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

Jocelyn R. Grunwell, Scott L. Weiss, Natalie Z. Cvijanovich, Geoffrey L. Allen, Neal J. Thomas, Robert J. Freishtat, Nick Anas, Keith Meyer, Paul A. Checchia, Thomas P. Shanley, Michael T. Bigham, Julie Fitzgerald, Kelli Howard, Erin Frank, Kelli Harmon, Hector R. Wong*

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Article number327
JournalCritical Care
Volume19
Issue number1
DOIs
StatePublished - Sep 17 2015

Fingerprint

Septic Shock
Pediatrics
Genes
NF-E2 Transcription Factor
Databases
Pediatric Intensive Care Units
Retinoic Acid Receptors
Peroxisome Proliferator-Activated Receptors
Gene Regulatory Networks
Computational Biology
Lipid Metabolism
Sepsis
Oxidoreductases
Up-Regulation
Down-Regulation
Animal Models
Antioxidants
Genome
RNA
Gene Expression

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Grunwell, J. R., Weiss, S. L., Cvijanovich, N. Z., Allen, G. L., Thomas, N. J., Freishtat, R. J., ... Wong, H. R. (2015). Differential expression of the Nrf2-linked genes in pediatric septic shock. Critical Care, 19(1), [327]. https://doi.org/10.1186/s13054-015-1052-0
Grunwell, Jocelyn R. ; Weiss, Scott L. ; Cvijanovich, Natalie Z. ; Allen, Geoffrey L. ; Thomas, Neal J. ; Freishtat, Robert J. ; Anas, Nick ; Meyer, Keith ; Checchia, Paul A. ; Shanley, Thomas P. ; Bigham, Michael T. ; Fitzgerald, Julie ; Howard, Kelli ; Frank, Erin ; Harmon, Kelli ; Wong, Hector R. / Differential expression of the Nrf2-linked genes in pediatric septic shock. In: Critical Care. 2015 ; Vol. 19, No. 1.
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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.",
author = "Grunwell, {Jocelyn R.} and Weiss, {Scott L.} and Cvijanovich, {Natalie Z.} and Allen, {Geoffrey L.} and Thomas, {Neal J.} and Freishtat, {Robert J.} and Nick Anas and Keith Meyer and Checchia, {Paul A.} and Shanley, {Thomas P.} and Bigham, {Michael T.} and Julie Fitzgerald and Kelli Howard and Erin Frank and Kelli Harmon and Wong, {Hector R.}",
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Grunwell, JR, Weiss, SL, Cvijanovich, NZ, Allen, GL, Thomas, NJ, Freishtat, RJ, Anas, N, Meyer, K, Checchia, PA, Shanley, TP, Bigham, MT, Fitzgerald, J, Howard, K, Frank, E, Harmon, K & Wong, HR 2015, 'Differential expression of the Nrf2-linked genes in pediatric septic shock', Critical Care, vol. 19, no. 1, 327. https://doi.org/10.1186/s13054-015-1052-0

Differential expression of the Nrf2-linked genes in pediatric septic shock. / Grunwell, Jocelyn R.; Weiss, Scott L.; Cvijanovich, Natalie Z.; Allen, Geoffrey L.; Thomas, Neal J.; Freishtat, Robert J.; Anas, Nick; Meyer, Keith; Checchia, Paul A.; Shanley, Thomas P.; Bigham, Michael T.; Fitzgerald, Julie; Howard, Kelli; Frank, Erin; Harmon, Kelli; Wong, Hector R.

In: Critical Care, Vol. 19, No. 1, 327, 17.09.2015.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Differential expression of the Nrf2-linked genes in pediatric septic shock

AU - Grunwell, Jocelyn R.

AU - Weiss, Scott L.

AU - Cvijanovich, Natalie Z.

AU - Allen, Geoffrey L.

AU - Thomas, Neal J.

AU - Freishtat, Robert J.

AU - Anas, Nick

AU - Meyer, Keith

AU - Checchia, Paul A.

AU - Shanley, Thomas P.

AU - Bigham, Michael T.

AU - Fitzgerald, Julie

AU - Howard, Kelli

AU - Frank, Erin

AU - Harmon, Kelli

AU - Wong, Hector R.

PY - 2015/9/17

Y1 - 2015/9/17

N2 - 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.

AB - 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.

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Grunwell JR, Weiss SL, Cvijanovich NZ, Allen GL, Thomas NJ, Freishtat RJ et al. Differential expression of the Nrf2-linked genes in pediatric septic shock. Critical Care. 2015 Sep 17;19(1). 327. https://doi.org/10.1186/s13054-015-1052-0