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Type: Journal article
Title: Therapeutic targeting of HMGB1 during experimental sepsis modulates the inflammatory cytokine profile to one associated with improved clinical outcomes
Author: Stevens, N.
Chapman, M.
Fraser, C.
Kuchel, T.
Hayball, J.
Diener, K.
Citation: Scientific Reports, 2017; 7(1):5850-1-5850-14
Publisher: Springer Nature
Issue Date: 2017
ISSN: 2045-2322
Statement of
Natalie E. Stevens, Marianne J. Chapman, Cara K. Fraser, Tim R. Kuchel, John D. Hayball and Kerrilyn R. Diener
Abstract: Sepsis remains a significant health burden and a major clinical need exists for therapeutics to dampen the excessive and uncontrolled immune activation. Nuclear protein high mobility group box protein 1 (HMGB1) is released following cell death and is a late mediator in sepsis pathogenesis. While approaches targeting HMGB1 have demonstrated reduced mortality in pre-clinical models of sepsis, the impact of HMGB1 blockade on the complex septic inflammatory milieu and the development of subsequent immunosuppression remain enigmatic. Analysis of plasma samples obtained from septic shock patients established an association between increased HMGB1 and non-survival, higher APACHE II scores, and increased pro-inflammatory cytokine responses. Pre-clinically, administration of neutralising ovine anti-HMGB1 polyclonal antibodies improved survival in murine endotoxaemia and caecal ligation and puncture-induced sepsis models, and altered early cytokine profiles to one which corresponded to patterns observed in the surviving patient cohort. Additionally, anti-HMGB1 treated murine sepsis survivors were significantly more resistant to secondary bacterial infection and exhibited altered innate immune cell phenotypes and cytokine responses. These findings demonstrate that anti-HMGB1 antibodies alter inflammation in murine sepsis models and reduce sepsis mortality without potentiating immunosuppression.
Keywords: Cecum; Dendritic Cells; Macrophages; Animals; Mice, Inbred C57BL; Sheep; Humans; Pseudomonas aeruginosa; Sepsis; Shock, Septic; Endotoxemia; Disease Models, Animal; Inflammation; HMGB1 Protein; Cytokines; Punctures; Treatment Outcome; Ligation; Survival Analysis; Cohort Studies; Aged; Middle Aged; Female; Male; Molecular Targeted Therapy
Rights: © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit
RMID: 0030073457
DOI: 10.1038/s41598-017-06205-z
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