Genome-level expression profiles in pediatric septic shock indicate a role for altered zinc homeostasis in poor outcome

Hector R. Wong, Thomas P. Shanley, Bhuvaneswari Sakthivel, Natalie Cvijanovich, Richard Lin, Geoffrey L. Allen, Neal J. Thomas, Allan Doctor, Meena Kalyanaraman, Nancy M. Tofil, Scott Penfil, Marie Monaco, Mary Ann Tagavilla, Kelli Odoms, Katherine Dunsmore, Michael Barnes, Bruce J. Aronow

Research output: Contribution to journalArticle

161 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)146-155
Number of pages10
JournalPhysiological genomics
Volume30
Issue number2
DOIs
StatePublished - Jul 18 2007

All Science Journal Classification (ASJC) codes

  • Physiology
  • Genetics

Fingerprint Dive into the research topics of 'Genome-level expression profiles in pediatric septic shock indicate a role for altered zinc homeostasis in poor outcome'. Together they form a unique fingerprint.

  • Cite this

    Wong, H. R., Shanley, T. P., Sakthivel, B., Cvijanovich, N., Lin, R., Allen, G. L., Thomas, N. J., Doctor, A., Kalyanaraman, M., Tofil, N. M., Penfil, S., Monaco, M., Tagavilla, M. A., Odoms, K., Dunsmore, K., Barnes, M., & Aronow, B. J. (2007). Genome-level expression profiles in pediatric septic shock indicate a role for altered zinc homeostasis in poor outcome. Physiological genomics, 30(2), 146-155. https://doi.org/10.1152/physiolgenomics.00024.2007