BACKGROUND AND AIMS: Sterile inflammation is a major clinical concern during ischemia-reperfusion injury (IRI) triggered by traumatic events, including stroke, myocardial infarction, and solid organ transplantation. Despite high-mobility group box 1 (HMGB1) clearly being involved in sterile inflammation, its role is controversial because of a paucity of patient-focused research. APPROACH AND RESULTS: Here, we examined the role of HMGB1 oxidation states in human IRI following liver transplantation. Portal blood immediately following allograft reperfusion (liver flush; LF) had increased total HMGB1, but only LF from patients with histopathological IRI had increased disulfide-HMGB1 and induced Toll-like receptor 4-dependent tumor necrosis factor alpha production by macrophages. Disulfide HMGB1 levels increased concomitantly with IRI severity. IRI+ prereperfusion biopsies contained macrophages with hyperacetylated, lysosomal disulfide-HMGB1 that increased postreperfusion at sites of injury, paralleling increased histone acetyltransferase general transcription factor IIIC subunit 4 and decreased histone deacetylase 5 expression. Purified disulfide-HMGB1 or IRI+ blood stimulated further production of disulfide-HMGB1 and increased proinflammatory molecule and cytokine expression in macrophages through a positive feedback loop. CONCLUSIONS: These data identify disulfide-HMGB1 as a mechanistic biomarker of, and therapeutic target for, minimizing sterile inflammation during human liver IRI.
BACKGROUND AND AIMS: Sterile inflammation is a major clinical concern during ischemia-reperfusion injury (IRI) triggered by traumatic events, including stroke, myocardial infarction, and solid organ transplantation. Despite high-mobility group box 1 (HMGB1) clearly being involved in sterile inflammation, its role is controversial because of a paucity of patient-focused research. APPROACH AND RESULTS: Here, we examined the role of HMGB1 oxidation states in human IRI following liver transplantation. Portal blood immediately following allograft reperfusion (liver flush; LF) had increased total HMGB1, but only LF from patients with histopathological IRI had increased disulfide-HMGB1 and induced Toll-like receptor 4-dependent tumor necrosis factor alpha production by macrophages. Disulfide HMGB1 levels increased concomitantly with IRI severity. IRI+ prereperfusion biopsies contained macrophages with hyperacetylated, lysosomal disulfide-HMGB1 that increased postreperfusion at sites of injury, paralleling increased histone acetyltransferase general transcription factor IIIC subunit 4 and decreased histone deacetylase 5 expression. Purified disulfide-HMGB1 or IRI+ blood stimulated further production of disulfide-HMGB1 and increased proinflammatory molecule and cytokine expression in macrophages through a positive feedback loop. CONCLUSIONS: These data identify disulfide-HMGB1 as a mechanistic biomarker of, and therapeutic target for, minimizing sterile inflammation during human liver IRI.
Authors: Paul A Harris; Robert Taylor; Robert Thielke; Jonathon Payne; Nathaniel Gonzalez; Jose G Conde Journal: J Biomed Inform Date: 2008-09-30 Impact factor: 6.317
Authors: Kojiro Nakamura; Min Zhang; Shoichi Kageyama; Bibo Ke; Takehiro Fujii; Rebecca A Sosa; Elaine F Reed; Nakul Datta; Ali Zarrinpar; Ronald W Busuttil; Jesus A Araujo; Jerzy W Kupiec-Weglinski Journal: J Hepatol Date: 2017-08-23 Impact factor: 25.083
Authors: Minna Ilmakunnas; Eija M Tukiainen; Ari Rouhiainen; Heikki Rauvala; Johanna Arola; Arno Nordin; Heikki Mäkisalo; Krister Höckerstedt; Helena Isoniemi Journal: Liver Transpl Date: 2008-10 Impact factor: 5.799
Authors: Hai Huang; Gary W Nace; Kerry-Ann McDonald; Sheng Tai; John R Klune; Brian R Rosborough; Qing Ding; Patricia Loughran; Xiaorong Zhu; Donna Beer-Stolz; Eugene B Chang; Timothy Billiar; Allan Tsung Journal: Hepatology Date: 2014-04-01 Impact factor: 17.425
Authors: Rebecca A Sosa; Maura Rossetti; Bita V Naini; Victoria M Groysberg; Fady M Kaldas; Ronald W Busuttil; Yu-Ling Chang; David W Gjertson; Jerzy W Kupiec-Weglinski; Elaine F Reed Journal: Ann Surg Date: 2020-05 Impact factor: 13.787
Authors: Min He; Bin Zhang; Xinbing Wei; Ziying Wang; Baoxia Fan; Pengchao Du; Yan Zhang; Wencheng Jian; Lin Chen; Linlin Wang; Hao Fang; Xiang Li; Ping-An Wang; Fan Yi Journal: J Cell Mol Med Date: 2013-03-11 Impact factor: 5.310
Authors: Joohyun Kim; Michael A Zimmerman; Woo Young Shin; Brent T Boettcher; Ju-Seog Lee; Jong-In Park; Muhammed Ali; Meiying Yang; Jyotsna Mishra; Catherine E Hagen; Joseph E McGraw; Angela Mathison; Harvey J Woehlck; Gwen Lomberk; Amadou K S Camara; Raul A Urrutia; David F Stowe; Johnny C Hong Journal: Ann Surg Date: 2021-08-13 Impact factor: 12.969
Authors: Di Zhang; Yicun Wang; Song Zeng; Min Zhang; Xin Zhang; Yuxuan Wang; Zijian Zhang; Xi Wang; Xiaopeng Hu Journal: Front Immunol Date: 2021-09-07 Impact factor: 7.561