Physiol. Genomics 30: 146-155, 2007.
First published March 20, 2007; doi:10.1152/physiolgenomics.00024.2007
1094-8341/07 $8.00
Received 1 February 2007;
accepted in final form 19 March 2007.
Physiological Genomics 30:146-155 (2007)
1094-8341/07 $8.00 © 2007 American Physiological Society
Genome-level expression profiles in pediatric septic shock indicate a role for altered zinc homeostasis in poor outcome
Hector R. Wong1,
Thomas P. Shanley2,
Bhuvaneswari Sakthivel1,
Natalie Cvijanovich3,
Richard Lin4,
Geoffrey L. Allen5,
Neal J. Thomas6,
Allan Doctor7,
Meena Kalyanaraman8,
Nancy M. Tofil9,
Scott Penfil10,
Marie Monaco1,
Mary Ann Tagavilla1,
Kelli Odoms1,
Katherine Dunsmore1,
Michael Barnes1,
Bruce J. Aronow1 for the Genomics of Pediatric SIRS/Septic Shock Investigators
*
1 Cincinnati Children's Hospital Medical Center and Cincinnati Children's Hospital Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
2 C. S. Mott Children's Hospital at the University of Michigan, Ann Arbor, Michigan
3 Children's Hospital and Research Center Oakland, Oakland, California
4 Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
5 Children's Mercy Hospital, Kansas City, Missouri
6 Penn State Children's Hospital, Hershey, Pennsylvania
7 University of Virginia Medical Center, Charlottesville, Virginia
8 Newark Beth Israel Medical Center, Newark, New Jersey
9 University of Alabama at Birmingham, Birmingham, Alabama
10 DuPont Hospital for Children, Wilmington, Delaware
Human septic shock involves multiple genome-level perturbations. We have conducted microarray analyses in children with septic shock within 24 h of intensive care unit admission, using whole blood-derived RNA. Based on sequential statistical and expression filters, there were 2,482 differentially regulated gene probes (1,081 upregulated and 1,401 downregulated) between patients with septic shock (n = 42) and controls (n = 15). Both gene lists encompassed several biologically relevant gene ontologies and canonical pathways. Notably, many of the genes downregulated in the patients with septic shock, relative to the controls, participate in gene ontologies related to metal or zinc homeostasis. Comparison of septic shock survivors (n = 33) and nonsurvivors (n = 9) demonstrated differential regulation of 63 gene probes. Among the 63 gene probes differentially regulated between septic shock survivors and nonsurvivors, two isoforms of metallothionein (MT) demonstrated increased expression in the nonsurvivors. Consistent with the ability of MT to sequester zinc in the intracellular compartment, nonsurvivors had lower serum zinc levels compared with survivors. In a corroborating study of murine sepsis, MT-null mice demonstrated a survival advantage compared with wild-type mice. These data represent the largest reported cohort of pediatric patients with septic shock that has undergone genome-level expression profiling based on microarray. The data are biologically plausible and demonstrate that genome-level alterations of zinc homeostasis may be prevalent in clinical pediatric septic shock.
inflammation; pediatrics; innate immunity
Copyright © 2007 by the American Physiological Society.
