Disulfide High-Mobility Group Box 1 Drives Ischemia-Reperfusion Injury in Human Liver Transplantation.
Hepatology
; 73(3): 1158-1175, 2021 03.
Article
em En
| MEDLINE
| ID: mdl-32426849
ABSTRACT
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 ANDRESULTS:
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.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Traumatismo por Reperfusão
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Transplante de Fígado
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Proteína HMGB1
Limite:
Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Hepatology
Ano de publicação:
2021
Tipo de documento:
Article