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In several cell types, including pancreatic acinar, stellate cells (PaSCs) and immune cells, SOCE is mediated via channels composed primarily of Orai1 and stromal interaction molecule 1 (STIM1). CM4620, a selective Orai1 inhibitor, prevents Ca<jats:sup>2+<\/jats:sup> entry in acinar cells. This study investigates the effects of CM4620 in preventing or reducing acute pancreatitis features and severity. We tested the effects of CM4620 on SOCE, trypsinogen activation, acinar cell death, activation of NFAT and NF\u2010\u03baB, and inflammatory responses in <jats:italic>ex vivo<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> rodent models of acute pancreatitis and human pancreatic acini. We also examined whether CM4620 inhibited cytokine release in immune cells, fibro\u2010inflammatory responses in PaSCs, and oxidative burst in neutrophils, all cell types participating in pancreatitis. CM4620 administration to rats by <jats:sc>i.v.<\/jats:sc> infusion starting 30\u00a0min after induction of pancreatitis significantly diminished pancreatitis features including pancreatic oedema, acinar cell vacuolization, intrapancreatic trypsin activity, cell death signalling and acinar cell death. CM4620 also decreased myeloperoxidase activity and inflammatory cytokine expression in pancreas and lung tissues, fMLF peptide\u2010induced oxidative burst in human neutrophils, and cytokine production in human peripheral blood mononuclear cells (PBMCs) and rodent PaSCs, indicating that Orai1\/STIM1 channels participate in the inflammatory responses of these cell types during acute pancreatitis. These findings support pathological Ca<jats:sup>2+<\/jats:sup> entry\u2010mediated cell death and proinflammatory signalling as central mechanisms in acute pancreatitis pathobiology.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp277856","type":"journal-article","created":{"date-parts":[[2019,5,3]],"date-time":"2019-05-03T16:43:48Z","timestamp":1556901828000},"page":"3085-3105","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":126,"title":["The Orai Ca<sup>2+<\/sup> channel inhibitor CM4620 targets both parenchymal and immune cells to reduce inflammation in experimental acute pancreatitis"],"prefix":"10.1113","volume":"597","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3151-6002","authenticated-orcid":false,"given":"Richard T.","family":"Waldron","sequence":"first","affiliation":[{"name":"Cedars\u2010Sinai Medical Center  Los Angeles CA USA"},{"name":"Veterans Affairs Greater Los Angeles Healthcare System  Los Angeles CA USA"},{"name":"University of California  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yafeng","family":"Chen","sequence":"additional","affiliation":[{"name":"Cedars\u2010Sinai Medical Center  Los Angeles CA USA"},{"name":"Putuo Hospital Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung","family":"Pham","sequence":"additional","affiliation":[{"name":"Cedars\u2010Sinai Medical Center  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel","family":"Go","sequence":"additional","affiliation":[{"name":"Cedars\u2010Sinai Medical Center  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin\u2010Yuan","family":"Su","sequence":"additional","affiliation":[{"name":"Cedars\u2010Sinai Medical Center  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Hu","sequence":"additional","affiliation":[{"name":"Cedars\u2010Sinai Medical Center  Los Angeles CA USA"},{"name":"Department of Integrated Traditional Chinese and Western Medicine West China Hospital\/West China Medical School  Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wen","sequence":"additional","affiliation":[{"name":"University of Pittsburgh  Pittsburgh PA USA"},{"name":"UPMC Children's Hospital of Pittsburgh  Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sohail Z.","family":"Husain","sequence":"additional","affiliation":[{"name":"University of Pittsburgh  Pittsburgh PA USA"},{"name":"UPMC Children's Hospital of Pittsburgh  Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine A.","family":"Sugar","sequence":"additional","affiliation":[{"name":"University of California  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Roos","sequence":"additional","affiliation":[{"name":"CalciMedica Inc.  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