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During HIRI, high\u2010mobility group box 1 (HMGB1) promotes hepatocellular death and proinflammatory cytokine secretion by toll\u2010like receptor 4 (TLR4). Because salicylates inhibit HMGB1\/TLR4 interaction, we hypothesized that salicylates may ameliorate HIRI\u2010induced liver damage by inhibiting HMGB1\/TLR4 axis activation. Using a murine model of HIRI, we found that the salicylate acetyl\u20103\u2010aminoethyl salicylic acid (ac3AESA) reduced serum alanine aminotransferase and aspartate aminotransferase as well as Suzuki scores and apoptotic cell counts after HIRI. Ac3AESA also down\u2010regulated hepatocellular HMGB1 and TLR4 expression, phosphorylated inhibitor of \u03baB\u03b1, extracellular signal\u2010regulated kinase 1\/2, c\u2010Jun N\u2010terminal kinase, p38 mitogen\u2010activated protein kinase, cleaved caspase 3, and cleaved caspase 1 levels after HIRI. Ac3AESA reduced liver Kupffer cell transcription of proinflammatory mediators tumor necrosis factor \u03b1 (TNF\u2010\u03b1), interleukin (IL) 6, IL1\u03b2, chemokine (C\u2010X\u2010C motif) ligand (CXCL) 1, CXCL2, and CXCL8 after HIRI. Ac3AESA also dose\u2010dependently reduced in vitro release of Kupffer cell TNF\u2010\u03b1. Employing a murine orthotopic liver transplantation model, we found daily ac3AESA administration up to day 10 after transplant improved liver graft survival, suppressed allograft damage, and down\u2010regulated HMGB1\/TLR4 signaling. These benefits to survival and allograft health were maintained for cold ischemia times of 12 and 18 hours. Notably, TLR4 knockout eliminated all foregoing ac3AESA\u2010induced effects. In conclusion, ac3AESA partially rescues the negative effects of HIRI and prolongs liver graft survival in a TLR4\u2010dependent manner.<\/jats:p>","DOI":"10.1002\/lt.25575","type":"journal-article","created":{"date-parts":[[2019,5,24]],"date-time":"2019-05-24T16:26:48Z","timestamp":1558715208000},"page":"1220-1232","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Acetyl\u20103\u2010Aminoethyl Salicylate Ameliorates Hepatic Ischemia\/Reperfusion Injury and Liver Graft Survival Through a High\u2010Mobility Group Box 1\/Toll\u2010Like Receptor 4\u2013Dependent Mechanism"],"prefix":"10.1097","volume":"25","author":[{"given":"Xing","family":"Lai","sequence":"first","affiliation":[{"name":"Chongqing Key Laboratory of Hepatobiliary Surgery, Department of Hepatobiliary Surgery,Second Affiliated Hospital, Chongqing Medical University,Chongqing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhua","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Organ Transplantation Center,First Affiliated Hospital, Kunming Medical University,Kunming,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiming","family":"Wang","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Hepatobiliary Surgery, Department of Hepatobiliary Surgery,Second Affiliated Hospital, Chongqing Medical University,Chongqing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ding","family":"Cao","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Hepatobiliary Surgery, Department of Hepatobiliary Surgery,Second Affiliated Hospital, Chongqing Medical University,Chongqing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menghao","family":"Wang","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Hepatobiliary Surgery, Department of Hepatobiliary Surgery,Second Affiliated Hospital, Chongqing Medical University,Chongqing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Liu","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Hepatobiliary Surgery, Department of Hepatobiliary Surgery,Second Affiliated Hospital, Chongqing Medical University,Chongqing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wu","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Hepatobiliary Surgery, Department of Hepatobiliary Surgery,Second Affiliated Hospital, Chongqing Medical 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