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Mediators of septic shock: new approaches for interrupting the endogenous inflammatory cascade
1Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75235-9063.
Objectives:
To review the molecular pathogenesis of septic shock, with particular emphasis on the induction of cytokines by endotoxin. By understanding the mechanisms that result in the systemic inflammatory response, novel clinical interventions may be more effectively studied.
Data Sources:
The English medical literature was reviewed, including human clinical trials, animal experiments, and in vitro studies elucidating cellular and molecular interactions. Expert testimony from the Roundtable Conference on Sepsis (Brussels, March 1992) was also used to synthesize emerging concepts and to ensure inclusion of ongoing investigations.
Study Selection:
Emphasis on controlled experimental studies which elucidated the molecular and cellular interactions during sepsis.
Data Extraction:
This study focused only on data that directly involved the induction and regulation of protein mediators of sepsis, especially tumor necrosis factor (TNF) and interleukin-1. Data concerning the role of TNF during health were extracted from the author's peer-reviewed data.
Data Synthesis:
Information concerning the many facets of the systemic inflammatory response was integrated into a chronological, clinically oriented model of cytokine induction during endotoxemia.
Conclusions:
The induction of inflammation during sepsis is a complex, but increasingly understood, biological cascade that is dependent on inter- and intracellular signaling. Novel biotherapies may improve patient outcome in sepsis by interrupting any or all points of signal transduction.
Insights
Understanding endotoxin-induced cytokine production in septic shock reveals a complex signaling cascade. This knowledge aids in developing novel biotherapies targeting signal transduction to improve patient outcomes.
Area of Science:
- Molecular biology
- Immunology
- Pathogenesis of sepsis
Background:
- Septic shock involves a complex systemic inflammatory response.
- Endotoxin plays a key role in initiating this response through cytokine induction.
Purpose of the Study:
- To review the molecular pathogenesis of septic shock.
- To emphasize the induction of cytokines by endotoxin.
- To understand mechanisms for developing novel clinical interventions.
Main Methods:
- Review of English medical literature, including human trials, animal experiments, and in vitro studies.
- Inclusion of expert testimony from the Roundtable Conference on Sepsis.
- Focus on controlled studies of molecular and cellular interactions in sepsis.
Main Results:
- A chronological, clinically oriented model of cytokine induction during endotoxemia was developed.
- Emphasis was placed on the induction and regulation of key mediators like tumor necrosis factor (TNF) and interleukin-1.
Conclusions:
- Inflammation in sepsis is a complex biological cascade involving inter- and intracellular signaling.
- Novel biotherapies targeting signal transduction pathways offer potential for improved patient outcomes in sepsis.