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Biochim Biophys Acta Mol Basis Dis. 2019 Jan 15. pii: S0925-4439(19)30014-6. doi: 10.1016/j.bbadis.2019.01.014. [Epub ahead of print]

The damage-associated molecular pattern HMGB1 is released early after clinical hepatic ischemia/reperfusion.

Author information

1
Department of Surgery (Experimental Laboratory), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
2
Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
3
Liver Research Group, Australian National University at The Canberra Hospital, Canberra, Australia.
4
Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary AB T2N 1N4, Alberta, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary AB T2N 1N4, Alberta, Canada; Snyder Institute for Chronic diseases, University of Calgary, Calgary, Canada.
5
Department of Surgery (Experimental Laboratory), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Tytgat Institute for Gastrointestinal and Liver Research, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
6
Department of Cell Biology and Immunology, Wageningen University, Wageningen, the Netherlands.
7
Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
8
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
9
Medical Research Council Mitochondrial Biology Unit, Cambridge, United Kingdom.
10
Department of Surgery (Experimental Laboratory), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. Electronic address: m.heger@amc.uva.nl.

Abstract

OBJECTIVE AND BACKGROUND:

Activation of sterile inflammation after hepatic I/R culminates in liver injury. The route to liver damage starts with mitochondrial oxidative stress and cell death during early reperfusion. The link between mitochondrial oxidative stress, damage-associate molecular pattern (DAMP) release, and sterile immune signaling is incompletely understood and lacks clinical validation. The aim of the study was to validate this relation in a clinical liver I/R cohort and to limit DAMP release using a mitochondria-targeted antioxidant in I/R-subjected mice.

METHODS:

Plasma levels of the DAMPs high-mobility group box 1 (HMGB1), mitochondrial DNA, and nucleosomes were measured in 39 patients enrolled in an observational study who underwent a major liver resection with (N = 29) or without (N = 13) intraoperative liver ischemia. Circulating cytokine and neutrophil activation markers were also determined. In mice, the mitochondria-targeted antioxidant MitoQ was intravenously infused in attempt to limit DAMP release, reduce sterile inflammation, and suppress I/R injury.

RESULTS:

In patients, HMGB1 was elevated following liver resection with I/R compared to liver resection without I/R. HMGB1 correlated positively with ischemia duration and peak post-operative transaminase (ALT) levels. There were no differences in mitochondrial DNA, nucleosome, or cytokine release. In mice, MitoQ neutralized hepatic oxidative stress and decreased HMGB1 release by ±50%. MitoQ suppressed transaminase release, hepatocellular necrosis, and cytokine production. Reconstituting disulfide HMGB1 during reperfusion reversed these protective effects.

CONCLUSION:

HMGB1 seems the most pertinent DAMP in clinical hepatic I/R injury. Neutralizing mitochondrial oxidative stress may limit DAMP release after hepatic I/R and reduce liver damage.

KEYWORDS:

Antioxidants; Damage-associated molecular patterns; Intravital microscopy; Liver resection; Mitochondrial DNA; Sterile inflammation

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