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

Rowan F. van Golen, Megan J. Reiniers, Gerben Marsman, Lindy K. Alles, Derrick M. van Rooyen, Björn Petri, Vincent A. Van der Mark, Adriaan A. van Beek, Ben Meijer, Martinus A. Maas, Sacha Zeerleder, Joanne Verheij, Geoffrey C. Farrell, Brenda M. Luken, Narci C. Teoh, Thomas M. van Gulik, Michael P. Murphy, Michal Heger*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)

Abstract

Objective and background: Activation 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. 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 an 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 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. 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.

Original languageEnglish
Pages (from-to)1192-1200
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1865
Issue number6
Early online date15 Jan 2019
DOIs
Publication statusPublished - 1 Jun 2019

Keywords

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

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    van Golen, R. F., Reiniers, M. J., Marsman, G., Alles, L. K., van Rooyen, D. M., Petri, B., Van der Mark, V. A., van Beek, A. A., Meijer, B., Maas, M. A., Zeerleder, S., Verheij, J., Farrell, G. C., Luken, B. M., Teoh, N. C., van Gulik, T. M., Murphy, M. P., & Heger, M. (2019). The damage-associated molecular pattern HMGB1 is released early after clinical hepatic ischemia/reperfusion. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1865(6), 1192-1200. https://doi.org/10.1016/j.bbadis.2019.01.014