TY - JOUR
T1 - Genome-level expression profiles in pediatric septic shock indicate a role for altered zinc homeostasis in poor outcome
AU - Wong, Hector R.
AU - Shanley, Thomas P.
AU - Sakthivel, Bhuvaneswari
AU - Cvijanovich, Natalie
AU - Lin, Richard
AU - Allen, Geoffrey L.
AU - Thomas, Neal J.
AU - Doctor, Allan
AU - Kalyanaraman, Meena
AU - Tofil, Nancy M.
AU - Penfil, Scott
AU - Monaco, Marie
AU - Tagavilla, Mary Ann
AU - Odoms, Kelli
AU - Dunsmore, Katherine
AU - Barnes, Michael
AU - Aronow, Bruce J.
PY - 2007/7/18
Y1 - 2007/7/18
N2 - 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.
AB - 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.
KW - Inflammation
KW - Innate immunity
KW - Pediatrics
UR - http://www.scopus.com/inward/record.url?scp=34547470882&partnerID=8YFLogxK
U2 - 10.1152/physiolgenomics.00024.2007
DO - 10.1152/physiolgenomics.00024.2007
M3 - Article
C2 - 17374846
AN - SCOPUS:34547470882
SN - 1094-8341
VL - 30
SP - 146
EP - 155
JO - Physiological genomics
JF - Physiological genomics
IS - 2
ER -