Endotoxemia induced by the administration of low-dose lipopolysaccharide (LPS) to healthy human volunteers is a well-established experimental protocol and has served as a reproducible platform for investigating the responses to systemic inflammation. Since metabolic composition of a tissue or body fluid is uniquely altered by stimuli and provide information about the dominant regulatory mechanisms at various cellular processes, understanding the global metabolic response to systemic inflammation constitutes a major part in this investigation complementing the studies undertaken so far in both clinical and systems biology fields. This article communicates the first proof-of-principle metabonomic analysis which comprised of global biochemical profiles in human plasma samples from healthy subjects given intravenous endotoxin at 2 ng/kg. Concentrations of a total of 366 plasma biochemicals were determined in archived blood samples collected from 15 endotoxin treated subjects at 5 time points within 24 hour post-treatment and compared with control samples collected from 4 saline treated subjects. Principal component analysis within this dataset determined the 6th hour as a critical time point separating development and recovery phases of the LPS induced metabolic changes. Consensus clustering of the differential metabolites identified two distinct subsets of metabolites which displayed common coherent profiles with opposing directionality. The first group of metabolites, which were mostly associated with pathways related to lipid metabolism, was up-regulated within the first 6 hr and down-regulated by the 24th hr following LPS administration. The second group of metabolites, in contrast, was first down-regulated until the 6th hr, then up-regulated. Metabolites in this group were predominantly amino acids or their derivatives. In sum, non-targeted biochemical profiling and unsupervised multivariate analyses highlighted the prominent roles of lipid and protein metabolism in regulating the response to systemic inflammation while also revealing their dynamics in opposite directions.

Severe traumas are associated with hypercortisolemia due to both disruption of cortisol secretion rhythm and increase in its total concentration. Understanding the effects of altered cortisol levels and rhythms on immune function is of great clinical interest, to prevent conditions such as sepsis from complicating the recovery. This in vivo study assesses the responses of circulating leukocytes to coupled dose and rhythm manipulation of cortisol, preceding an immune challenge induced by endotoxin administration. Through continuous infusion, plasma cortisol concentration was increased to and kept constant at a level associated with major physiologic stress. In response, transcriptional programming of leukocytes was altered to display a priming response before endotoxin exposure. Enhanced expression of a number of receptors and signaling proteins, as well as lowered protein translation and mitochondrial function indicated a sensitization against potential infectious threats. Despite these changes, response to endotoxin followed very similar patterns in both cortisol and saline pre-treated groups except one cluster including probe sets associated with major players regulating inflammatory response. In sum, altered dose and rhythm of plasma cortisol levels engendered priming of circulating leukocytes when preceded an immune challenge. This transcriptional program change associated with stimulated surveillance function and suppressed energy-intensive processes, emphasized permissive actions of cortisol on immune function.