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Neutralization of extracellular histones by sodium-Β-O-methyl cellobioside sulfate in septic shock
BACKGROUND: Extracellular histones have been associated with severity and outcome in sepsis. The aim of the present study was to assess the effects of sodium-β-O-Methyl cellobioside sulfate (mCBS), a histone-neutralizing polyanion, on the severity and outcome of sepsis in an experimental model. METH...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10675855/ https://www.ncbi.nlm.nih.gov/pubmed/38001494 http://dx.doi.org/10.1186/s13054-023-04741-x |
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author | Garcia, Bruno Su, Fuhong Dewachter, Laurence Wang, Yong Li, Ning Remmelink, Myriam Eycken, Marie Van Khaldi, Amina Favory, Raphaël Herpain, Antoine Moreau, Anthony Moiroux-Sahraoui, Alexander Manicone, Francesca Annoni, Filippo Shi, Lin Vincent, Jean-Louis Creteur, Jacques Taccone, Fabio S. |
author_facet | Garcia, Bruno Su, Fuhong Dewachter, Laurence Wang, Yong Li, Ning Remmelink, Myriam Eycken, Marie Van Khaldi, Amina Favory, Raphaël Herpain, Antoine Moreau, Anthony Moiroux-Sahraoui, Alexander Manicone, Francesca Annoni, Filippo Shi, Lin Vincent, Jean-Louis Creteur, Jacques Taccone, Fabio S. |
author_sort | Garcia, Bruno |
collection | PubMed |
description | BACKGROUND: Extracellular histones have been associated with severity and outcome in sepsis. The aim of the present study was to assess the effects of sodium-β-O-Methyl cellobioside sulfate (mCBS), a histone-neutralizing polyanion, on the severity and outcome of sepsis in an experimental model. METHODS: This randomized placebo-controlled experimental study was performed in 24 mechanically ventilated female sheep. Sepsis was induced by fecal peritonitis. Animals were randomized to three groups: control, early treatment, and late treatment (n = 8 each). mCBS was given as a bolus (1 mg/kg) followed by a continuous infusion (1 mg/kg/h) just after sepsis induction in the early treatment group, and 4 h later in the late treatment group. Fluid administration and antimicrobial therapy were initiated 4 h T4 after feces injection, peritoneal lavage performed, and a norepinephrine infusion titrated to maintain mean arterial pressure (MAP) between 65–75 mmHg. The experiment was blinded and lasted maximum 24 h. RESULTS: During the first 4 h, MAP remained > 65 mmHg in the early treatment group but decreased significantly in the others (p < 0.01 for interaction, median value at T4: (79 [70–90] mmHg for early treatment, 57 [70–90] mmHg for late treatment, and 55 [49–60] mmHg for the control group). mCBS-treated animals required significantly less norepinephrine to maintain MAP than controls (p < 0.01 for interaction) and had lower creatinine (p < 0.01), lactate (p < 0.01), and interleukin-6 (p < 0.01) levels, associated with reduced changes in H3.1 nucleosome levels (p = 0.02). Early treatment was associated with lower norepinephrine requirements than later treatment. Two control animals died; all the mCBS-treated animals survived. CONCLUSIONS: Neutralization of extracellular histones with mCBS was associated with reduced norepinephrine requirements, improved tissue perfusion, less renal dysfunction, and lower circulating IL-6 in experimental septic shock and may represent a new therapeutic approach to be tested in clinical trials. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13054-023-04741-x. |
format | Online Article Text |
id | pubmed-10675855 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-106758552023-11-24 Neutralization of extracellular histones by sodium-Β-O-methyl cellobioside sulfate in septic shock Garcia, Bruno Su, Fuhong Dewachter, Laurence Wang, Yong Li, Ning Remmelink, Myriam Eycken, Marie Van Khaldi, Amina Favory, Raphaël Herpain, Antoine Moreau, Anthony Moiroux-Sahraoui, Alexander Manicone, Francesca Annoni, Filippo Shi, Lin Vincent, Jean-Louis Creteur, Jacques Taccone, Fabio S. Crit Care Research BACKGROUND: Extracellular histones have been associated with severity and outcome in sepsis. The aim of the present study was to assess the effects of sodium-β-O-Methyl cellobioside sulfate (mCBS), a histone-neutralizing polyanion, on the severity and outcome of sepsis in an experimental model. METHODS: This randomized placebo-controlled experimental study was performed in 24 mechanically ventilated female sheep. Sepsis was induced by fecal peritonitis. Animals were randomized to three groups: control, early treatment, and late treatment (n = 8 each). mCBS was given as a bolus (1 mg/kg) followed by a continuous infusion (1 mg/kg/h) just after sepsis induction in the early treatment group, and 4 h later in the late treatment group. Fluid administration and antimicrobial therapy were initiated 4 h T4 after feces injection, peritoneal lavage performed, and a norepinephrine infusion titrated to maintain mean arterial pressure (MAP) between 65–75 mmHg. The experiment was blinded and lasted maximum 24 h. RESULTS: During the first 4 h, MAP remained > 65 mmHg in the early treatment group but decreased significantly in the others (p < 0.01 for interaction, median value at T4: (79 [70–90] mmHg for early treatment, 57 [70–90] mmHg for late treatment, and 55 [49–60] mmHg for the control group). mCBS-treated animals required significantly less norepinephrine to maintain MAP than controls (p < 0.01 for interaction) and had lower creatinine (p < 0.01), lactate (p < 0.01), and interleukin-6 (p < 0.01) levels, associated with reduced changes in H3.1 nucleosome levels (p = 0.02). Early treatment was associated with lower norepinephrine requirements than later treatment. Two control animals died; all the mCBS-treated animals survived. CONCLUSIONS: Neutralization of extracellular histones with mCBS was associated with reduced norepinephrine requirements, improved tissue perfusion, less renal dysfunction, and lower circulating IL-6 in experimental septic shock and may represent a new therapeutic approach to be tested in clinical trials. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13054-023-04741-x. BioMed Central 2023-11-24 /pmc/articles/PMC10675855/ /pubmed/38001494 http://dx.doi.org/10.1186/s13054-023-04741-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Garcia, Bruno Su, Fuhong Dewachter, Laurence Wang, Yong Li, Ning Remmelink, Myriam Eycken, Marie Van Khaldi, Amina Favory, Raphaël Herpain, Antoine Moreau, Anthony Moiroux-Sahraoui, Alexander Manicone, Francesca Annoni, Filippo Shi, Lin Vincent, Jean-Louis Creteur, Jacques Taccone, Fabio S. Neutralization of extracellular histones by sodium-Β-O-methyl cellobioside sulfate in septic shock |
title | Neutralization of extracellular histones by sodium-Β-O-methyl cellobioside sulfate in septic shock |
title_full | Neutralization of extracellular histones by sodium-Β-O-methyl cellobioside sulfate in septic shock |
title_fullStr | Neutralization of extracellular histones by sodium-Β-O-methyl cellobioside sulfate in septic shock |
title_full_unstemmed | Neutralization of extracellular histones by sodium-Β-O-methyl cellobioside sulfate in septic shock |
title_short | Neutralization of extracellular histones by sodium-Β-O-methyl cellobioside sulfate in septic shock |
title_sort | neutralization of extracellular histones by sodium-β-o-methyl cellobioside sulfate in septic shock |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10675855/ https://www.ncbi.nlm.nih.gov/pubmed/38001494 http://dx.doi.org/10.1186/s13054-023-04741-x |
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