J Bauzá-Martinez1, F Aletti2, B B Pinto3, V Ribas4, M A Odena1, R Díaz1, E Romay5, R Ferrer6, E B Kistler7, G Tedeschi8, G W Schmid-Schönbein2, A Herpain9, K Bendjelid10, E de Oliveira11. 1. Proteomics Platform, Barcelona Science Park, Barcelona, Spain. 2. Department of Bioengineering, University of California San Diego, La Jolla, CA, USA. 3. Geneva University Hospital, Geneva, Switzerland. 4. Eurecat, Technology Centre of Catalonia, Barcelona, Spain. 5. University Hospital Mútua Terrassa, Barcelona, Spain. 6. Intensive Care Department, Vall d'Hebron University Hospital, Barcelona, Spain. 7. Department of Anesthesiology and Critical Care, VA San Diego Healthcare System, San Diego, CA, USA. 8. Dipartimento di Medicina Veterinaria, Università degli Studi di Milano, Milan, Italy; Fondazione Filarete Milano, Milan, Italy. 9. Université Libre de Bruxelles, Brussels, Belgium. 10. Geneva University Hospital, Geneva, Switzerland. Electronic address: Karim.Bendjelid@hcuge.ch. 11. Proteomics Platform, Barcelona Science Park, Barcelona, Spain. Electronic address: eoliveira@pcb.ub.es.
Abstract
BACKGROUND: Uncontrolled proteolysis contributes to cell injury and organ dysfunction in animal models of circulatory shock. We investigated in humans the relationship between septic shock, proteolysis, and outcome. METHODS: Intensive care patients with septic shock (n=29) or sepsis (n=6) and non-hospitalised subjects (n=9) were recruited as part of the prospective observational trial 'ShockOmics' (ClinicalTrials.gov Identifier NCT02141607). A mass spectrometry-based approach was used to analyse the plasma peptidomes and the origin of circulating peptides from proteolysis in the enrolled subjects. RESULTS: Evidence of systemic proteolysis was indicated by a larger number of circulating peptides in septic shock patients, compared with septic patients and non-hospitalised healthy subjects. The peptide count and abundance in the septic shock patients were greater in patients who died (n=6) than in survivors (n=23), suggesting an association between magnitude of proteolysis and outcome. In silico analysis of the peptide sequences and of the sites of cleavage on the proteins of origin indicated a predominant role for serine proteases, such as chymotrypsin, and matrix metalloproteases in causing the observed proteolytic degradation. CONCLUSIONS: Systemic proteolysis is a novel fundamental pathological mechanism in septic shock. Plasma peptidomics is proposed as a new tool to monitor clinical trajectory in septic shock patients. CLINICAL TRIAL REGISTRATION: NCT02141607.
BACKGROUND: Uncontrolled proteolysis contributes to cell injury and organ dysfunction in animal models of circulatory shock. We investigated in humans the relationship between septic shock, proteolysis, and outcome. METHODS: Intensive care patients with septic shock (n=29) or sepsis (n=6) and non-hospitalised subjects (n=9) were recruited as part of the prospective observational trial 'ShockOmics' (ClinicalTrials.gov Identifier NCT02141607). A mass spectrometry-based approach was used to analyse the plasma peptidomes and the origin of circulating peptides from proteolysis in the enrolled subjects. RESULTS: Evidence of systemic proteolysis was indicated by a larger number of circulating peptides in septic shockpatients, compared with septicpatients and non-hospitalised healthy subjects. The peptide count and abundance in the septic shockpatients were greater in patients who died (n=6) than in survivors (n=23), suggesting an association between magnitude of proteolysis and outcome. In silico analysis of the peptide sequences and of the sites of cleavage on the proteins of origin indicated a predominant role for serine proteases, such as chymotrypsin, and matrix metalloproteases in causing the observed proteolytic degradation. CONCLUSIONS: Systemic proteolysis is a novel fundamental pathological mechanism in septic shock. Plasma peptidomics is proposed as a new tool to monitor clinical trajectory in septic shockpatients. CLINICAL TRIAL REGISTRATION: NCT02141607.
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