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

Liu, Shu Fang, and Asrar B. Malik. NFB activation as a pathological mechanism of septic shock and inflammation. Am J Physiol Lung Cell Mol Physiol 290: L622–L645, 2006; doi:10.1152/ajplung.00477.2005.—The pathophysiology of sepsis and septic shock involves complex cytokine and inflammatory mediator networks. NFB activation is a central event leading to the activation of these networks. The role of NFB in septic pathophysiology and the signal transduction pathways leading to NFB activation during sepsis have been an area of intensive investigation. NFB is activated by a variety of pathogens known to cause septic shock syndrome. NFB activity is markedly increased in every organ studied, both in animal models of septic shock and in human subjects with sepsis. Greater levels of NFB activity are associated with a higher rate of mortality and worse clinical outcome. NFB 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 NFB-dependent genes are resistant to the development of septic shock and to septic lethality. More importantly, blockade of NFB pathway corrects septic abnormalities. Inhibition of NFB 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 NFB activation prevents multiple organ injury and improves survival in rodent models of septic shock. Thus NFB activation plays a central role in the pathophysiology of septic shock.