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Sepsis

New forms of attack

Nature Reviews Drug Discovery volume 3, page 113 (2004)Cite this article

Now, two studies have identified new targets that focus on, and reveal more about, different mechanisms in sepsis. The first, from Tracey and colleagues in Proceedings of the National Academy of Sciences, describes how antagonists of the transcription factor high-mobility group box 1 (HMGB1) can target mediators of the cytokine response of host cells to bacterial toxins. What makes this different from other early inflammatory mediator targets that have been identified, such as tumour-necrosis factor (TNF) and interleukin-1β (IL-1β), is that HMGB1 has a more delayed kinetic profile: the acute kinetics of TNF and IL-1β provide too narrow a therapeutic window for inhibitors of these cytokines to be clinically useful.

Using the cecal ligation and puncture (CLP) mouse model, regarded as the most clinically relevant model for sepsis, the authors showed that serum HMGB1 levels are increased significantly 18 hours post CLP, corresponding with the clinical development of the disorder. Antibodies to HMGB1 administered 24 hours after surgery increased survival significantly, which is striking as this is the first cytokine-based therapy that is effective when administered 8 hours after CLP, and antibodies to TNF worsened outcome in the CLP model. Structure-function studies showed that a domain called the HMGB1 A box inhibits HMGB1 activity, and animals treated with this HMGB1 antagonist were protected from organ injury and were conferred with lasting protection against lethality.

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References

ORIGINAL RESEARCH PAPERS

  1. Yang, H. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc. Natl Acad. Sci. USA 101, 296–301 (2004)

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  2. Yan, J. -J. Therapeutic effects of lysophosphatidylcholine in experimental sepsis. Nature Med. 11 Jan 2004 doi:10.1038/nm989

FURTHER READING

  1. Marshall, J. C. Such stuff as dreams are made on: mediator-directed therapy in sepsis. Nature Rev. Drug Discov. 2, 391–405 (2003)

    Article  CAS  Google Scholar 

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Authors
  1. Simon Frantz
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Frantz, S. New forms of attack. Nat Rev Drug Discov 3, 113 (2004). https://doi.org/10.1038/nrd1324

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  • DOI: https://doi.org/10.1038/nrd1324

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