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 #
5P50GM049222-18
Application #
8382281
Study Section
Special Emphasis Panel (ZGM1-PPBC-5)
Project Start
2012-06-01
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
18
Fiscal Year
2012
Total Cost
$338,895
Indirect Cost
$117,395
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Moore, Frederick A; Moore, Ernest E; Billiar, Timothy R et al. (2017) The role of NIGMS P50 sponsored team science in our understanding of multiple organ failure. J Trauma Acute Care Surg 83:520-531
Stettler, Gregory R; Moore, Ernest E; Moore, Hunter B et al. (2017) Platelet adenosine diphosphate receptor inhibition provides no advantage in predicting need for platelet transfusion or massive transfusion. Surgery 162:1286-1294
Moore, Hunter B; Moore, Ernest E; Chapman, Michael P et al. (2017) Viscoelastic Tissue Plasminogen Activator Challenge Predicts Massive Transfusion in 15 Minutes. J Am Coll Surg 225:138-147
Clendenen, Nathan; Nunns, Geoffrey R; Moore, Ernest E et al. (2017) Hemorrhagic shock and tissue injury drive distinct plasma metabolome derangements in swine. J Trauma Acute Care Surg 83:635-642
Sauaia, Angela; Moore, Frederick A; Moore, Ernest E (2017) Postinjury Inflammation and Organ Dysfunction. Crit Care Clin 33:167-191
Slaughter, Anne L; Nunns, Geoffrey R; D'Alessandro, Angelo et al. (2017) The Metabolopathy of Tissue Injury, Hemorrhagic Shock and Resuscitation in a Rat Model. Shock :
Silliman, Christopher C; Kelher, Marguerite R; Khan, Samina Y et al. (2017) Supernatants and lipids from stored red blood cells activate pulmonary microvascular endothelium through the BLT2 receptor and protein kinase C activation. Transfusion 57:2690-2700
Reisz, Julie A; Slaughter, Anne L; Culp-Hill, Rachel et al. (2017) Red blood cells in hemorrhagic shock: a critical role for glutaminolysis in fueling alanine transamination in rats. Blood Adv 1:1296-1305
D?Alessandro, Angelo; Moore, Hunter B; Moore, Ernest E et al. (2017) Plasma succinate is a predictor of mortality in critically injured patients. J Trauma Acute Care Surg 83:491-495

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