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Cited by 1,126Sepsis Diagnosis and TreatmentAdvanced Glycation End Products researchInflammation biomarkers and pathways

Reversing established sepsis with antagonists of endogenous high-mobility group box 1

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Yang, Huan, Ochani, Mahendar, Li, Jianhua, Qiang, Xiaoling, Tanovic, Mahira, Harris, Helena E., Susarla, Srinivas M., Ulloa, Luis +10 more·2004·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2434651100PMC PMC314179
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Abstract

Despite significant advances in intensive care therapy and antibiotics, severe sepsis accounts for 9% of all deaths in the United States annually. The pathological sequelae of sepsis are characterized by a systemic inflammatory response, but experimental therapeutics that target specific early inflammatory mediators [tumor necrosis factor (TNF) and IL-1β] have not proven efficacious in the clinic. We recently identified high mobility group box 1 (HMGB1) as a late mediator of endotoxin-induced lethality that exhibits significantly delayed kinetics relative to TNF and IL-1β. Here, we report that serum HMGB1 levels are increased significantly in a standardized model of murine sepsis, beginning 18 h after surgical induction of peritonitis. Specific inhibition of HMGB1 activity [with either anti-HMGB1 antibody (600 μg per mouse) or the DNA-binding A box (600 μg per mouse)] beginning as late as 24 h after surgical induction of peritonitis significantly increased survival (nonimmune IgG-treated controls = 28% vs. anti-HMGB1 antibody group = 72%, P < 0.03; GST control protein = 28% vs. A box = 68%, P < 0.03). Animals treated with either HMGB1 antagonist were protected against the development of organ injury, as evidenced by improved levels of serum creatinine and blood urea nitrogen. These observations demonstrate that specific inhibition of endogenous HMGB1 therapeutically reverses lethality of established sepsis indicating that HMGB1 inhibitors can be administered in a clinically relevant time frame.

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Authors
Yang, H., Ochani, M., Li, J., Qiang, X., Tanovic, M., Harris, H. E., Susarla, S. M., Ulloa, L., Wang, H., DiRaimo, R., Czura, C. J., Wang, H., Roth, J., Warren, H. S., Fink, M. P., Fenton, M. J., Andersson, U., & Tracey, K. J.
Affiliations
Karolinska University Hospital (SE)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2003-12-26
Volume
101
Issue
1
Pages
296-301
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2434651100
PMC
PMC314179
OpenAlex
W2160369507
Cited by
1,126
References
31
Citations by year
2026: 13 · 2025: 16 · 2024: 26 · 2023: 27 · 2022: 25 · 2021: 38 · 2020: 37 · 2019: 42 · 2018: 38 · 2017: 41 · 2016: 68 · 2015: 68 · 2014: 82 · 2013: 70 · 2012: 74
FWCI
27.13
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
  • Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
Keywords
sepsis, high mobility group box 1, anti-HMGB1 antibody, A-box, peritonitis, systemic inflammatory response, organ damage, survival, treatment timing
MeSH terms
Animals, Antibodies, Cell Line, Disease Models, Animal, Humans, Kinetics, Neutralization Tests, Peptide Fragments, DNA, Complementary, Sepsis, HMGB1 Protein, Mice, In Vitro Techniques

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