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An integrated clinico-transcriptomic approach identifies a central role of the heme degradation pathway for septic complications after trauma


Rittirsch, Daniel; Schoenborn, Veit; Lindig, Sandro; Wanner, Elisabeth; Sprengel, Kai; Günkel, Sebastian; Blaess, Markus; Schaarschmidt, Barbara; Sailer, Patricia; Märsmann, Sonja; Simmen, Hans-Peter; Cinelli, Paolo; Bauer, Michael; Claus, Ralf A; Wanner, Guido A (2016). An integrated clinico-transcriptomic approach identifies a central role of the heme degradation pathway for septic complications after trauma. Annals of Surgery, 264(6):1125-1134.

Abstract

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.

Abstract

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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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Department of Trauma Surgery
04 Faculty of Medicine > University Hospital Zurich > Clinic for Reconstructive Surgery
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Surgery
Language:English
Date:2016
Deposited On:12 Jan 2016 09:23
Last Modified:26 Jan 2022 07:52
Publisher:Lippincott Williams & Wilkins
ISSN:0003-4932
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1097/SLA.0000000000001553
PubMed ID:26727089

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