Document Detail


Integrative 'Omic Analysis of Experimental Bacteremia Identifies a Metabolic Signature that Distinguishes Human Sepsis from SIRS.
MedLine Citation:
PMID:  25054455     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Rationale: Sepsis is a leading cause of morbidity and mortality. Currently, early diagnosis and the progression of the disease are difficult to make. The integration of metabolomic and transcriptomic data in a primate model of sepsis may provide a novel molecular signature of clinical sepsis. Objectives: Develop a biomarker panel to characterize sepsis in primates and ascertain its relevance to early diagnosis and progression of human sepsis. Methods: Intravenous inoculation of Macaca fascicularis with Escherichia coli produced mild to severe sepsis, lung injury and death. Plasma samples were obtained before and after one, three, and five days of E. coli challenge and at the time of euthanasia. At necropsy, blood, lung, kidney and spleen samples were collected. An integrative analysis of the metabolomic and transcriptomic datasets was performed to identify a panel of sepsis biomarkers. Measurements and Main Results: The extent of E. coli invasion, respiratory distress, lethargy and mortality was dependent on the bacterial dose. Metabolomic and transcriptomic changes characterized severe infections and death and indicated impaired mitochondrial, peroxisomal and liver functions. Analysis of the pulmonary transcriptome and plasma metabolome suggested impaired fatty acid catabolism regulated by peroxisome-proliferator activated receptor signaling. A representative 4-metabolite model effectively diagnosed sepsis in primates (AUC 0.966) and in two human sepsis cohorts (AUC=0.78 and 0.82). Conclusion: A model of sepsis based on reciprocal metabolomic and transcriptomic data was developed in primates and validated in two human patient cohorts. It is anticipated that the identified parameters will facilitate early diagnosis and management of sepsis.
Authors:
Raymond J Langley; Jennifer L Tipper; Shannon Bruse; Rebecca M Baron; Ephraim L Tsalik; James Huntley; Angela J Rogers; Richard J Jaramillo; Denise O'Donnell; William M Mega; Mignon Keaton; Elizabeth Kensicki; Lee Gazourian; Laura E Fredenburgh; Anthony F Massaro; Ronny M Otero; Vance G Fowler Jr; Emanuel P Rivers; Chris W Woods; Stephen F Kingsmore; Mohan L Sopori; Mark A Perrella; Augustine M K Choi; Kevin S Harrod
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-7-23
Journal Detail:
Title:  American journal of respiratory and critical care medicine     Volume:  -     ISSN:  1535-4970     ISO Abbreviation:  Am. J. Respir. Crit. Care Med.     Publication Date:  2014 Jul 
Date Detail:
Created Date:  2014-7-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421642     Medline TA:  Am J Respir Crit Care Med     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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