{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T14:25:30Z","timestamp":1787495130747,"version":"build-2736575974"},"reference-count":34,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T00:00:00Z","timestamp":1636934400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K09277"],"award-info":[{"award-number":["20K09277"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acute pancreatitis is still a life-threatening disease without an evidenced therapeutic agent. In this study, the effect of chymase in acute pancreatitis and the possible effect of a chymase inhibitor in acute pancreatitis were investigated. Hamsters were subcutaneously administered 3.0 g\/kg of L-arginine to induce acute pancreatitis. Biological markers were measured 1, 2, and 8 h after L-arginine administration. To investigate the effect of a chymase inhibitor, a placebo (saline) or a chymase inhibitor TY-51469 (30 mg\/kg) was given 1 h after L-arginine administration. The survival rates were evaluated for 24 h after L-arginine administration. Significant increases in serum lipase levels and pancreatic neutrophil numbers were observed at 1 and 2 h after L-arginine administration, respectively. Significant increases in pancreatic neutrophil numbers were observed in the placebo-treated group, but they were significantly reduced in the TY-51469-treated group. A significant increase in the pancreatic tumor necrosis factor-\u03b1 mRNA level was observed in the placebo-treated group, but it disappeared in the TY-51469-treated group. Chymase activity significantly increased in the placebo-treated group, but it was significantly reduced by treatment with TY-51469. The survival rate significantly improved in the TY-51469-treated group. A chymase inhibitor may become a novel therapeutic agent for acute pancreatitis.<\/jats:p>","DOI":"10.3390\/ijms222212313","type":"journal-article","created":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T08:19:20Z","timestamp":1636964360000},"page":"12313","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Chymase as a Novel Therapeutic Target in Acute Pancreatitis"],"prefix":"10.3390","volume":"22","author":[{"given":"Toru","family":"Kuramoto","sequence":"first","affiliation":[{"name":"Department of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5820-8168","authenticated-orcid":false,"given":"Denan","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Innovative Medicine, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Komeda","sequence":"additional","affiliation":[{"name":"Department of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Taniguchi","sequence":"additional","affiliation":[{"name":"Translational Research Program, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumitoshi","family":"Hirokawa","sequence":"additional","affiliation":[{"name":"Department of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Takai","sequence":"additional","affiliation":[{"name":"Department of Innovative Medicine, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhisa","family":"Uchiyama","sequence":"additional","affiliation":[{"name":"Department of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1053\/j.gastro.2018.01.031","article-title":"Initial Medical Treatment of Acute Pancreatitis: American Gastroenterological Association Institute Technical Review","volume":"154","author":"Vege","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1002\/jhbp.259","article-title":"Japanese Guidelines for the Management of Acute Pancreatitis: Japanese Guidelines 2015","volume":"22","author":"Yokoe","year":"2015","journal-title":"J. Hepato-Biliary-Pancreat. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1053\/j.gastro.2018.01.032","article-title":"American Gastroenterological Association Institute Guideline on Initial Management of Acute Pancreatitis","volume":"154","author":"Crockett","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1038\/ajg.2013.218","article-title":"American College of Gastroenterology Guideline: Management of Acute Pancreatitis","volume":"108","author":"Tenner","year":"2013","journal-title":"Am. J. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3411","DOI":"10.3748\/wjg.v16.i27.3411","article-title":"Pancreatic and pulmonary mast cells activation during experimental acute pancreatitis","volume":"16","author":"Closa","year":"2010","journal-title":"World J. Gastroenterol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1385\/IJGC:29:3:163","article-title":"Effects of mast-cell stabilization in cerulein-induced acute pancreatitis in rats","volume":"29","author":"Celik","year":"2001","journal-title":"Int. J. Pancreatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1046\/j.1365-2168.2002.01991.x","article-title":"Role of mast cells in the development of pancreatitis-induced multiple organ dysfunction","volume":"89","author":"Dib","year":"2002","journal-title":"Br. J. Surg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1254\/jphs.11R11CP","article-title":"Multiple mechanisms for the action of chymase inhibitors","volume":"118","author":"Takai","year":"2012","journal-title":"J. Pharmacol. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1159\/000357684","article-title":"Chymase inhibition attenuates lipopolysaccharide\/d-galactosamine-induced acute liver failure in hamsters","volume":"93","author":"Imai","year":"2014","journal-title":"Pharmacology"},{"key":"ref_10","first-page":"207","article-title":"Marked species-difference in the vascular angiotensin II-forming pathways: Humans versus rodents","volume":"62","author":"Okunishi","year":"1993","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1124\/jpet.109.162933","article-title":"Significance of chymase-dependent matrix metalloproteinase-9 activation on indomethacin-induced small intestinal damages in rats","volume":"332","author":"Kakimoto","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11850","DOI":"10.1002\/jcp.27874","article-title":"Targeting peptidylarginine deiminase reduces neutrophil extracellular trap formation and tissue injury in severe acute pancreatitis","volume":"234","author":"Madhi","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1189\/jlb.0811443","article-title":"Neutrophil-derived matrix metalloproteinase-9 is a potent activator of trypsinogen in acinar cells in acute pancreatitis","volume":"91","author":"Awla","year":"2012","journal-title":"J. Leukoc. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1111\/j.1477-2574.2011.00408.x","article-title":"Review of experimental animal models of biliary acute pancreatitis and recent advances in basic research","volume":"14","author":"Wan","year":"2012","journal-title":"HPB"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"17324","DOI":"10.3748\/wjg.v20.i46.17324","article-title":"Oxidative stress and inflammatory signaling in cerulein pancreatitis","volume":"20","author":"Yu","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1093\/jn\/114.3.467","article-title":"Effects of injecting excess arginine on rat pancreas","volume":"114","author":"Mizunuma","year":"1984","journal-title":"J. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"28014","DOI":"10.1038\/srep28014","article-title":"Experimental models in syrian golden hamster replicate human acute pancreatitis","volume":"6","author":"Wang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/0024-3205(95)02328-3","article-title":"Purification and characterization of angiotensin II-generating chymase from hamster cheek pouch","volume":"58","author":"Takai","year":"1996","journal-title":"Life Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/S0009-8981(01)00379-5","article-title":"Different angiotensin II-forming pathways in human and rat vascular tissues","volume":"305","author":"Takai","year":"2001","journal-title":"Clin. Chim. Acta"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1007\/s10620-018-5036-1","article-title":"Anti-inflammatory and antioxidant effects of captopril compared to methylprednisolone in L-arginine-induced acute pancreatitis","volume":"63","author":"Khedr","year":"2018","journal-title":"Dig. Dis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1254\/jphs.09115FP","article-title":"Chymase inhibition provides pancreatic islet protection in hamsters with streptozotocin-induced diabetes","volume":"110","author":"Takai","year":"2009","journal-title":"J. Pharmacol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1016\/S0140-6736(03)13139-X","article-title":"Pancreatitis","volume":"361","author":"Mitchell","year":"2003","journal-title":"Lancet"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.cca.2007.10.004","article-title":"Chymase activates promatrix metalloproteinase-9 in human abdominal aortic aneurysm","volume":"388","author":"Furubayashi","year":"2008","journal-title":"Clin. Chim. Acta"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"222","DOI":"10.3109\/10409238.2013.770819","article-title":"Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): The next decade","volume":"48","author":"Vandooren","year":"2013","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/0003-9861(87)90098-1","article-title":"Measurement of the internal pH of mast cell granules using microvolumetric fluorescence and isotopic techniques","volume":"254","author":"Nemeth","year":"1987","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9017","DOI":"10.1073\/pnas.94.17.9017","article-title":"Chymase cleavage of stem cell factor yields a bioactive, soluble product","volume":"94","author":"Longley","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","first-page":"8","article-title":"Inhibition of TNF \u03b1 improves survival in an experimental model of acute pancreatitis","volume":"62","author":"Hughes","year":"1996","journal-title":"Am. Surg."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1006\/jsre.2001.6244","article-title":"Increased matrix metalloproteinase expression and activation following experimental acute pancreatitis","volume":"101","author":"Muhs","year":"2001","journal-title":"J. Surg. Res."},{"key":"ref_29","first-page":"1183","article-title":"Structural evaluation of plasma \u03b12-macroglobulin in acute pancreatitis","volume":"43","author":"Ramos","year":"2005","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1159\/000506985","article-title":"Novel insight into the in vivo function of mast cell chymase: Lessons from knockouts and inhibitors","volume":"12","author":"Pejler","year":"2020","journal-title":"J. Innate Immun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1124\/jpet.107.131946","article-title":"Role of chymase-dependent matrix metalloproteinase-9 activation in mice with dextran sodium sulfate-induced colitis","volume":"324","author":"Ishida","year":"2008","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Watase, K., Jin, D., Terai, K., Kanemiya, T., Nakakura, H., Shibahara, N., Arima, S., and Takai, S. (2020). Possible roles of periostin in the formation of hemodialysis vascular access stenosis after polytetrafluoroethylene graft implantation in dogs. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093251"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.jphs.2017.04.005","article-title":"Chymase inhibitor prevents the development and progression of non-alcoholic steatohepatitis in rats fed a high-fat and high-cholesterol diet","volume":"134","author":"Miyaoka","year":"2017","journal-title":"J. Pharmacol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1538\/expanim.17-0126","article-title":"A novel hamster nonalcoholic steatohepatitis model induced by a high-fat and high-cholesterol diet","volume":"67","author":"Miyaoka","year":"2018","journal-title":"Exp. Anim."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/22\/12313\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:30:19Z","timestamp":1760167819000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/22\/12313"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,15]]},"references-count":34,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222212313"],"URL":"https:\/\/doi.org\/10.3390\/ijms222212313","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,15]]}}}