| Affiliation: | 1. Department of Experimental Surgery, 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;5. Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary AB T2N 1N4, Alberta, Canada;6. Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Canada;7. Tytgat Institute for Gastrointestinal and Liver Research, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands;8. Department of Cell Biology and Immunology, Wageningen University, Wageningen, the Netherlands;9. Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Switzerland;10. Department for BioMedical Research, University of Bern, Switzerland;11. Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands;12. Medical Research Council Mitochondrial Biology Unit, Cambridge, United Kingdom;13. Department of Medicine, University of Cambridge, Cambridge, United Kingdom |
| Abstract: | Objective and backgroundActivation of sterile inflammation after hepatic ischemia/reperfusion (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.MethodsPlasma 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 an attempt to limit DAMP release, reduce sterile inflammation, and suppress I/R injury.ResultsIn patients, HMGB1 was elevated following liver resection with I/R compared to liver resection without I/R. HMGB1 levels correlated positively with ischemia duration and peak post-operative transaminase (ALT) levels. There were no differences in mitochondrial DNA, nucleosome, or cytokine levels between the two groups. 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.ConclusionHMGB1 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. |
