The caecal ligation and puncture (CLP) animal model for polymicrobial septic peritonitis


Figure: The caecal ligation and puncture (CLP) model of sepsis at Fraunhofer-TMP, induced by laparotomy and exposure of the junction between the large and small intestines. Source: Buras JA, Holzmann B, Sitkovsky M. Animal Models of sepsis: setting the stage. Nature Reviews Drug Discovery 4, 854-865 (October 2005). doi:10.1038/nrd1854

Systemic inflammation or sepsis is a reaction of the immune system in response to intensive and massive infections. To study the pathophysiology of human sepsis, caecal ligation and puncture (CLP), an animal model of polymicrobial septic peritonitis, was developed and described in 1980 by Wichtermann et al. Today, CLP is one the most widely used animal models of the systemic inflammatory response syndrome (SIRS), sepsis and septic shock because it closely mimics the progression and characteristics of human sepsis. Sepsis is induced by the perforation of the caecum leading to the release of fecal material into the peritoneal cavity to generate an exacerbated immune response induced by polymicrobial infection.

Species

Rodents (mouse; rat)

Field of application:

  • Basic sepsis research
  • Modelling of pathophysiological processes within the human immune system during SIRS, sepsis and septic shock
  • Testing novel therapeutic agents
  • Drug testing

Endpoints/Outcome parameter

  • Organ damage
  • Defined time
  • Survival

Readout parameter

Post mortem blood and organs are recovered for further analysis by various methods such as flow cytometry, cell sorting, western blot, immunohistochemistry, quantitative real‑time polymerase chain reaction (qPCR), cytometric bead array (CBA) or enzyme‑linked immunosorbent assay (ELISA) and high‑performance liquid chromatography (HPLC).

Quality management and validation

Thiazolidinediones (TZDs) like ciglitazone, pioglitazone and rosiglitazone are effective in reducing inflammation when administered in the hyperinflammatory phase of sepsis. In contrast, selective peroxisome proliferator-activated receptor gamma modulators (SPPARγMs) and/or PPARγ antagonists, for example, 2-chloro-5-nitrobenzanilide (GW9662), are effective in reducing T cell apoptosis when administered in the hypoinflammatory phase of sepsis. Such compounds can be used as reference compounds for the development of new compounds for the treatment of sepsis.

References

  • von Knethen A, Sha LK, Knape T, Kuchler L, Giegerich AK, Schulz M, Hauser IA, Brüne B. Activation of the peroxisome proliferator-activated receptor gamma counteracts sepsis-induced T cell cytotoxicity toward alloantigenic target cells. J Mol Med. Jun 2015; 93(6):633-644.

  • Knape T, Flesch D, Kuchler L, Sha LK, Giegerich AK, Labocha S, Ferreirós N, Schmid T, Wurglics M, Schubert-Zsilavecz M, Proschak E, Brüne B, Parnham MJ, von Knethen A. Identification and characterisation of a prototype for a new class of competitive PPARγ antagonists. Eur J Pharmacol. 15 May 2015;755:16-26.

  • Schmidt MV, Paulus P, Kuhn AM, Weigert A, Morbitzer V, Zacharowski K, Kempf VA, Brüne B, von Knethen A. Peroxisome proliferator-activated receptor gamma-induced T cell apoptosis reduces survival during polymicrobial sepsis. Am J Respir Crit Care Med. Jul 1 2011;184(1):64-74.