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An Integrated Clinico-transcriptomic Approach Identifies a Central Role of the Heme Degradation Pathway for Septic
Daniel Rittirsch1, Veit Schoenborn, Sandro Lindig
1*Division of Trauma Surgery, Department of Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland†Department of Anaesthesiology and Intensive Care Therapy, Jena University Hospital, Jena, Germany‡Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
Objective:
The present study was aimed to identify mechanisms linked to complicated courses and adverse events after severe trauma by a systems biology approach.
Summary Background Data:
In severe trauma, overwhelming systemic inflammation can result in additional damage and the development of complications, including sepsis.
Methods:
In a prospective, longitudinal single-center study, RNA samples from circulating leukocytes from patients with multiple injury (injury severity score ≥17 points; n = 81) were analyzed for dynamic changes in gene expression over a period of 21 days by whole-genome screening (discovery set; n = 10 patients; 90 samples) and quantitative RT-PCR (validation set; n = 71 patients, 517 samples). Multivariate correlational analysis of transcripts and clinical parameters was used to identify mechanisms related to sepsis.
Results:
Transcriptome profiling of the discovery set revealed the strongest changes between patients with either systemic inflammation or sepsis in gene expression of the heme degradation pathway. Using quantitative RT-PCR analyses (validation set), the key components haptoglobin (HP), cluster of differentiation (CD) 163, heme oxygenase-1 (HMOX1), and biliverdin reductase A (BLVRA) showed robust changes following trauma. Upregulation of HP was associated with the severity of systemic inflammation and the development of sepsis. Patients who received allogeneic blood transfusions had a higher incidence of nosocomial infections and sepsis, and the amount of blood transfusion as source of free heme correlated with the expression pattern of HP.
Conclusions:
These findings indicate that the heme degradation pathway is associated with increased susceptibility to septic complications after trauma, which is indicated by HP expression in particular.
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