Abstract
IntroductionExperimental data from animal models of sepsis support a role for a transcription factor, nuclear erythroid-related factor 2 p45-related factor 2 (Nrf2), as a master regulator of antioxidant and detoxifying genes and intermediary metabolism during stress. Prior analysis of a pediatric septic shock transcriptomic database showed that the Nrf2 response is a top 5 upregulated signaling pathway in early pediatric septic shock.MethodsWe conducted a focused analysis of 267 Nrf2-linked genes using a multicenter, genome-wide expression database of 180 children with septic shock 10 years of age or younger and 53 healthy controls. The analysis involved RNA isolated from whole blood within 24 h of pediatric intensive care unit admission for septic shock and a false discovery rate of 5 %. We compared differentially expressed genes from (1) patients with septic shock and healthy controls and (2) across validated gene expression–based subclasses of pediatric septic shock (endotypes A and B) using several bioinformatic methods.ResultsWe found upregulation of 123 Nrf2-linked genes in children with septic shock. The top gene network represented by these genes contained primarily enzymes with oxidoreductase activity involved in cellular lipid metabolism that were highly connected to the peroxisome proliferator activated receptor and the retinoic acid receptor families. Endotype A, which had higher organ failure burden and mortality, exhibited a greater downregulation of Nrf2-linked genes than endotype B, with 92 genes differentially regulated between endotypes.ConclusionsOur findings indicate that Nrf2-linked genes may contribute to alterations in oxidative signaling and intermediary metabolism in pediatric septic shock.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-1052-0) contains supplementary material, which is available to authorized users.
Highlights
Experimental data from animal models of sepsis support a role for a transcription factor, nuclear erythroid-related factor 2 p45-related factor 2 (Nrf2), as a master regulator of antioxidant and detoxifying genes and intermediary metabolism during stress
Evidence for mitochondrial dysfunction in pediatric septic shock is supported by a recent report that nuclearencoded mitochondrial genes are differentially expressed early in pediatric septic shock compared with healthy controls and across septic shock endotypes [16]
Nrf2-linked genes involved in cellular lipid metabolism were predominantly upregulated early in pediatric septic shock compared with healthy controls
Summary
Experimental data from animal models of sepsis support a role for a transcription factor, nuclear erythroid-related factor 2 p45-related factor 2 (Nrf2), as a master regulator of antioxidant and detoxifying genes and intermediary metabolism during stress. Prior analysis of a pediatric septic shock transcriptomic database showed that the Nrf response is a top 5 upregulated signaling pathway in early pediatric septic shock. Direct measurements of mitochondrial respiration demonstrated decreased bioenergetic reserve and increased mitochondrial uncoupling in peripheral blood mononuclear cells of children with early sepsis [17]. Analysis of an established genome-wide expression database of children with septic shock [22] demonstrated that the Nrf oxidative stress response pathway is upregulated in children with septic shock [23]
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