pancreas. 2013;42:596–600.

    Article  CAS  PubMed  Google Scholar 

  59. Zhang L, Kline RH, McNearney TA, Johnson MP, Westlund KN. Cannabinoid receptor 2 agonist attenuates pain related behavior in rats with chronic alcohol/high fat diet induced pancreatitis. Mol Pain. 2014;10:66.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Wang Y, Li Y, Wang L, Kang Y, et al. Tanshinone IIA attenuates chronic pancreatitis- induced pain in rats via downregulation of HMGB1 and TRL4 expression in the spinal cord. Pain Phys. 2015;18:E615–E628.

    Google Scholar 

  61. Ceppa E, Cattaruzza F, Lyo V, Amadesi S, et al. Transient receptor potential ion channels V4 and A1 contribute to pancreatitis pain in mice. Am J Physiol Gastrointest Liver Physiol. 2010;299:G556–G571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zhang LP, Ma F, Abshire SM, Westlund KN. Prolonged high fat/alcohol exposure increases TRPV4 and its functional responses in pancreatic stellate cells. Am J Physiol Regul Integr Comp Physiol. 2013;304:R702–R711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhang LP, Kline RH, Deevska IG, Ma F, et al. Alcohol and high fat induced chronic pancreatitis: TRPV4 antagonist reduces hypersensitivity. Neuroscience. 2015;311:166–179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kapural L, Cywinski JB, Sparks DA. Spinal cord stimulation for visceral pain from chronic pancreatitis. Neuromodulation. 2011;14:423–427.

    Article  PubMed  Google Scholar 

  65. Midha S, Khajuria R, Shastri S, Kabra M, Garg PK. Idiopathic chronic pancreatitis in India: phenotypic characterization and strong genetic susceptibility due to SPINK1 and CFTR gene mutations. Gut. 2010;59:800–807.

    Article  CAS  PubMed  Google Scholar 

  66. Van Goor F, Hadida S, Grootenhuis PD, Burton B, et al. Correction of the F508delCFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci USA. 2011;108:18843–18848.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Jih KY, Hwang TC. Vx-770 potentiates CFTR function by promoting decoupling between the gating cycle and ATP hydrolysis cycle. Proc Natl Acad Sci USA. 2013;110:4404–4409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hayes D Jr, McCoy KS, Sheikh SI. Resolution of cystic fibrosis-related diabetes with ivacaftor therapy. Am J Respir Crit Care Med. 2014;190:590–591.

    Article  PubMed  Google Scholar 

  69. Bellin MD, Laguna T, Leschyshyn J, Regelmann W, et al. Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small pilot study. Pediatr Diabetes. 2013;14:417–421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Welch EM, Barton ER, Zhuo J, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007;447:87–91.

    Article  CAS  PubMed  Google Scholar 

  71. Alton EW, Armstrong DK, Ashby D, Bayfield KJ, et al. UK Cystic Fibrosis Gene Therapy Consortium. Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebocontrolled, phase 2b trial. Lancet Respir Med. 2015;3:684–691.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Zhou CH, Li ML, Qin AL, Lv SX, et al. Reduction of fibrosis in dibutyltin dichloride-induced chronic pancreatitis using rat umbilical mesenchymal stem cells from Wharton’s jelly. Pancreas. 2013;42:1291–1302.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors acknowledge that the figures of the article were assisted by Mr. Sanjay Saini, who is not employed by any corporate agency.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India

    Soumya Jagannath & Pramod Kumar Garg

Authors
  1. Soumya Jagannath
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pramod Kumar Garg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pramod Kumar Garg.

Ethics declarations

Conflict of interest

The authors disclose no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Jagannath, S., Garg, P.K. Novel and Experimental Therapies in Chronic Pancreatitis. Dig Dis Sci 62, 1751–1761 (2017). https://doi.org/10.1007/s10620-017-4604-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-017-4604-0

Keywords

  • Chronic pancreatitis
  • Pancreatic stellate cells
  • Immune system
  • Experimental therapy