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Nintedanib Alleviates Chronic Pancreatitis by Inhibiting the Activation of Pancreatic Stellate Cells via the JAK/STAT3 and ERK1/2 Pathways

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Abstract

Background

Nintedanib (Ninte) has been approved for the treatment of pulmonary fibrosis, and whether it can ameliorate chronic pancreatitis (CP) is unknown.

Aims

This study was conducted to investigate the effect and molecular mechanism of Ninte on pancreatic fibrosis and inflammation in vivo and in vitro.

Methods

The caerulein-induced CP model of murine was applied, and Ninte was orally administered. Pathological changes in pancreas were evaluated using hematoxylin & eosin, Sirius Red, Masson’s trichrome, and anti-Ki-67 staining. For in vitro studies, the effects of Ninte on cell viability, apoptosis, and migration of pancreatic stellate cells (PSCs) were determined by CCK-8, flow cytometry, and wound healing assays, respectively. The potential molecular mechanisms of the effects of Ninte on PSCs were analyzed by RNA-Seq and verified at the gene expression and protein activity levels by qRT-PCR and Western Blot.

Results

Ninte significantly alleviated the weight loss in mice with caerulein-induced CP and simultaneously attenuated the pancreatic damage, as evidenced by reduced acinar atrophy, collagen deposition, infiltration of inflammatory cells, and inhibited cell proliferation/regeneration. Besides, Ninte markedly suppressed the transcription of fibrogenic and proinflammatory genes in pancreatic tissues. Further in vitro studies showed that Ninte significantly inhibited the transcription and protein expression of genes corresponding to fibrogenesis and proliferation in PSCs. The results of RNA-Seq analysis and subsequent verification assays indicated that Ninte inhibited the activation and proliferation of PSCs via the JAK/STAT3 and ERK1/2 pathways.

Conclusions

These findings indicate that Ninte may be a potential anti-inflammatory and anti-fibrotic therapeutic agent for CP.

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References

  1. Beyer G, Habtezion A, Werner J, Lerch MM, Mayerle J. Chronic pancreatitis. Lancet. 2020;396:499–512.

    Article  PubMed  Google Scholar 

  2. Vege SS, Chari ST. Chronic Pancreatitis. N Engl J Med. 2022;386:869–878.

    Article  PubMed  Google Scholar 

  3. Singh VK, Yadav D, Garg PK. Diagnosis and Management of Chronic Pancreatitis: A Review. JAMA. 2019;322:2422–2434.

    Article  CAS  Google Scholar 

  4. Apte M, Pirola R, Wilson J. The fibrosis of chronic pancreatitis: new insights into the role of pancreatic stellate cells. Antioxid Redox Signal. 2011;15:2711–2722.

    Article  CAS  PubMed  Google Scholar 

  5. Lee AT, Xu Z, Pothula SP et al. Alcohol and cigarette smoke components activate human pancreatic stellate cells: implications for the progression of chronic pancreatitis. Alcohol Clin Exp Res. 2015;39:2123–2133.

    Article  CAS  PubMed  Google Scholar 

  6. Jin G, Hong W, Guo Y, Bai Y, Chen B. Molecular Mechanism of Pancreatic Stellate Cells Activation in Chronic Pancreatitis and Pancreatic Cancer. J Cancer. 2020;11:1505–1515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Farkas G Jr, Hofner P, Balog A et al. Relevance of transforming growth factor-beta1, interleukin-8, and tumor necrosis factor-alpha polymorphisms in patients with chronic pancreatitis. Eur Cytokine Netw. 2007;18:31–37.

    CAS  PubMed  Google Scholar 

  8. van Laethem JL, Deviere J, Resibois A et al. Localization of transforming growth factor beta 1 and its latent binding protein in human chronic pancreatitis. Gastroenterology. 1995;108:1873–1881.

    Article  PubMed  Google Scholar 

  9. Aoki H, Ohnishi H, Hama K et al. Existence of autocrine loop between interleukin-6 and transforming growth factor-beta1 in activated rat pancreatic stellate cells. J Cell Biochem. 2006;99:221–228.

    Article  CAS  PubMed  Google Scholar 

  10. Luttenberger T, Schmid-Kotsas A, Menke A et al. Platelet-derived growth factors stimulate proliferation and extracellular matrix synthesis of pancreatic stellate cells: implications in pathogenesis of pancreas fibrosis. Lab Invest. 2000;80:47–55.

    Article  CAS  PubMed  Google Scholar 

  11. Masamune A, Satoh M, Kikuta K, Suzuki N, Shimosegawa T. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Xu XF, Liu F, Xin JQ et al. Respective roles of the mitogen-activated protein kinase (MAPK) family members in pancreatic stellate cell activation induced by transforming growth factor-β1 (TGF-β1). Biochem Biophys Res Commun. 2018;501:365–373.

    Article  CAS  Google Scholar 

  13. Zhang Q, Zhao C, Zhang L et al. Escin Sodium Improves the Prognosis of Acute Pancreatitis via Promoting Cell Apoptosis by Suppression of the ERK/STAT3 Signaling Pathway. Oxid Med Cell Longev. 2021;2021:9921839.

    PubMed  PubMed Central  Google Scholar 

  14. Hilberg F, Roth GJ, Krssak M et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008;68:4774–4782.

    Article  CAS  PubMed  Google Scholar 

  15. Flaherty KR, Wells AU, Cottin V et al. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. N Engl J Med. 2019;381:1718–1727.

    Article  CAS  PubMed  Google Scholar 

  16. Richeldi L, Costabel U, Selman M et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011;365:1079–1087.

    Article  CAS  PubMed  Google Scholar 

  17. Richeldi L, du Bois RM, Raghu G et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2071–2082.

    Article  PubMed  Google Scholar 

  18. Behr J, Günther A, Bonella F et al. German Guideline for Idiopathic Pulmonary Fibrosis - Update on Pharmacological Therapies 2017. Pneumologie. 2018;72:155–168.

    Article  PubMed  Google Scholar 

  19. Homma S, Bando M, Azuma A et al. Japanese guideline for the treatment of idiopathic pulmonary fibrosis. Respir Investig. 2018;56:268–291.

    Article  PubMed  Google Scholar 

  20. Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2022;205:e18–18e47.

  21. Öztürk Akcora B, Storm G, Prakash J, Bansal R. Tyrosine kinase inhibitor BIBF1120 ameliorates inflammation, angiogenesis and fibrosis in CCl4-induced liver fibrogenesis mouse model. Sci Rep. 2017;7:44545.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Feng L, Li W, Chao Y et al. Synergistic Inhibition of Renal Fibrosis by Nintedanib and Gefitinib in a Murine Model of Obstructive Nephropathy. Kidney Dis (Basel). 2021;7:34–49.

    Article  PubMed  Google Scholar 

  23. Liu F, Wang L, Qi H et al. Nintedanib, a triple tyrosine kinase inhibitor, attenuates renal fibrosis in chronic kidney disease. Clin Sci (Lond). 2017;131:2125–2143.

    Article  CAS  PubMed  Google Scholar 

  24. Wang LJ, He L, Hao L et al. Isoliquiritigenin ameliorates caerulein-induced chronic pancreatitis by inhibiting the activation of PSCs and pancreatic infiltration of macrophages. J Cell Mol Med. 2020;24:9667–9681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zeng XP, Wang LJ, Guo HL et al. Dasatinib ameliorates chronic pancreatitis induced by caerulein via anti-fibrotic and anti-inflammatory mechanism. Pharmacol Res. 2019;147:104357.

    Article  CAS  PubMed  Google Scholar 

  26. Zhang GX, Wang MX, Nie W, Liu DW, Zhang Y, Liu HB. P2X7R Blockade Prevents NLRP3 Inflammasome Activation and Pancreatic Fibrosis in a Mouse Model of Chronic Pancreatitis. Pancreas. 2017;46:1327–1335.

    Article  CAS  PubMed  Google Scholar 

  27. McCarroll JA, Phillips PA, Kumar RK et al. Pancreatic stellate cell migration: role of the phosphatidylinositol 3-kinase(PI3-kinase) pathway. Biochem Pharmacol. 2004;67:1215–1225.

    Article  CAS  PubMed  Google Scholar 

  28. Jones TE, Bellin MD, Yadav D et al. The histopathology of SPINK1-associated chronic pancreatitis. Pancreatology. 2020;20:1648–1655.

    Article  CAS  PubMed  Google Scholar 

  29. Chowdhury P, Gupta P. Pathophysiology of alcoholic pancreatitis: an overview. World J Gastroenterol. 2006;12:7421–7427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wynn TA, Vannella KM. Macrophages in Tissue Repair, Regeneration, and Fibrosis. Immunity. 2016;44:450–462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Apte MV, Haber PS, Applegate TL et al. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut. 1998;43:128–133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bachem MG, Schneider E, Gross H et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology. 1998;115:421–432.

    Article  CAS  PubMed  Google Scholar 

  33. Watari N, Hotta Y, Mabuchi Y. Morphological studies on a vitamin A-storing cell and its complex with macrophage observed in mouse pancreatic tissues following excess vitamin A administration. Okajimas Folia Anat Jpn. 1982;58:837–858.

    Article  CAS  Google Scholar 

  34. Apte M, Pirola RC, Wilson JS. Pancreatic stellate cell: physiologic role, role in fibrosis and cancer. Curr Opin Gastroenterol. 2015;31:416–423.

    Article  CAS  PubMed  Google Scholar 

  35. C L, A C, L V, et al. Common molecular pathways targeted by nintedanib in cancer and IPF: A bioinformatic study. Pulm Pharmacol Ther. 2020;64:101941.

  36. Chen WC, Chen NJ, Chen HP, et al. Nintedanib Reduces Neutrophil Chemotaxis via Activating GRK2 in Bleomycin-Induced Pulmonary Fibrosis. Int J Mol Sci. 2020;21.

  37. Kasembeli MM, Bharadwaj U, Robinson P, Tweardy DJ. Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment. Int J Mol Sci. 2018;19.

  38. Komar HM, Serpa G, Kerscher C et al. Inhibition of Jak/STAT signaling reduces the activation of pancreatic stellate cells in vitro and limits caerulein-induced chronic pancreatitis in vivo. Sci Rep. 2017;7:1787.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Zhao SQ, Shen ZC, Gao BF, Han P. microRNA-206 overexpression inhibits epithelial-mesenchymal transition and glomerulosclerosis in rats with chronic kidney disease by inhibiting JAK/STAT signaling pathway. J Cell Biochem. 2019;120:14604–14617.

    Article  CAS  PubMed  Google Scholar 

  40. Cimica V, Chen HC, Iyer JK, Reich NC. Dynamics of the STAT3 transcription factor: nuclear import dependent on Ran and importin-β1. PLoS One. 2011;6:e20188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Johnson DE, O’Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 2018;15:234–248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wakahara R, Kunimoto H, Tanino K et al. Phospho-Ser727 of STAT3 regulates STAT3 activity by enhancing dephosphorylation of phospho-Tyr705 largely through TC45. Genes Cells. 2012;17:132–145.

    Article  CAS  PubMed  Google Scholar 

  43. Mandal T, Bhowmik A, Chatterjee A, Chatterjee U, Chatterjee S, Ghosh MK. Reduced phosphorylation of Stat3 at Ser-727 mediated by casein kinase 2 - protein phosphatase 2A enhances Stat3 Tyr-705 induced tumorigenic potential of glioma cells. Cell Signal. 2014;26:1725–1734.

    Article  CAS  PubMed  Google Scholar 

  44. Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature. 2001;410:37–40.

    Article  CAS  PubMed  Google Scholar 

  45. Uchida M, Ito T, Nakamura T et al. ERK pathway and sheddases play an essential role in ethanol-induced CX3CL1 release in pancreatic stellate cells. Lab Invest. 2013;93:41–53.

    Article  CAS  PubMed  Google Scholar 

  46. Masamune A, Kikuta K, Suzuki N, Satoh M, Satoh K, Shimosegawa T. A c-Jun NH2-terminal kinase inhibitor SP600125 (anthra[1,9-cd]pyrazole-6 (2H)-one) blocks activation of pancreatic stellate cells. J Pharmacol Exp Ther. 2004;310:520–527.

    Article  CAS  Google Scholar 

  47. Liu J, Chen B, Lu Y, Guan Y, Chen F. JNK-dependent Stat3 phosphorylation contributes to Akt activation in response to arsenic exposure. Toxicol Sci. 2012;129:363–371.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang Y, Liu G, Dong Z. MSK1 and JNKs mediate phosphorylation of STAT3 in UVA-irradiated mouse epidermal JB6 cells. J Biol Chem. 2001;276:42534–42542.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

This study was supported by the National Natural Science Foundation of China [Grant No. 82070664 (LHH), 82270679 (LHH), 31600620 (LJW)].

Author information

Author notes

  1. Chao Han, Li-Juan Wang, Zhi-Qi Dong, and Peng-Yuan Wang have contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China

    Chao Han, Li-Juan Wang, Peng-Yuan Wang, Yan-Wei Lv, Dan Wang & Liang-Hao Hu

  2. The Hospital of 91876 Troops of Chinese People’s Liberation Army, Qinhuangdao, 066299, Hebei, China

    Chao Han

  3. Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China

    Li-Juan Wang, Peng-Yuan Wang, Yan-Wei Lv & Dan Wang

  4. Department of Gastroenterology, Shanghai Fourth People’s Hospital, Tongji University School of Medicine, Shanghai, 200434, China

    Zhi-Qi Dong

  5. National Key Laboratory of Immunity and Inflammation, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China

    Liang-Hao Hu

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Contributions

CH, L-JW, Z-QD, and P-YW participated in the acquisition, analysis, and interpretation of data, as well as manuscript drafting and revision; Y-WL and DW participated in manuscript revision; L-JW and L-HH contributed to the conception, design, data interpretation, and manuscript revision. All authors revised the manuscript critically and approved the final version.

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Correspondence to Liang-Hao Hu.

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Han, C., Wang, LJ., Dong, ZQ. et al. Nintedanib Alleviates Chronic Pancreatitis by Inhibiting the Activation of Pancreatic Stellate Cells via the JAK/STAT3 and ERK1/2 Pathways. Dig Dis Sci 68, 3644–3659 (2023). https://doi.org/10.1007/s10620-023-08052-7

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