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Author Notes:

Email Address:Hector R Wong hector.wong@cchmc.org

JRG conceived and developed the study and wrote the manuscript.

HRW obtained funding for the study, conducted analyses, and edited the manuscript.

SLW, NZC, GLA, NJT, RJF, NA, KM, PAC, TPS, MTP, and JF enrolled subjects at the participating institutions and provided clinical data and biological samples.

KHo and EF maintained the clinical database and coordinated all interinstitutional research activity.

KHa maintained the biological repository and processed all biological samples. All authors read, edited, and approved the manuscript.

The NIH had no role in the design, collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.

The authors declare that they have no competing interests.

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Research Funding:

Financial support was provided by National Institutes of Health (NIH) grants R01 GM108025 and R01 GM099773 (to HRW).

JRG is supported by NIH grant T32GM095442. SLW is supported by National Institute of General Medical Sciences grant K23GM110496.

Differential expression of the Nrf2-linked genes in pediatric septic shock

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Journal Title:

Critical Care Nursing Quarterly

Volume:

Volume 19, Number 1

Publisher:

Type of Work:

Article | Final Publisher PDF

Abstract:

Introduction 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 Nrf2 response is a top 5 upregulated signaling pathway in early pediatric septic shock. Methods We 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. Results We 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. Conclusions Our findings indicate that Nrf2-linked genes may contribute to alterations in oxidative signaling and intermediary metabolism in pediatric septic shock.

Copyright information:

© 2015 Grunwell et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

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