The etiology of sepsis: turned inside out.
The sepsis syndrome is thought to occur when microbial products activate Toll-like receptors stimulating widespread inflammation, in turn causing organ failure, shock and death. However, recent discoveries reveal that: (i) not only microbial substances but also endogenous molecules can trigger Toll-like receptors; (ii) Toll-like receptor-4, the endotoxin receptor, is constitutively suppressed; and (iii) the first step in sepsis could be the release of Toll-like receptor-4 from suppression. These discoveries suggest that endotoxin might not always initiate the sepsis syndrome and they explain why anti-endotoxin therapies fail. The discoveries also suggest new therapeutic targets - endogenous agonists and Toll-like receptor regulators - for treatment of sepsis.
Brunn
Gregory J
GJ
Transplantation Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Platt
Jeffrey L
JL
D000222:Adaptation, Physiological; D000818:Animals; D001424:Bacterial Infections / Q000150:complications; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008954:Models, Biological; D018805:Sepsis / Q000453:epidemiology / Q000209:etiology* / Q000276:immunology; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology; D051197:Toll-Like Receptor 4 / Q000276:immunology
D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4