Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Record number 548928
Title The damage-associated molecular pattern HMGB1 is released early after clinical hepatic ischemia/reperfusion
Author(s) Golen, Rowan F. van; Reiniers, Megan J.; Marsman, Gerben; Alles, Lindy K.; Rooyen, Derrick M. van; Petri, Björn; Mark, Vincent A. Van der; Beek, Adriaan A. van; Meijer, Ben; Maas, Martinus A.; Zeerleder, Sacha; Verheij, Joanne; Farrell, Geoffrey C.; Luken, Brenda M.; Teoh, Narci C.; Gulik, Thomas M. van; Murphy, Michael P.; Heger, Michal
Source Biochimica et Biophysica Acta. Molecular Basis of Disease 1865 (2019)6. - ISSN 0925-4439 - p. 1192 - 1200.
DOI https://doi.org/10.1016/j.bbadis.2019.01.014
Department(s) Cell Biology and Immunology
Publication type Refereed Article in a scientific journal
Publication year 2019
Keyword(s) Antioxidants - Damage-associated molecular patterns - Intravital microscopy - Liver resection - Mitochondrial DNA - Sterile inflammation
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.

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