Nintedanib Alleviates Chronic Pancreatitis by Inhibiting the Activation of Pancreatic Stellate Cells via the JAK/STAT3 and ERK1/2 Pathways.
Chronic pancreatitis
ERK1/2
JAK/STAT3
Nintedanib
Pancreatic fibrosis
Pancreatic stellate cells
Journal
Digestive diseases and sciences
ISSN: 1573-2568
Titre abrégé: Dig Dis Sci
Pays: United States
ID NLM: 7902782
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
received:
07
03
2023
accepted:
19
07
2023
medline:
24
8
2023
pubmed:
1
8
2023
entrez:
1
8
2023
Statut:
ppublish
Résumé
Nintedanib (Ninte) has been approved for the treatment of pulmonary fibrosis, and whether it can ameliorate chronic pancreatitis (CP) is unknown. This study was conducted to investigate the effect and molecular mechanism of Ninte on pancreatic fibrosis and inflammation in vivo and in vitro. 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. 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. These findings indicate that Ninte may be a potential anti-inflammatory and anti-fibrotic therapeutic agent for CP.
Sections du résumé
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.
Identifiants
pubmed: 37526905
doi: 10.1007/s10620-023-08052-7
pii: 10.1007/s10620-023-08052-7
doi:
Substances chimiques
nintedanib
G6HRD2P839
Ceruletide
888Y08971B
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3644-3659Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
Beyer G, Habtezion A, Werner J, Lerch MM, Mayerle J. Chronic pancreatitis. Lancet. 2020;396:499–512.
pubmed: 32798493
doi: 10.1016/S0140-6736(20)31318-0
Vege SS, Chari ST. Chronic Pancreatitis. N Engl J Med. 2022;386:869–878.
pubmed: 35235728
doi: 10.1056/NEJMcp1809396
Singh VK, Yadav D, Garg PK. Diagnosis and Management of Chronic Pancreatitis: A Review. JAMA. 2019;322:2422–2434.
doi: 10.1001/jama.2019.19411
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.
pubmed: 21728885
doi: 10.1089/ars.2011.4079
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.
pubmed: 26463405
doi: 10.1111/acer.12882
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.
pubmed: 32047557
pmcid: 6995390
doi: 10.7150/jca.38616
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.
pubmed: 17400536
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.
pubmed: 7768393
doi: 10.1016/0016-5085(95)90152-3
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.
pubmed: 16598747
doi: 10.1002/jcb.20906
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.
pubmed: 10653002
doi: 10.1038/labinvest.3780007
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.
pubmed: 15948243
pmcid: 4315992
doi: 10.3748/wjg.v11.i22.3385
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.
doi: 10.1016/j.bbrc.2018.04.176
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: 34422214
pmcid: 8378969
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.
pubmed: 18559524
doi: 10.1158/0008-5472.CAN-07-6307
Flaherty KR, Wells AU, Cottin V et al. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. N Engl J Med. 2019;381:1718–1727.
pubmed: 31566307
doi: 10.1056/NEJMoa1908681
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.
pubmed: 21992121
doi: 10.1056/NEJMoa1103690
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.
pubmed: 24836310
doi: 10.1056/NEJMoa1402584
Behr J, Günther A, Bonella F et al. German Guideline for Idiopathic Pulmonary Fibrosis - Update on Pharmacological Therapies 2017. Pneumologie. 2018;72:155–168.
pubmed: 29341047
doi: 10.1055/s-0043-123035
Homma S, Bando M, Azuma A et al. Japanese guideline for the treatment of idiopathic pulmonary fibrosis. Respir Investig. 2018;56:268–291.
pubmed: 29980444
doi: 10.1016/j.resinv.2018.03.003
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.
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.
pubmed: 28291245
pmcid: 5349608
doi: 10.1038/srep44545
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.
pubmed: 33614732
doi: 10.1159/000509670
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.
pubmed: 28646122
doi: 10.1042/CS20170134
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.
pubmed: 32678498
pmcid: 7520303
doi: 10.1111/jcmm.15498
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.
pubmed: 31356863
doi: 10.1016/j.phrs.2019.104357
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.
pubmed: 28930866
doi: 10.1097/MPA.0000000000000928
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.
pubmed: 15006556
doi: 10.1016/j.bcp.2003.11.013
Jones TE, Bellin MD, Yadav D et al. The histopathology of SPINK1-associated chronic pancreatitis. Pancreatology. 2020;20:1648–1655.
pubmed: 33097431
doi: 10.1016/j.pan.2020.10.030
Chowdhury P, Gupta P. Pathophysiology of alcoholic pancreatitis: an overview. World J Gastroenterol. 2006;12:7421–7427.
pubmed: 17167828
pmcid: 4087585
doi: 10.3748/wjg.v12.i46.7421
Wynn TA, Vannella KM. Macrophages in Tissue Repair, Regeneration, and Fibrosis. Immunity. 2016;44:450–462.
pubmed: 26982353
pmcid: 4794754
doi: 10.1016/j.immuni.2016.02.015
Apte MV, Haber PS, Applegate TL et al. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut. 1998;43:128–133.
pubmed: 9771417
pmcid: 1727174
doi: 10.1136/gut.43.1.128
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.
pubmed: 9679048
doi: 10.1016/S0016-5085(98)70209-4
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.
doi: 10.2535/ofaj1936.58.4-6_837
Apte M, Pirola RC, Wilson JS. Pancreatic stellate cell: physiologic role, role in fibrosis and cancer. Curr Opin Gastroenterol. 2015;31:416–423.
pubmed: 26125317
doi: 10.1097/MOG.0000000000000196
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.
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.
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.
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.
pubmed: 28496202
pmcid: 5431930
doi: 10.1038/s41598-017-01973-0
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.
pubmed: 31148248
doi: 10.1002/jcb.28722
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.
pubmed: 21625522
pmcid: 3098288
doi: 10.1371/journal.pone.0020188
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.
pubmed: 29405201
pmcid: 5858971
doi: 10.1038/nrclinonc.2018.8
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.
pubmed: 22233524
doi: 10.1111/j.1365-2443.2011.01575.x
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.
pubmed: 24726840
doi: 10.1016/j.cellsig.2014.04.003
Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature. 2001;410:37–40.
pubmed: 11242034
doi: 10.1038/35065000
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.
pubmed: 23147224
doi: 10.1038/labinvest.2012.156
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.
doi: 10.1124/jpet.104.067280
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.
pubmed: 22696236
pmcid: 3529643
doi: 10.1093/toxsci/kfs199
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.
pubmed: 11553624
doi: 10.1074/jbc.M106044200