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Store-operated Ca2+ entry (SOCE) through ORAI1 channels in pancreatic acinar cells triggers acute pancreatitis, and ORAI1 inhibitors ameliorate experimental acute pancreatitis, but the role of ORAI1 in pancreatitis-associated acute lung injury has not been determined. Here, we showed mice with pancreas-specific deletion of Orai1 (Orai1\u0394Pdx1, \u223c70% reduction in the expression of Orai1) are protected against pancreatic tissue damage and immune cell infiltration, but not pancreatitis-associated acute lung injury, suggesting the involvement of unknown cells that may cause such injury through SOCE via ORAI1. Genetic (Orai1\u0394MRP8) or pharmacological inhibition of ORAI1 in murine and human neutrophils decreased Ca2+ influx and impaired chemotaxis, reactive oxygen species production, and neutrophil extracellular trap formation. Unlike pancreas-specific Orai1 deletion, mice with neutrophil-specific deletion of Orai1 (Orai1\u0394MRP8) were protected against pancreatitis- and sepsis-associated lung cytokine release and injury, but not pancreatic injury in experimental acute pancreatitis. These results define critical differences between contributions from different cell types to either pancreatic or systemic organ injury in acute pancreatitis. Our findings suggest that any therapy for acute pancreatitis that targets multiple rather than single cell types is more likely to be effective.<\/jats:p>","DOI":"10.1093\/function\/zqad061","type":"journal-article","created":{"date-parts":[[2023,10,21]],"date-time":"2023-10-21T09:13:57Z","timestamp":1697879637000},"source":"Crossref","is-referenced-by-count":13,"title":["Neutrophil-specific ORAI1 Calcium Channel Inhibition Reduces Pancreatitis-associated Acute Lung Injury"],"prefix":"10.1152","volume":"5","author":[{"given":"Mengya","family":"Niu","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences, Zhengzhou University , Zhengzhou 450001 , China"},{"name":"Department of Gastroenterology and Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 201600 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Biomarker Discovery and Validation, National Infrastructures for Translational Medicine (PUMCH), Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College , Beijing 100730 , China"},{"name":"Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College , Beijing 100730 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zengkai","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 201600 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 201600 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingpiao","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 201600 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juanjuan","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 201600 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College , Beijing 100730 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 201600 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 201600 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Pandol","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cedars-Sinai Medical Center , Los Angeles, CA 90048 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Sutton","sequence":"additional","affiliation":[{"name":"Liverpool Pancreatitis Research Group, Liverpool University Hospitals NHS Foundation Trust and Institute of Translational Medicine, University of Liverpool , Liverpool L69 3BX , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2621-0239","authenticated-orcid":false,"given":"Li","family":"Wen","sequence":"additional","affiliation":[{"name":"Center for Biomarker Discovery and Validation, National Infrastructures for Translational Medicine (PUMCH), Institute of Clinical Medicine, Peking Union Medical College Hospital, 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