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Review
. 2008 Nov 4:10:e32.
doi: 10.1017/S1462399408000884.

Therapeutic potential of HMGB1-targeting agents in sepsis

Affiliations
Review

Therapeutic potential of HMGB1-targeting agents in sepsis

Haichao Wang et al. Expert Rev Mol Med. .

Abstract

Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection. The inflammatory response is partly mediated by innate immune cells (such as macrophages, monocytes and neutrophils), which not only ingest and eliminate invading pathogens but also initiate an inflammatory response upon recognition of pathogen-associated molecular patterns (PAMPs). The prevailing theories of sepsis as a dysregulated inflammatory response, as manifested by excessive release of inflammatory mediators such as tumour necrosis factor and high-mobility group box 1 protein (HMGB1), are supported by extensive studies employing animal models of sepsis. Here we review emerging evidence that support extracellular HMGB1 as a late mediator of experimental sepsis, and discuss the therapeutic potential of several HMGB1-targeting agents (including neutralising antibodies and steroid-like tanshinones) in experimental sepsis.

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Figures

Figure 1
Figure 1
A microbial infection can trigger a local or systemic inflammatory response. The disruption of an epithelial barrier allows invasion of microbial pathogens, which elicit an innate immune response at the site of infection. If invading pathogens are effectively eliminated by phagocytes, local inflammation resolves normally to regain immunological homeostasis. If invading pathogens are not effectively eliminated, they can leak into the bloodstream, and trigger a potentially injurious systemic inflammatory response (such as sepsis).
Figure 2
Figure 2
Extracellular HMGB1 functions as an alarmin signal. HMGB1 is actively secreted by innate immune cells in response to exogenous bacterial products (e.g. endotoxin or CpG-DNA) or endogenous inflammatory stimuli (e.g. TNF, IFN-γ or hydrogen peroxide), and passively released by damaged or virus-infected cells. Extracellular HMGB1 sustains an inflammatory response by stimulating migration of innate immune cells, facilitating innate recognition of bacterial products (e.g. CpG by TLR9 and endotoxin by TLR4), activating various innate immune cells, and inhibiting phagocytosis of apoptotic neutrophils. Thus, HMGB1 can function as an alarmin signal, which recruits, alerts and activates various innate immune cells, thereby sustaining a potentially injurious inflammatory response. Abbreviations: HMGB1, high-mobility group box 1 protein; IFN-γ interferon, γ; TLR, Toll-like receptor; TNF, tumour necrosis factor.
Figure 3
Figure 3
Early versus late mediators of septic lethality. Vertebrates subjected to septic insult succumb at latencies of up to several days, long after serum TNF has returned to basal levels. By contrast to early pro-inflammatory cytokines, systemic HMGB1 accumulation occurs in a delayed fashion, which precedes and parallels the onset of septic lethality (Refs 96, 146). This delayed systemic accumulation makes HMGB1 a better therapeutic target with a wider therapeutic window for experimental sepsis. CLP, caecal ligation and puncture; HMGB1, high-mobility group box 1 protein; IFN-γ, interferon γ; TNF, tumour necrosis factor.
Figure 4
Figure 4
Steroid-like tanshinones and water-soluble derivatives. Several steroid-like pigments (tanshinone I, tanshinone IIA, and cryptotanshinone) of the medicinal Chinese herb danshen (Salvia miltiorrhiza) are structurally similar to steroidal anti-inflammatory drugs (such as dexamethasone and cortisone) – that is, they all have a fused four-ring structure (Ref. 133). Tanshinone IIA sodium sulphonate is water-soluble, and widely used in China as a cardiovascular medicine. MW, molecular weight.

References

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Further reading, resources and contacts

    1. Chadwick D.J. Goode J. New Therapies. John Wiley & Sons; New York, USA: 2007. Novartis Foundation Symposium 280: Sepsis – New Insights. and . , eds (
    2. Sepsis.com provides more information about the signs, diagnosis and potential treatment for severe sepsis:

    1. http://www.sepsis.com http://www.sepsis.com
    2. Surviving sepsis.org promotes the Surviving Sepsis Campaign (SSC), an initiative to improve the management, diagnosis and treatment of sepsis:

    1. http://www.survivingsepsis.org http://www.survivingsepsis.org
    2. MDidea.com provides a detailed description about potential use of Danshen and components (Tanshinone IIA) in the treatment of various inflammatory ailments:

    1. http://www.mdidea.com/products/herbextract/danshen/data.html http://www.mdidea.com/products/herbextract/danshen/data.html

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