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Neutrophils can release DNA and granular proteins to form cytotoxic neutrophil extracellular traps (NETs), which promotes bystander tissue injury. However, whether NETs are responsible for the remote ALI after intestinal I\/R and the mechanisms underlying the dissemination of harmful gut-derived mediators to the lungs are unknown. In the C57BL\/6J mouse intestinal I\/R model, DNase I\u2013mediated degradation and protein arginine deiminase 4 (PAD4) inhibitor\u2013mediated inhibition of NET treatments reduced NET formation, tissue inflammation, and pathological injury in the lung. High-mobility group protein B1 (HMGB1) blocking prevented NET formation and protected against tissue inflammation, as well as reduced cell apoptosis and improved survival rate. Moreover, recombinant human HMGB1 administration further drives NETs and concurrent tissue toxic injury, which in turn can be reversed by neutrophil deletion via anti-Ly6G Ab i.p. injection. Furthermore, global MyD88 deficiency regulated NET formation and alleviated the development of ALI induced by intestinal I\/R. Thus, HMGB1 released from necroptotic enterocytes caused ALI after intestinal I\/R by inducing NET formation. Targeting NETosis and the HMGB1 pathway might extend effective therapeutic strategies to minimize intestinal I\/R-induced ALI.<\/jats:p>","DOI":"10.4049\/jimmunol.2100593","type":"journal-article","created":{"date-parts":[[2022,1,21]],"date-time":"2022-01-21T11:00:14Z","timestamp":1642762814000},"page":"968-978","source":"Crossref","is-referenced-by-count":106,"title":["HMGB1-Mediated Neutrophil Extracellular Trap Formation Exacerbates Intestinal Ischemia\/Reperfusion-Induced Acute Lung Injury"],"prefix":"10.1093","volume":"208","author":[{"given":"YaQing","family":"Zhan","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YiHong","family":"Ling","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center , Guangzhou,","place":["China"]},{"name":"Department of Pathology, Sun Yat-sen University Cancer Center , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiwen","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YuXin","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JianTong","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"HanJin","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ZhaoRong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3155-5127","authenticated-orcid":false,"given":"ChanYan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"LiQun","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JianFeng","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"WenQi","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First 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