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  • Review Article
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Model organisms

Animal Models of sepsis: setting the stage

Nature Reviews Drug Discovery volume 4, pages 854–865 (2005)Cite this article

Key Points

  • Sepsis remains a major cause of morbidity and mortality in human patients despite active research. The pathogenesis of sepsis involves a dysregulated balance of pro- and anti-inflammatory mediators. The evolving definition of sepsis makes clinical therapeutic trials difficult to capture a homogeneous patient sample.

  • Animal models of sepsis have been used to study sepsis pathogenesis and assess efficacy of potential therapeutic agents. Unfortunately, agents successful in animal model studies have rarely proven successful in large human clinical studies.

  • There are three main classes of sepsis animal models: toxaemia models (for example, lipopolysaccharide (LPS) infusion); bacterial infection models (for example, intravenous or intraperitoneal Escherichia coli infusion); and host-barrier disruption models (for example, caecal ligation and puncture (CLP) and colon ascendens stent peritonitis (CASP)). No individual model is a perfect vehicle for drug therapy testing and complementary model use is optimal for studies on therapy mechanisms.

  • The preclinical studies of anti-TNF and activated protein C therapy demonstrate diverse use of animal models. These studies suggest that testing of preclinical therapeutic agents did not always correlate with human clinical trial data as expected.

  • Clinical studies indicate that sepsis drug therapy efficacy might depend on the severity of sepsis. This hypothesis has been supported by sepsis animal model studies, which indicate that animal models could benefit from better efforts to stage the severity of disease during both mechanism and drug efficacy studies. Better staging of animal models will improve our knowledge of sepsis pathogenesis, better the ability to deliver targeted drug therapy depending on an individual inflammatory bias, and allow more focused clinical trials.

Abstract

Sepsis is a state of disrupted inflammatory homeostasis that is often initiated by infection. The development and progression of sepsis is multi-factorial, and affects the cardiovascular, immunological and endocrine systems of the body. The complexity of sepsis makes the clinical study of sepsis and sepsis therapeutics difficult. Animal models have been developed in an effort to create reproducible systems for studying sepsis pathogenesis and preliminary testing of potential therapeutic agents. However, demonstrated benefit from a therapeutic agent in animal models has rarely been translated into success in human clinical trials. This review summarizes the common animal sepsis models and highlights how results of recent human clinical trials might affect their use.

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Figure 1: Sepsis pathogenesis.
Figure 2: SIRS and CARS in sepsis.
Figure 3: Experimental models of sepsis: caecal ligation and puncture (CLP) and colon ascendens stent peritonitis (CASP).

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Acknowledgements

This work was supported in part by a National Institutes of Health grant to J.A.B.

Author information

Authors and Affiliations

  1. Department of Emergency Medicine, Beth Israel Deaconess Medical Center, 1 Deaconess Road, Boston, 02215, Massachusetts, USA

    Jon A. Buras

  2. Department of Surgery, Technische Universitat Munchen, Ismaninger Strasse 22, Munchen, Munich, D-81675, Germany

    Bernhard Holzmann

  3. Departments of Biology and Pharmaceutical Sciences, New England Inflammation and Tissue Protection Institute, Consortium at Northeastern University, Boston, 134 Mugar Life Sciences Bldg, Boston, 02115, Massachusetts, USA

    Michail Sitkovsky

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TLR2

TLR4

TLR 9

FURTHER INFORMATION

Surviving Sepsis

Society of Critical Care Medicine:

Glossary

TOLL-LIKE RECEPTORS (TLR)

A class of cell surface proteins that recognize components of pathogenic organisms and regulate early activation of the immuno-inflammatory response.

MIDLINE LAPAROTOMY

Surgical opening of the abdominal cavity in the midline.

LD100

The lethal dose of a substance (for example, a toxin or infective agent) that causes 100% mortality in the study animals at a given time.

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Buras, J., Holzmann, B. & Sitkovsky, M. Animal Models of sepsis: setting the stage. Nat Rev Drug Discov 4, 854–865 (2005). https://doi.org/10.1038/nrd1854

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