Models of Sepsis and Bacterial Peritonitis

Charles River’s immunology expertise allows us to aid you with your sepsis research. Sepsis and Bacterial Peritonitis have become a key area of pharmaceutical development as it now ranks as the third leading cause of death in the U.S., becoming a significant burden on healthcare systems. Sepsis is a serious complication of infection, caused by the presence of bacteria within the blood, and when left untreated can lead to a systemic immune response including; tissue damage, multiple organ failure and systemic immune response syndrome. Sepsis is a severe and toxic reaction to infection, involving an extreme inflammatory response to bacterial or viral infection including pneumonia and influenza.

At Charles River we offer a range of sepsis models:

  • Peritoneal and Intravenous sepsis models - this model results in bacteria colonizing different organs leading to organ failure and death.

Bacterial lung infection

  • Pulmonary sepsis model - the lungs are a common location for primary and secondary infections leading to exacerbation of disease and possible sepsis.
  • Cecal ligation and puncture - offers a clinically relevant polymicrobial model of sepsis.
  • LPS-induced sepsis model - injection of lipopolysaccharide replicates the pathology of sepsis

Our murine sepsis models can be performed with neutropenic or non-neutropenic animals, and can be modelled using single or combination treatments. Bacterial load can be measured, in life, using in vivo imaging systems for detection of bioluminescent bacteria, and in different organs post termination, and survival can be assessed to determine efficacy of client treatments.

 

Study Endpoints

  • Clinical disease observations
  • Survival – Kaplan-Meier survival curves
  • Change in bodyweight and temperature
  • Bacterial load
    • CFU burden in blood and infected organs (e.g. blood, lungs, kidneys, liver and spleen)
    • Luminescence – IVIS technology
  • Pathology – gross observations, H&E staining and Gram staining.
  • Bio-analysis – infiltrating immune cells and cytokines in plasma, bronchoalveolar lavage (BAL), peritoneal washes.
  • In vitro analysis of immune responses – ELISA, Luminex, T cell assays, FACS inhibition assays

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Validation Data

Bacterial burden in kidney following intravenous infection with S. aureus
Figure 1. Bacterial burden in the kidney following intravenous infection with S. aureus is significantly reduced in treated animals.

 

Survival in a mouse model of sepsis following intravenous infection with E. coli
Figure 2. Survival is significantly increased with treatment following intravenous infection with E. coli. Mantel Cox test, p-value = ****<0.0001.

 

Frequently Asked Questions (FAQs) in Sepsis Research:

  • What are the animal models of sepsis?

    There are three types of animal models of sepsis; toxemia models (e.g. LPS infusion), bacterial infection models (e.g. intravenous, intraperitoneal or lung infection models) or host-barrier disruption models (e.g. cecal ligation and puncture, wound models). Progression of disease in the murine sepsis model is measured by; clinical disease observations, bodyweight and temperature changes, survival curves, bacterial load and pathology.

  • Which models of sepsis are most clinically relevant?

    Due to the complex immune environment associated with sepsis, researchers rely on in vivo models. The most clinically relevant models involve a localized infection, such as cecal ligation and puncture, and wound models, that gradually propagates a systemic immune response. Pneumosepsis models (pulmonary infection models) are particularly clinically relevant because previous respiratory tract infection is a common cause of sepsis in patients, and may result in co-infection.

  • What is the cecal ligation and puncture model of sepsis?

    The cecal ligation and puncture (CLP) model, a method that induces polymicrobial bacterial peritonitis, is considered the gold standard of sepsis research because it is more clinically relevant than pure inflammation/infection models. The model became popular because it reproduces the changes in cardiovascular function seen in humans with sepsis. In addition, the cecal ligation and puncture model recreates the progressive release of proinflammatory mediators, so more closely models the complex immune environment associated with sepsis. Therefore, CLP is considered to be one of the most clinically relevant sepsis models.

  • What are live bacterial infection models of sepsis?

    Bacterial infection models of sepsis involve administration of live bacteria into the animal model via an appropriate route to mimic different clinical situations. As opposed to toxemia models such as LPS model of sepsis where injection of lipopolysaccharide replicates the physiology of sepsis.

  • What is sepsis, and how is it different from septic shock, septicemia and bacterial peritonitis?

    Sepsis is when the immune system has a severe or toxic response to infection. Sepsis and septicemia refer to the same condition. Septicemia is an older term for sepsis, but sepsis is the preferred term. The inflammatory response can be caused by bacterial, or viral infection as well as parasitic or fungal infections. While fighting off the infection the immune system works overtime and has an extreme reaction, and begins to attack the body. When complicated by low blood pressure sepsis is termed septic shock, leading to a high risk of death.

    Peritonitis is an inflammation of the peritoneum, the serosal membrane that lines the abdominal cavity and supports most of the abdominal organs. Peritonitis is usually caused by bacteria or fungi. When exposed to infection stimuli the peritoneum exhibits an inflammatory response, but when left untreated peritonitis can rapidly spread into the blood as sepsis, affecting other organs.

  • What other diseases are associated with sepsis?

    Within the pulmonary system, secondary inflammation may cause progressive lung injury that leads to acute respiratory distress syndrome and organ failure. In addition, inflammation and vascular collapse can lead to gastrointestinal dysfunction, compromised gut barriers, and bacterial translocation. Sepsis-associated inflammation has been linked to functional changes in liver, kidney and endocrine organs. Unchecked, the result of overwhelming sepsis is progressive, system-wide organ failure and death.

  • How important is sepsis research?

    The CDC (Centers for Disease Control and Prevention) ranks sepsis higher than chronic lower respiratory diseases, stroke, Alzheimer’s disease, and diabetes. A Healthcare Cost and Utilization Project (H-CUP) study in 2011 identified over 1.6m cases of sepsis in 2009, leading to more than 258,000 deaths, making sepsis the third highest cause of death in the U.S. (after cardiovascular disease and cancer). Sepsis has become a high burden on healthcare systems as it is the most expensive in-hospital condition in the U.S., costing more than $20 billion each year.

 

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