Nuclear factor-kappaB and its role in sepsis-associated organ failure.
Nuclear factor (NF)-kappaB is involved in regulating the transcription of many of the immunomodulatory mediators involved in the development of sepsis-induced organ failure. Kinase pathways involving p38 and Akt and initiated by engagement of Toll-like receptors modulate transcriptional activity of NF-kappaB, but apparently through different mechanisms. Increased activation of NF-kappaB occurs with sepsis, and greater levels of nuclear accumulation of NF-kappaB are associated with higher rates of mortality and worse clinical outcome. The percentage of apoptotic neutrophils is reduced in sepsis, and inhibition of nuclear translocation of NF-kappaB restores neutrophil apoptosis to baseline levels. In models of sepsis, suppression of NF-kappaB activation decreases acute inflammatory processes and organ dysfunction. Because NF-kappaB occupies a central role in signaling pathways important in sepsis, modulation of NF-kappaB activity may be an appropriate therapeutic target in patients with sepsis.
Abraham
Edward
E
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. edward.abraham@uchsc.edu
D000818:Animals; D017209:Apoptosis; D004731:Endotoxins / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D009102:Multiple Organ Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction
D004731:Endotoxins; D016328:NF-kappa B