Eastern Regional Meeting - 2008 Program & Abstracts
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A CROSS-SPECIES ANALYSIS OF PLATELET GENE EXPRESSION IN SEPSIS SHOWS DYSREGULATION OF THE INNATE IMMUNE CYTOKINES IL-1 AND TNFα
A. S. Benton1, W. M. Ngor 1, B. Mojgani 1, R. J. Freishtat 1, 2, 3; 1. Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA. 2. Division of Emergency Medicine, Children's National Medical Center, Washington, DC, USA. 3. School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.
Purpose of Study: Little is known about the role of platelets in sepsis such that insights can be gained by investigating conserved platelet gene expression patterns across species. We aimed to identify evolutionarily conserved novel gene products and networks using a genome-wide cross-species comparison analysis.
Methods Used: We studied two publicly-available datasets of platelet mRNA in human and murine models of sepsis. In the murine dataset (n=3 microarrays) platelet mRNA was isolated from male BALB/c mice at 0, 24, and 48h status post cecal ligation and puncture and profiled using Affymetrix MOE430_2 GeneChips. A second dataset of platelet mRNA from septic children (n=6 microarrays) at 0 and 72h post diagnosis was profiled using Affymetrix U133A GeneChips. Both datasets were processed through the dChip difference model probe set algorithm to generate signals and imported into Genespring GX for analysis.
Summary of Results: We identified 2,381 probe sets (p<0.05) showing differential regulation in the murine sepsis model. These probe sets were translated into the human genome and used to generate a list of 247 significant probe sets (p<0.05) showing up- or down-regulation in human sepsis. We clustered the 247 probe sets and by visual inspection found down-regulation at 0h for two IL-1 probe sets and TNFa in patients with severe sepsis versus those with milder disease. Normalized expression values at 0h in severe sepsis were markedly lower than at any other time point or severity state (all p<0.02).
Conclusions: IL-1 and TNFa are cytokines crucial to the innate immune response. The lack of early up-regulation found in severe sepsis may be due to a selective immune deficiency. If this dysregulation is supported by ongoing studies, it will give new insight into the relatively poor clinical course seen in some patients.
Expression values in mild vs. severe sepsis
| |
Mild 0h |
Mild 72h |
Severe 0h |
Severe 72h |
| IL-1 probe set #1 |
24.09 |
32.48 |
0.82 |
21.62 |
| IL-1 probe set #2 |
14.54 |
17.19 |
0.19 |
13.06 |
| TNFα |
4.50 |
8.75 |
0.58 |
4.41 |
Expression values normalized to 1.0
|
