Trends in Microbiology
Volume 19, Issue 4, April 2011, Pages 198-208
Journal home page for Trends in Microbiology

Review
Cecal ligation and puncture: the gold standard model for polymicrobial sepsis?

https://doi.org/10.1016/j.tim.2011.01.001Get rights and content

Sepsis is a serious medical condition characterized by dysregulated systemic inflammatory responses followed by immunosuppression. To study the pathophysiology of sepsis, diverse animal models have been developed. Polymicrobial sepsis induced by cecal ligation and puncture (CLP) is the most frequently used model because it closely resembles the progression and characteristics of human sepsis. Here we summarize the role of several immune components in the pathogenesis of sepsis induced by CLP. However, several therapies proposed on the basis of promising results obtained by CLP could not be translated to the clinic. This demonstrates that experimental sepsis models do not completely mimic human sepsis. We propose several strategies to narrow the gap between experimental sepsis models and clinical sepsis, including targeting factors that contribute to the immunosuppressive phase of sepsis, and reproducing the heterogeneity of human patients.

Section snippets

Sepsis therapies: search for a needle in a haystack

Tight regulation of the immune system is essential for maintaining the balance between protective and tissue-damaging inflammatory responses. Therefore, local inflammatory responses are finely regulated and cease when the causative factor is removed. However, if the inflammatory reaction becomes dysregulated, systemic activation of the innate immune system becomes excessive and results in systemic inflammatory response syndrome (SIRS) or sepsis [1].

SIRS and sepsis are systemic reactions to

The upsides and downsides of animal models of sepsis: is CLP the gold standard?

Although sepsis is one of the most difficult clinical conditions to model in animals, different animal models have been developed. These commonly follow one of three strategies: (i) administration of exogenous toxins, such as zymosan and lipopolysaccharadide (LPS); (ii) administration of viable pathogens, such as bacteria and viruses; and (iii) alteration of the endogenous protective barrier of the animal. The CLP model and the colon ascendens stent peritonitis (CASP) model are examples of

The CLP model is important for sepsis research

Animal models are an indispensable tool for understanding the molecular and genetic mechanisms of sepsis. The availability of a variety of mutant mouse strains allows the study of the role of specific genes and has greatly contributed to our knowledge of the immune responses associated with experimental sepsis. Here, we summarize the findings obtained by targeting specific components of the immune system in CLP-induced sepsis.

Strategies to bridge the gap between bench and bedside

Although the CLP model has greatly contributed to our understanding of the pathophysiological and immunological features of clinical sepsis, it does not reproduce the whole spectrum of human sepsis. Many promising therapeutic agents that were effective in animal studies, including high-dose GCs [34], LPS-targeting agents 35, 36, and selective blockers of inflammatory mediators, all failed to demonstrate a similar benefit in human clinical trials [33]; very few therapies have been translated to

Concluding remarks and future perspectives

Sepsis is a major problem with high incidence and mortality rates. Appropriate animal models are crucial for studying sepsis, although most such models are not directly relevant for investigations of the pathophysiology of human sepsis. Nevertheless, the CLP model is one of the best representations of human sepsis and has made important contributions to our knowledge of the inflammatory components involved in sepsis and to the identification of therapeutic targets. The CLP model has been

Acknowledgments

The authors wish to acknowledge Dr. Amin Bredan for critical review of the manuscript. Research in the authors’ laboratory is sponsored by the Fund for Scientific Research-Flanders, the Interuniversity Attraction Poles Program of the Belgian Science Policy (IAP VI/18), the Belgische Vereniging tegen Kanker, and the VIB.

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