Molecular signatures of sepsis - Multiorgan gene expression profiles of systemic inflammation

During sepsis the host's system-wide response to microbial invasion seems d ysregulated. Here we explore the diverse multiorgan transcriptional program s activated during systemic inflammation in a cecal ligation/puncture model of sepsis in rats. Using DNA microarrays representing 7398 genes, we exami ned the temporal sequence of sepsis-induced gene expression patterns in maj or organ systems including lung, liver, kidney, thymus, spleen, and brain. Although genes known to be associated with systemic inflammation were ident ified by our global transcript analysis, many genes and expressed sequence tags not previously linked to the septic response were also elucidated. Tak en together, our results suggest activation of a highly complex transcripti onal response in individual organs of the septic animal. Several overlying themes emerged from our genome-scale analysis that includes 1) the sepsis r esponse elicited gene expression profiles that were either organ-specific, common to more than one organ, or distinctly opposite in some organs; 2) th e brain is protected from sepsis-induced gene activation relative to other organs; 3) the thymus and spleen have an interesting cohort of genes with o pposing gene expression patterns; 4) genes with proinflammatory effects wer e often balanced by genes with anti-inflammatory effects (eg, interfeukin-1 beta /decoy receptor, xanthine oxidase/superoxide dismutase, Ca2+-dependen t PLA(2)/Ca2+-independent PLA(2)); and 5) differential gene expression was observed in proteins responsible for preventing tissue injury and promoting homeostasis including anti-proteases (TIMP-1, Cpi-26), oxidant neutralizin g enzymes (metallothionein), cytokine decoy receptors (interleukin-1RII), a nd tissue/vascular permeability factors (aquaporin 5, vascular endothelial growth factor). This global perspective of the sepsis response should provi de a molecular framework for future research into the pathophysiology of sy stemic inflammation. Understanding, on a genome scale, how an organism resp onds to infection, may facilitate the development of enhanced detection and treatment modalities for sepsis.