title: Differential expression of the Nrf2-linked genes in pediatric septic shock.
abstract: BACKGROUND
  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.
authors.affiliation: Division of Critical Care Medicine, Department of Pediatrics, Children's Healthcare of Atlanta at Egleston, Emory University School of Medicine, 1405 Clifton Road N.E., Atlanta, GA, 30322, USA. jgrunwe@emory.edu.
authors.forename: Jocelyn R
authors.initials: JR
authors.lastname: Grunwell
authors.affiliation: Division of Critical Care Medicine, Department of Anesthesia and Critical Care, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, 3620 Hamilton Walk, Philadelphia, PA, 19104, USA. weiss5@email.chop.edu.|Center for Resuscitation Science, University of Pennsylvania Perelman School of Medicine, 3620 Hamilton Walk, Philadelphia, PA, 19104, USA. weiss5@email.chop.edu.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Weiss
authors.affiliation: UCSF, Benioff Children's Hospital Oakland, 757 52nd Street, Oakland, CA, 94609, USA. ncvijanovich@mail.cho.org.
authors.forename: Natalie Z
authors.initials: NZ
authors.lastname: Cvijanovich
authors.affiliation: Children's Mercy Hospital, 2401 Gillham Road, Kansas City, MO, 64108, USA. glallen@cmh.edu.
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Allen
authors.affiliation: Penn State Children's Hospital, 500 University Drive, Hershey, PA, 17033, USA. nthomas@hmc.psu.edu.
authors.forename: Neal J
authors.initials: NJ
authors.lastname: Thomas
authors.affiliation: Children's National Medical Center, 111 Michigan Avenue N.W., Washington, DC, 20010, USA. rfreishtat@childrensnational.org.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Freishtat
authors.affiliation: Children's Hospital of Orange County, 1201 West La Veta Avenue, Orange, CA, 92868, USA. nanas@choc.org.
authors.forename: Nick
authors.initials: N
authors.lastname: Anas
authors.affiliation: Miami Children's Hospital, 3100 S.W. 62nd Avenue, Miami, FL, 33155, USA. keith.meyer@mch.com.
authors.forename: Keith
authors.initials: K
authors.lastname: Meyer
authors.affiliation: Texas Children's Hospital, 6621 Fannin Street, Houston, TX, 77030, USA. pachecch@texaschildrens.org.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Checchia
authors.affiliation: C.S. Mott Children's Hospital at the University of Michigan, 1540 East Hospital Drive, Ann Arbor, MI, 48109, USA. tshanley@med.umich.edu.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Shanley
authors.affiliation: Akron Children's Hospital, 1 Perkins Square, Akron, OH, 44302, USA. mbigham@chmca.org.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bigham
authors.affiliation: Division of Critical Care Medicine, Department of Anesthesia and Critical Care, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, 3620 Hamilton Walk, Philadelphia, PA, 19104, USA. fitzgeraldj@email.chop.edu.
authors.forename: Julie
authors.initials: J
authors.lastname: Fitzgerald
authors.affiliation: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, 3333 Burnet Avenue, MLC 2005, Cincinnati, OH, 45229, USA. kelli.howard@cchmc.org.
authors.forename: Kelli
authors.initials: K
authors.lastname: Howard
authors.affiliation: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, 3333 Burnet Avenue, MLC 2005, Cincinnati, OH, 45229, USA. erin.frank@cchmc.org.
authors.forename: Erin
authors.initials: E
authors.lastname: Frank
authors.affiliation: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, 3333 Burnet Avenue, MLC 2005, Cincinnati, OH, 45229, USA. kelli.harmon@cchmc.org.
authors.forename: Kelli
authors.initials: K
authors.lastname: Harmon
authors.affiliation: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, 3333 Burnet Avenue, MLC 2005, Cincinnati, OH, 45229, USA. hector.wong@cchmc.org.|Department of Pediatrics, University of Cincinnati College of Medicine, 3230 Eden Avenue, Cincinnati, OH, 45267, USA. hector.wong@cchmc.org.|Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA. hector.wong@cchmc.org.
authors.forename: Hector R
authors.initials: HR
authors.lastname: Wong
mesh_terms: D002675:Child, Preschool; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D018805:Sepsis / Q000175:diagnosis / Q000235:genetics*; D012772:Shock, Septic / Q000235:genetics / Q000401:mortality / Q000473:pathology*
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human