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Updated: Sep 27, 2026
Use of Animal Model of Sepsis to Evaluate Novel Herbal Therapies
Published on: April 11, 2012
Cytokine therapeutics for the treatment of sepsis: why has nothing worked?
1Department of Pathology, University of Michigan, Ann Arbor, MI 48109-6476, USA. remickd@umich.edu
Abstract:
Several clinical trials have attempted to treat sepsis by blocking certain aspects of the inflammatory response. Tumor necrosis factor and interleukin 1 have been specific targets for inhibition but none of the trials have been successful. These trials were started on the basis of preclinical trials that suggested these would be effective. There were three lines of evidence to support the idea of cytokine inhibition. First, patients with increased levels of cytokines are more likely to die. Second, experimental animal models demonstrated that blocking the cytokines would improve outcome. Third, injection of purified, recombinant cytokines would cause both organ injury and death in experimental animals. Several additional aspects of the inflammatory response have been discovered since these trials were initiated. Included among these potential new targets are interleukin 18 and HMG-1. However, before new clinical trials are started there must be careful consideration of why previous interventions were not effective. The concept of blocking a single elevated cytokine may be too simple to deal with the complex problem of sepsis. As patients move through different phases of the septic response, there may be intervals when it is appropriate to inhibit multiple cytokines while at other times it may be appropriate to augment the immune response.
Insights
Treating sepsis by blocking inflammatory cytokines like tumor necrosis factor has failed. Future sepsis treatments must consider the complex immune response, not just single cytokine inhibition.
Area of Science:
- Immunology
- Critical Care Medicine
- Pharmacology
Background:
- Sepsis treatment has historically targeted inflammatory responses.
- Clinical trials inhibiting tumor necrosis factor and interleukin 1 failed to improve outcomes.
- Preclinical data suggested cytokine inhibition would be effective in sepsis.
Purpose of the Study:
- To analyze the reasons for the failure of previous sepsis treatment trials.
- To explore new potential therapeutic targets in sepsis.
- To propose a more nuanced approach to sepsis immunomodulation.
Main Methods:
- Review of clinical trial data for sepsis interventions.
- Analysis of preclinical evidence supporting cytokine inhibition.
- Examination of evolving understanding of the inflammatory response in sepsis.
Main Results:
- Despite promising preclinical data, clinical trials blocking single cytokines (TNF, IL-1) were unsuccessful.
- New targets like interleukin 18 and HMG-1 have been identified.
- The complex, dynamic nature of sepsis suggests single-target inhibition is insufficient.
Conclusions:
- Previous sepsis treatment failures highlight the inadequacy of targeting single cytokines.
- A dynamic, phase-specific immunomodulatory strategy, potentially involving multiple targets or immune augmentation, is needed for effective sepsis treatment.
- Further research into the complex inflammatory pathways of sepsis is crucial for developing successful therapies.
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