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Updated: Aug 14, 2026
A Reproducible Intensive Care Unit-Oriented Endotoxin Model in Rats
Published on: February 20, 2021
Evaluation of endotoxin models for the study of sepsis
Daniel G Remick1, Peter A Ward
1Department of Pathology, University of Michigan, Ann Arbor, MI 48109-0602, USA. pward@umich.edu
Abstract:
Many strategies have been proposed for the treatment of sepsis, and most of the proposed treatment modalities have failed in clinical trials. Many of the previous treatment protocols called for blocking the activity of a single, clearly defined mediator. The underlying hypothesis was that sepsis induced a specific mediator that then caused organ injury and death. This simple, linear reasoning was frequently based on cytokines that were defined using endotoxin models of sepsis. The endotoxin models were widely used to study the pathophysiology of sepsis and were felt to adequately reproduce the full spectrum of inflammatory changes observed in patients with sepsis. Based on mortality and hematologic changes, these assumptions appeared justified. As the models were examined more closely, and directly compared with focus of infection models that more accurately portray the changes in sepsis, it became apparent that the endotoxin models did not accurately mimic the patient with sepsis. In the endotoxin models, the explosive release of cytokines into the circulating blood volume was reproducibly found regardless of the species studied (human, primate, pig, rat, or mouse). This lead to a series of anticytokine sepsis trials, all of which failed. The cytokine response in focus of infection models, such as that induced by cecal ligation and puncture, was examined and found to be more similar to that observed in patients with sepsis. When cytokine inhibitor strategies were used in the cecal ligation and puncture model, they were also generally found to lack efficacy. Compounds that have been shown to be effective at reducing mortality in endotoxin models should be re-evaluated in more clinically relevant models of sepsis.
Insights
Sepsis treatments targeting single mediators, often based on endotoxin models, have failed. More clinically relevant infection models reveal these approaches lack efficacy, necessitating re-evaluation of sepsis treatment strategies.
Area of Science:
- Sepsis Pathophysiology
- Inflammatory Response
- Translational Medicine
Background:
- Sepsis treatment strategies have largely failed in clinical trials.
- Previous approaches focused on blocking single mediators, often using endotoxin models.
- Endotoxin models were assumed to accurately mimic sepsis but were later found to be inadequate.
Purpose of the Study:
- To evaluate the efficacy of sepsis treatment strategies in clinically relevant models.
- To compare the inflammatory response in endotoxin models versus focus of infection models.
- To guide future sepsis treatment development by re-evaluating existing approaches.
Main Methods:
- Comparison of endotoxin models with focus of infection models (e.g., cecal ligation and puncture).
- Analysis of cytokine release patterns in different sepsis models.
- Assessment of treatment efficacy in various preclinical sepsis models.
Main Results:
- Endotoxin models show explosive cytokine release, unlike human sepsis.
- Focus of infection models more accurately mimic human sepsis cytokine profiles.
- Anticytokine strategies effective in endotoxin models failed in focus of infection models.
Conclusions:
- Endotoxin models do not accurately represent human sepsis pathophysiology.
- Sepsis treatment strategies must be validated in clinically relevant models.
- Re-evaluation of compounds effective in endotoxin models is needed in more appropriate models.
