The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion
Open accessAbstract
High-mobility group box 1 (HMGB1) is a nuclear factor that is released extracellularly as a late mediator of lethality in sepsis as well as after necrotic, but not apoptotic, death. Here we demonstrate that in contrast to the delayed role of HMGB1 in the systemic inflammation of sepsis, HMGB1 acts as an early mediator of inflammation and organ damage in hepatic ischemia reperfusion (I/R) injury. HMGB1 levels were increased during liver I/R as early as 1 h after reperfusion and then increased in a time-dependent manner up to 24 h. Inhibition of HMGB1 activity with neutralizing antibody significantly decreased liver damage after I/R, whereas administration of recombinant HMGB1 worsened I/R injury. Treatment with neutralizing antibody was associated with less phosphorylation of c-Jun NH2-terminal kinase and higher nuclear factor–κB DNA binding in the liver after I/R. Toll-like receptor 4 (TLR4)-defective (C3H/Hej) mice exhibited less damage in the hepatic I/R model than did wild-type (C3H/HeOuj) mice. Anti-HMGB1 antibody failed to provide protection in C3H/Hej mice, but successfully reduced damage in C3H/Ouj mice. Together, these results demonstrate that HMGB1 is an early mediator of injury and inflammation in liver I/R and implicates TLR4 as one of the receptors that is involved in the process.
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Cytokine overproduction is implicated in the development of tissue damage and organ injury during hemorrhagic shock.
“Cytokine overproduction has been implicated in the development of tissue damage and organ injury during hemorrhagic shock (37)(38)(39).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [37]
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- Authors
- Tsung, A., Sahai, R., Tanaka, H., Nakao, A., Fink, M. P., Lotze, M. T., Yang, H., Li, J., Tracey, K. J., Geller, D. A., & Billiar, T. R.
- Affiliations
- University of Pittsburgh (US)
- North Shore University Hospital (US)
- ORCID
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2005-03-28
- Volume
- 201
- Issue
- 7
- Pages
- 1135-1143
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2213120
- OpenAlex
- W2135131688
- Cited by
- 1,113
- References
- 49
- Citations by year
- 2026: 17 · 2025: 23 · 2024: 24 · 2023: 30 · 2022: 33 · 2021: 36 · 2020: 49 · 2019: 59 · 2018: 58 · 2017: 66 · 2016: 71 · 2015: 67 · 2014: 72 · 2013: 65 · 2012: 78
- FWCI
- 36.01
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM052021, R01GM037631, R01GM050441, P50GM053789, R01-GM53789)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- HMGB1, high mobility group box 1, hepatic ischemia-reperfusion injury, TLR4, c-Jun N-terminal kinase, NF-κB, liver inflammation, necrosis, extracellular HMGB1 release, sepsis, neutralizing antibodies
- MeSH terms
- Animals, Antibodies, Electrophoresis, Polyacrylamide Gel, Immunohistochemistry, Liver, Male, Mice, Inbred C3H, Mice, Inbred C57BL, Phosphorylation, Receptors, Cell Surface, Time Factors, Blotting, Western, Reperfusion Injury, NF-kappa B, Reverse Transcriptase Polymerase Chain Reaction, Hepatocytes, Electrophoretic Mobility Shift Assay, HMGB1 Protein, JNK Mitogen-Activated Protein Kinases, Toll-Like Receptor 4, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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