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Anti-High-Mobility Group Box Chromosomal Protein 1 Antibodies Improve Survival of Rats with Sepsis

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Abstract

Background

High-mobility group box chromosomal protein 1 (HMGB1) has recently been shown to be an important late mediator of endotoxin shock, intraabdominal sepsis, and acute lung injury, and a promising therapeutic target of severe sepsis. We sought to investigate the effect of antibodies to HMGB1 on severe sepsis in a rat cecal ligation and puncture (CLP) model.

Methods

Adult male Sprague-Dawley rats underwent CLP and then were randomly divided into two groups: treatment with anti-HMGB1 polyclonal antibodies, and non-immune IgG-treated controls. The serum HMGB1 concentrations were measured at ten time points (preoperatively, and postoperatively at 4, 8, 20, 32, and 48 h and at 3, 4, 5, and 6 days). Hematoxylin-eosin staining, elastica-Masson staining, and immunohistochemical staining for HMGB1 were performed on the cecum and the lung to assess pathological changes 24 h after the CLP procedure.

Results

Treatment with anti-HMGB1 antibodies significantly increased survival [55% (anti-HMGB1) vs. 9% (controls); P< 0.01]. The serum HMGB1 concentrations at postoperative hours 20 and 32 of the anti-HMGB1 antibody-treated animals were significantly lower than those of the controls (P < 0.05). Treatment with anti-HMGB1 antibodies markedly diminished the pathological changes and the number of HMGB1-positive cells in the cecum and the lung.

Conclusions

The present study demonstrates that anti-HMGB1 antibodies are effective in the treatment of severe sepsis in a rat model, thereby supporting the relevance of HMGB1 eradication therapy for severe sepsis.

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Acknowledgements

We wish to thank Satoru Fukinbara for advice on statistical analyses. The authors are indebted to Prof. J. Patrick Barron of the International Medical Communications Center of Tokyo Medical University for his review of this manuscript.

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Authors and Affiliations

  1. Department of Surgery, School of Medicine, Keio University, Shinanomachi 35, Shinjuku-ku, Tokyo, 160-8582, Japan

    Koichi Suda MD, Yuko Kitagawa MD, PhD, Soji Ozawa MD, PhD, Yoshiro Saikawa MD, PhD, Masakazu Ueda MD, PhD & Masaki Kitajima MD, PhD

  2. Department of Respiratory Oncology and Molecular Medicine, Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan

    Masahito Ebina MD, PhD

  3. Department of Pathology, Tohoku University School of Medicine, Sendai, Japan

    Masahito Ebina MD, PhD

  4. Central Institute, Shino-Test Corporation, Kanagawa, Japan

    Shingo Yamada PhD

  5. Department of Anesthesiology and Intensive Care, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Satoru Hashimoto MD, PhD

  6. Department of Surgery, National Center for Geriatrics and Gerontology, Aichi, Japan

    Shinji Fukata MD, PhD

  7. Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA

    Edward Abraham MD

  8. Department of Laboratory and Molecular Medicine, Kagoshima University, Kagoshima, Japan

    Ikuro Maruyama MD, PhD

  9. Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan

    Akitoshi Ishizaka MD, PhD

Authors
  1. Koichi Suda MD
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  2. Yuko Kitagawa MD, PhD
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  3. Soji Ozawa MD, PhD
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  4. Yoshiro Saikawa MD, PhD
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  5. Masakazu Ueda MD, PhD
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  6. Masahito Ebina MD, PhD
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  7. Shingo Yamada PhD
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  8. Satoru Hashimoto MD, PhD
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  9. Shinji Fukata MD, PhD
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  10. Edward Abraham MD
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  11. Ikuro Maruyama MD, PhD
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  12. Masaki Kitajima MD, PhD
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  13. Akitoshi Ishizaka MD, PhD
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Corresponding author

Correspondence to Yuko Kitagawa MD, PhD.

Additional information

This work was supported, in part, by Health Sciences Research Grants (Comprehensive Research on Aging and Health 14-015) from the Ministry of Labor Health and Welfare, Japan.

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Suda, K., Kitagawa, Y., Ozawa, S. et al. Anti-High-Mobility Group Box Chromosomal Protein 1 Antibodies Improve Survival of Rats with Sepsis. World J. Surg. 30, 1755–1762 (2006). https://doi.org/10.1007/s00268-005-0369-2

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  • DOI: https://doi.org/10.1007/s00268-005-0369-2

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