Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

A genomic storm in critically injured humans

ABSTRACT: Human survival from injury requires an appropriate inflammatory and immune response. We describe the circulating leukocyte transcriptome after severe trauma and show that the severe stress produce a global reprioritization affecting >80% of the cellular functions and pathways, a truly unexpected “genomic storm.” In severe blunt trauma, the early leukocyte genomic response is consistent with simultaneously increased expression of genes involved in the systemic inflammatory, innate immune, and compensatory antiinflammatory responses, as well as in the suppression of genes involved in adaptive immunity. Furthermore, complications like nosocomial infections and organ failure are not associated with any genomic evidence of a second hit and differ only in the magnitude and duration of this genomic reprioritization. Blood was sampled from 167 severe blunt trauma patients under the age of 55 yr who consented to blood sampling. The first blood sample was taken within 12 h of the injury and 1, 4, 7, 14, 21, and 28 d after injury. Study subjects were treated under the guidance of standard operating procedures developed, implemented, and audited across all participating centers to minimize treatment variation. In addition, 37 healthy control subjects were sampled. Total blood leukocytes were isolated according to protocols published previously. Total cellular RNA was extracted and hybridized onto an HU133 Plus 2.0 GeneChip (Affymetrix) according to the manufacturer’s recommendations.

ORGANISM(S): Homo sapiens

SUBMITTER: IDDC Inflammation & the Host Response to Injury

PROVIDER: E-GEOD-36809 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

A genomic storm in critically injured humans.

Xiao Wenzhong W Mindrinos Michael N MN Seok Junhee J Cuschieri Joseph J Cuenca Alex G AG Gao Hong H Hayden Douglas L DL Hennessy Laura L Moore Ernest E EE Minei Joseph P JP Bankey Paul E PE Johnson Jeffrey L JL Sperry Jason J Nathens Avery B AB Billiar Timothy R TR West Michael A MA Brownstein Bernard H BH Mason Philip H PH Baker Henry V HV Finnerty Celeste C CC Jeschke Marc G MG López M Cecilia MC Klein Matthew B MB Gamelli Richard L RL Gibran Nicole S NS Arnoldo Brett B Xu Weihong W Zhang Yuping Y Calvano Steven E SE McDonald-Smith Grace P GP Schoenfeld David A DA Storey John D JD Cobb J Perren JP Warren H Shaw HS Moldawer Lyle L LL Herndon David N DN Lowry Stephen F SF Maier Ronald V RV Davis Ronald W RW Tompkins Ronald G RG

The Journal of experimental medicine 20111121 13

Human survival from injury requires an appropriate inflammatory and immune response. We describe the circulating leukocyte transcriptome after severe trauma and burn injury, as well as in healthy subjects receiving low-dose bacterial endotoxin, and show that these severe stresses produce a global reprioritization affecting >80% of the cellular functions and pathways, a truly unexpected "genomic storm." In severe blunt trauma, the early leukocyte genomic response is consistent with simultaneously ...[more]

PMID: 22110166

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Project description:INTRO: The ongoing challenge of accurately diagnosing infection in the ICU motivates a search for novel molecular diagnostics. In the current study, we tested the hypothesis that the informational content of circulating leukocytes differs, thereby allowing one to rank leukocyte populations on their potential to contribute to RNA diagnostics for pneumonia. METHODS: Sixteen patients (10 male, 6 female) at risk for VAP were entered into our IRB-approved study that collects blood and clinical data every 48 hours for up to 21 days. Four of the sixteen patients developed VAP as diagnosed and treated by the attending ICU physician. Previously reported blood protocols were used to isolate buffy coat, enriched neutrophil, and enriched monocyte populations by using negative selection. Cellular purity was assessed by FACS for one of the 4 VAP patients. Genome-wide expression analysis was performed on RMA-normalized signal from Affymetrix U133 2.0 Plus GeneChips. EDGE software (FDR=0.10) was used to determine changes in mRNA abundance over time for each cell population. RESULTS: During the 5-day window in which each of the four patients (all males) developed VAP, significant changes in gene expression were observed (Table 2), but the information content (number of genes altered) varied across leukocyte populations. These differences were not due to signal variance (coefficient of variation, CV) or differences in the number of samples available for analysis. Moreover, only 0.6% of the monocyte gene list overlaps with the neutrophil list, arguing that neutrophil contamination of monocyte populations is insufficient to explain the 40-fold difference in gene number. CONCLUSIONS: Enriched monocyte populations from circulating blood provide far more genes for study of the host response to VAP than the other 2 cell populations studied. This information should be considered when designing blood gene expression profiling experiments in patients at risk for sepsis. Keywords: time course Four patients over several timepoints measured three different cell types for VAP signal

Project description:Monitoring genome-wide, cell-specific responses to human disease, although challenging, holds great promise for medicineâs future. Patients with injury severe enough to develop multiple organ dysfunction syndrome (MODS) are known to have multiple immune derangements, including T-cell apoptosis and anergy combined with depressed monocyte antigen presentation. Genome-wide expression analysis of highly-enriched circulating leukocyte subpopulations, combined with cell-specific pathway analyses, offers a previously unavailable opportunity to discover novel leukocyte regulatory networks in critically injured patients. Severe injury induced significant changes in the T-cell, monocyte, and total leukocyte transcriptome, with only 12% of these genomic changes common to all three cell populations. T-cell-specific pathway analyses identified increased gene expression of several novel inhibitory receptors (PD-1, CD152, NRP-1, Lag3), and concomitant decreases in stimulatory receptors (CD28, CD4, IL-2Rï¡). Functional analysis of T-cells and monocytes confirmed reduced T-cell proliferation and increased cell surface expression of negative signaling receptors paired with decreased monocyte costimulation ligands. Thus, genome-wide expression from highly-enriched cell populations combined with knowledge-based pathway analyses leads to the identification of novel regulatory networks differentially expressed in injured patients. Importantly, application of cell separation, genome-wide expression, and cell specific pathway analyses can be used to discover novel pathway alterations in human disease. Experiment Overall Design: Type of experiment: Gene expression profiling of circulating total blood Experiment Overall Design: leukocytes, T-Cells, and Monocytes in severe trauma patients and healthy subjects. Experiment Overall Design: Experimental factors: Healthy subjects, 7 severely traumatized patients Experiment Overall Design: and 7 healthy subjects for transcriptome analysis. Venous blood samples Experiment Overall Design: were collected. Total blood leukocytes were isolated, and T-cell and Experiment Overall Design: monocyte populations were obtained from two subsequent aliquots of the Experiment Overall Design: leukocytes. Total leukocytes, enriched T-cells, and enriched monocytes were analyzed using Affymetrix GeneChip arrays. Experiment Overall Design: Number of hybridizations: 42 Human U133A GeneChip arrays (Affymetrix)

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A genomic storm in critically injured humans

Publications

A genomic storm in critically injured humans.

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