“Defining” Sepsis: Moving Toward Measuring the “Dysregulated Host Response”*
In this issue of Critical Care Medicine, Hoogendijk et al (8) take what is perhaps the first step in this process. These investigators obtained blood samples from septic patients and examined activity in a number of different leukocyte subpopulations, seeking evidence of an immune state that differed from those of the healthy individuals whose samples serve as controls. The study was appropriately conducted, and although there are some issues regarding design, it is most important to discuss what these investigations can tell us about the “dysregulated host response.”
Hoogendijk et al (8) focused on two key inflammatory pathways; one involving cytoplasmic responses mediated by the mitogen-activated protein kinase p38 and the second the activation of several key transcriptional regulators collectively referred to as “nuclear factor kappa B” (NF-κB). Because p38 activity in study septic patients and controls did not differ appreciably, our discussion will focus solely on NF-κB.
NF-κB has been called the “master regulator of inflammation” (9). Although Hoogendijk et al (8) discuss some basic aspects of NF-κB biology (8), it is important to add additional details. The name NF-κB reflects the initial discovery of this mediator; in 1968, Sen and Baltimore (10) identified its role in the transcription of immunoglobulin κ-light chains in B-lymphocytes. The basic, active NF-κB molecule (Fig. 1) is a dimer composed of two of five species (11). Among these five, three—RelA (also called p65), RelB, and c-Rel—have a highly conserved immunoglobulin-like N-terminus that facilitates dimerization, DNA binding and interaction with other proteins, especially cytoplasmic inhibitor molecules. The carboxy-terminus, in turn, contains an element that confers transcriptional activity. In contrast, the other two molecules p50 and p52 each arise from the proteosomal degradation of a precursor (p105 and p100, respectively) and lack the domain that effects transcription (12).