Resuscitation with blood products has been the mainstay of restoring oxygenation and pro-coagulant potential following major trauma/hemorrhagic shock (T/HS). With better overall survival due to the implementation of damage control surgery, the acute coagulopathy of trauma (ACoT) has emerged as a leading cause of mortality through the consumption of clotting factors and platelets and pro-inflammatory changes in the vascular endothelium (ECs) via activation of serine proteases. In sum, the physiologic mechanisms of T/HS and ACoT appear to deplete anti-proteases, while activating plasma proteases, changing the injured patients'phenotype to pro-inflammatory, mediated through stimulation of protease-activated receptors (PARS) on ECs and neutrophils (PMNs). These clinical events predispose patients to PMN-mediated post-injury multiple organ failure (MOF). Indiscriminate resuscitation with blood products may contribute to this bloody vicious cycle and the numbers of blood or plasma transfusions are leading predictors of mortality. Stored blood products contain bioactive lipids which activate ECs and prime PMNs in vitro and in vivo and are etiologic in acute lung injury (ALI), a part of MOF. Our global hypothesis is that standard resuscitation with stored blood components ignores ACoT and by further perturbing the patient's proteome and lipidome increases PIVIN-mediated patient morbidity. This hypothesis will be tested by completion of the following specific aims:
Aim 1 : Investigate the proteins that accumulate post-injury in patients: plasma or which are infused during resuscitation in transfused blood components, e.g.: proteases and metalloenzymes, anti-proteases, phospholipases, lipid carriers, and coagulation factors.
Aim 2 : Investigate the pro-inflammatory lipids, arachidonic acid (AA) and it metabolites infused during the resuscitation of injured patients that are present in the transfused blood components and in the injured patient: plasma.
Aim 3 : Employ these proteins and lipids in a two-event in vivo model of ALI as either the first event, if they activate HMVECs, or the second event, if they cause PMN priming.
Aim 4 : Measure the cytokines, chemokines, and growth factors in injured patients before, during, and after resuscitation by multiplex cytokine/chemokine/growth factor arrays or commercial ELISA to determine the role of injury and resuscitation on the concentrations of these pro-inflammatory mediators in vivo. Completion of these aims may discover improved methods of resuscitation and better ways to transfuse injured patients to make transfusions safer and to optimize survival for injured patients requiring massive transfusion.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM049222-20
Application #
8678940
Study Section
Special Emphasis Panel (ZGM1-PPBC-5)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
20
Fiscal Year
2014
Total Cost
$309,440
Indirect Cost
$107,191
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Slaughter, Anne L; D'Alessandro, Angelo; Moore, Ernest E et al. (2016) Glutamine metabolism drives succinate accumulation in plasma and the lung during hemorrhagic shock. J Trauma Acute Care Surg 81:1012-1019
D'Alessandro, Angelo; Moore, Hunter B; Moore, Ernest E et al. (2016) Plasma First Resuscitation Reduces Lactate Acidosis, Enhances Redox Homeostasis, Amino Acid and Purine Catabolism in a Rat Model of Profound Hemorrhagic Shock. Shock 46:173-82
Kelher, Marguerite R; McLaughlin, Nathan J D; Banerjee, Anirban et al. (2016) LysoPCs induce Hck- and PKCδ-mediated activation of PKCγ causing p47phox phosphorylation and membrane translocation in neutrophils. J Leukoc Biol :
Moore, Hunter B; Moore, Ernest E; Burlew, Clay C et al. (2016) Establishing Benchmarks for Resuscitation of Traumatic Circulatory Arrest: Success-to-Rescue and Survival among 1,708 Patients. J Am Coll Surg 223:42-50
Moore, Hunter B; Moore, Ernest E; Liras, Ioannis N et al. (2016) Acute Fibrinolysis Shutdown after Injury Occurs Frequently and Increases Mortality: A Multicenter Evaluation of 2,540 Severely Injured Patients. J Am Coll Surg 222:347-55
Chapman, Michael P; Moore, Ernest E; Moore, Hunter B et al. (2016) Overwhelming tPA release, not PAI-1 degradation, is responsible for hyperfibrinolysis in severely injured trauma patients. J Trauma Acute Care Surg 80:16-23; discussion 23-5
D'alessandro, Angelo; Nemkov, Travis; Moore, Hunter B et al. (2016) Metabolomics of trauma-associated death: shared and fluid-specific features of human plasma vs lymph. Blood Transfus 14:185-94
Nemkov, Travis; D'Alessandro, Angelo; Hansen, Kirk C (2015) Three-minute method for amino acid analysis by UHPLC and high-resolution quadrupole orbitrap mass spectrometry. Amino Acids 47:2345-57
Chapman, Michael P; Moore, Ernest E; Chin, Theresa L et al. (2015) Combat: Initial Experience with a Randomized Clinical Trial of Plasma-Based Resuscitation in the Field for Traumatic Hemorrhagic Shock. Shock 44 Suppl 1:63-70
D'Alessandro, Angelo; Nemkov, Travis; Kelher, Marguerite et al. (2015) Routine storage of red blood cell (RBC) units in additive solution-3: a comprehensive investigation of the RBC metabolome. Transfusion 55:1155-68

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