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INVITED REVIEW

NF-B activation as a pathological mechanism of septic shock and inflammation

Division of Pulmonary and Critical Care Medicine, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York; and Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois

The pathophysiology of sepsis and septic shock involves complex cytokine and inflammatory mediator networks. NF-B activation is a central event leading to the activation of these networks. The role of NF-B in septic pathophysiology and the signal transduction pathways leading to NF-B activation during sepsis have been an area of intensive investigation. NF-B is activated by a variety of pathogens known to cause septic shock syndrome. NF-B activity is markedly increased in every organ studied, both in animal models of septic shock and in human subjects with sepsis. Greater levels of NF-B activity are associated with a higher rate of mortality and worse clinical outcome. NF-B mediates the transcription of exceptional large number of genes, the products of which are known to play important roles in septic pathophysiology. Mice deficient in those NF-B-dependent genes are resistant to the development of septic shock and to septic lethality. More importantly, blockade of NF-B pathway corrects septic abnormalities. Inhibition of NF-B activation restores systemic hypotension, ameliorates septic myocardial dysfunction and vascular derangement, inhibits multiple proinflammatory gene expression, diminishes intravascular coagulation, reduces tissue neutrophil influx, and prevents microvascular endothelial leakage. Inhibition of NF-B activation prevents multiple organ injury and improves survival in rodent models of septic shock. Thus NF-B activation plays a central role in the pathophysiology of septic shock.

nuclear factor-B; septic pathophysiology; cytokines; signal transduction

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