The effect of the post-trauma milieu on endothelial metabolism: Ex-vivo trauma plasma from severely injured and shocked patients causes oxidative stress, mitochondrial dysfunction, and fatty acid oxidation deficiency in human endothelial cells

Abstract text (incl. references and figure legends)

Introduction: Trauma causes a thromboinflammatory milieu characterized by coagulopathy and metabolic perturbations, however, the specific metabolic response of endothelial cells remains unknown. We hypothesized that when exposed to ex-vivo trauma plasma, the metabolic underpinnings of the endothelial response to trauma can be elucidated and would be characterized by dysregulation of metabolic pathways.

Material & Methods: Ex-vivo plasma was collected upon arrival from trauma patients at a single level 1 trauma center. Patients were divided by injury severity score (ISS) and base deficit (BD) (Group 1 ISS=1 BD=0.6, Group 2 ISS=50 BD=16). Human umbilical vein endothelial cells were grown to 80% confluence and incubated with 10% trauma patient plasma. Cells and media were collected at multiple time points from 5 minutes to 24 hours and analyzed with mass spectrometry for metabolomic analysis. Significant metabolites were determined using FDR-corrected 2-way ANOVA (p<0.05) as well as multivariate empirical Bayes time-series analysis.

Results: The metabolic response of endothelial cells exposed to trauma plasma reflects a state of oxidative stress, mitochondrial dysfunction, and fatty acid oxidation deficiency. This state of oxidative stress is supported by increased dehydroascorbate in group 2, indicating an overwhelming of the glutathione reductase system (Fig 1). Group 2 had higher levels of succinate, malate, taurine, and creatine indicating mitochondrial dysfunction. Finally, group 2 exhibited increased acyl-carnitine species with decreased free fatty acids indicating an inability to oxidize fatty acids for ATP production (Fig 2).

Conclusions: The post-trauma milieu causes signaling resulting in metabolic crisis. Future studies will further probe the mechanism underlying this phenotype to identify the mediators responsible for the post-trauma response. Endotyping the post-trauma response can guide improved personalized resuscitation and treatment after injury.

Disclosure: Do you have a significant financial interest, consultancy or other relationship with products, manufacturer(s) of products or providers of services related to this abstract? (If not, please enter "No" in the text field.)

No