Omics Signatures of Tissue Injury and Hemorrhagic Shock in Swine

Abstract

Objective: Advanced mass spectrometry methods were leveraged to analyze both proteomics and metabolomics signatures in plasma upon controlled tissue injury (TI) and hemorrhagic shock (HS)-isolated or combined-in a swine model, followed by correlation to viscoelastic measurements of coagulopathy via thrombelastography. Background: TI and HS cause distinct molecular changes in plasma in both animal models and trauma patients. However, the contribution to coagulopathy of trauma, the leading cause of preventable mortality in this patient population remains unclear. The recent development of a swine model for isolated or combined TI+HS facilitated the current study. Methods: Male swine (n = 17) were randomized to either isolated or combined TI and HS. Coagulation status was analyzed by thrombelastography during the monitored time course. The plasma fractions of the blood draws (at baseline; end of shock; and at 30 minutes, 1, 2, and 4 hours after shock) were analyzed by mass spectrometry-based proteomics and metabolomics workflows. Results: HS-isolated or combined with TI-caused the most severe omic alterations during the monitored time course. While isolated TI delayed the activation of coagulation cascades. Correlation to thrombelastography parameters of clot strength (maximum amplitude) and breakdown (LY30) revealed signatures of coagulopathy which were supported by analysis of gene ontology-enriched biological pathways. Conclusion:The current study provides a comprehensive characterization of proteomic and metabolomic alterations to combined or isolated TI and HS in a swine model and identifies early and late omics correlates to viscoelastic measurements in this system.

Increase in Plasma Succinate Correlates With Aerobic Lactate Production in a Porcine Model of Endotoxic Shock

“…Our results are also consistent with metabolomic data from septic patients, which report elevated plasma citrate concentrations in nonsurviving subjects (6, 22) and in patients with deteriorating organic function (36). Concerning increased succinate levels, their increase has been reported in a retrospective cohort of septic shock patients (21) and in various animal shock models (13,14,27). Most of these studies associate the increase in citrate and succinate with a poor prognosis, since their elevation denotes a failure of the TCA cycle in the uptake of these metabolites, which represents a disturbance in the redox state of the cell (28, 29).…”

Multiomics Signatures of Coagulopathy in a Polytrauma Swine Model Contrasted with Severe Multisystem Injured Patients

“…Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), respiratory rate (RR), and end-tidal CO 2 were monitored continuously . Blood draws were performed at baseline, at the end of shock (EOS), and at 30 min and 1, 2, 3, and 4 h after EOS.…”

“…Over the past decade, the introduction of omics technologies to the field of surgery and critical care has expanded the concept of cell-based hemostasis to a more comprehensive and systems-level understanding of dysfunctional metabolism beyond elevated lactatemia, clotting, and fibrinolytic events. , A deeper understanding of drivers of metabolic acidosis and coagulopathy has been achieved by combining omics investigation of clinical cohorts of critically ill patients ,, and tractable preclinical mammalian models, from rodents − to swine − and nonhuman primates . Omics characterization of markers of coagulopathy in swine have been recently reported, suggesting that swine are an appropriate system to investigate the effect of polytrauma . Leveraging large mammals also affords the opportunity to monitor the impact of isolated variables, such as the effect of tissue injury alone, with or without hemorrhage, in the presence or absence of TBIwithout confounding iatrogenic interventions such as transfusion of blood products .…”