Non-targeted data analysis as a means of identifying common temporal patterns in plasma metabolite levels and leukocyte transcriptional response to endotoxemia
Creators: name: Sleight, Kirsten Elizabeth
Publisher: name: No Publisher Supplied
Year: 2018

description: An experimental procedure which has provided insight into organ, tissue, and cell response to systemic inflammation is the administration of lipopolysaccharide (LPS) bacterial endotoxin to healthy human volunteers. At low doses, LPS briefly mimics the effects of acute injury or systemic inflammation in altering physiologic and metabolic processes. In the case of endotoxemia, an understanding of its effects on the plasma metabolite concentrations is crucial, as metabolite levels affect the regulation of anti-inflammatory defenses by impacting important processes in immune cells. This study attempts to perform a complete metabolomic analysis of the changes in plasma metabolite composition after exposure to LPS. In healthy volunteers, LPS administration was observed to cause significant alterations in lipid and protein metabolism homeostasis within the first 6 hr following LPS. The use of untargeted bioinformatics-based exploration of the data allowed for the identification of the dominant patterns of response. Plasma lipid levels steadily increased during the 6 hr following the administration of a low dose of LPS, before reversing direction during the recovery phase. In contrast, plasma levels of amino acids and amino acid derivatives decreased in the first 6 hr after LPS, before also reversing direction during the recovery phase.  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. By looking at transcriptional profiling of whole blood leukocytes in vivo, this study assessed their response to coupled rhythm and dose manipulation of cortisol levels preceding an immune challenge caused by the administration of LPS. The identification and clustering of probesets differentially expressed over time was used to correctly identify both the saline control group and the cortisol group without any prior knowledge of group assignments, and then to separate out three types of response to LPS exposure – cortisol suppressed, cortisol enhanced, and LPS dominated. The overall effect of the cortisol infusion seems to be an increase in the preparedness of immune cells to respond to potential threats, creating a preparatory effect to enhance the effectiveness of the immune response. These changes included an increase in the expression of genes coding for several cytokine and pattern recognition receptors, signal transduction elements, and receptor regulatory elements. Along with this, there was a decrease in the expression of genes that code for elements involved in protein translation, and for mitochondrial proteins. The increase in receptor and signal transduction protein expression indicated that the higher cortisol concentration served to prime the immune response, sensitizing cells to recognize and respond to potential infection or danger signals.