Blood transfusions are linked to the development of acute lung injury and post-injury multiple organ failure (ALI/MOF). Epidemiological studies have associated infusion of older stored packed red blood cells (PRBCs) to the development of ALI/MOF. Acute organ injury, as demonstrated in both animal and in vitro models, is the result of at least two clinical events. The first event causes endothelial cell (EC) activation as evidenced by an increase in adhesion molecules and the synthesis and extracellular release of chemokines, resulting in PMN priming and adherence. Priming not only maximizes the release of both oxidative and nonoxidative cytotoxic agents that comprise the microbicidal arsenal of the PMN, but priming also changes the PMN phenotype to """"""""hyper-responsive"""""""", such that stimuli that do not activate resting PMNs activate primed PMNs. The second event causes activation of these adherent """"""""hyper-responsive"""""""" PMNs culminating in endothelial damage, capillary leak, and organ injury. Lipids accumulate during the routine storage of blood, and preliminary data (ours) have implicated these compounds in the activation of human pulmonary microvascular endothelial cells (HMVECs). Thus, because EC activation is a requirement for ALI/MOF and its abrogation inhibits ALI/MOF in vitro and in vivo, we hypothesize that the neutral lipophilic compounds in stored blood predispose injured patients to post-injury ALI/MOF by alteration of normal PMN: EC physiology. This alteration causes indiscriminant EC activation resulting in sequestration of hyper-reactive PMNs in specific organ beds that leads to post-injury ALI/MOF. This hypothesis will be tested by completion of the following specific aims. 1: To identify the lipids that accumulate during routine blood storage and are infused during resuscitation in both PRBCs and LRPRBCs. 2: To delineate the signaling pathways activated by these lipophilic compounds that cause altered PMN: EC physiology by examining PMNs and primary ECs, HMVECs and human liver sinusoidal ECs. 3: To test the ability of these lipids to produce ALI as the first event in a two-event, PMN- mediated model of ALI. 4. To elucidate methods to inhibit the accumulation of these compounds during routine storage of both PRBCs and LR-PRBCs. Completion of these specific aims will likely result in methods to abrogate or to ameliorate the clinical effects of these lipids and will ultimately make transfusions safer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM049222-14
Application #
7413747
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
14
Fiscal Year
2007
Total Cost
$386,465
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Loi, Michele M; Kelher, Marguerite; Dzieciatkowska, Monika et al. (2018) A comparison of different methods of red blood cell leukoreduction and additive solutions on the accumulation of neutrophil-priming activity during storage. Transfusion 58:2003-2012
Nemkov, Travis; Sun, Kaiqi; Reisz, Julie A et al. (2018) Hypoxia modulates the purine salvage pathway and decreases red blood cell and supernatant levels of hypoxanthine during refrigerated storage. Haematologica 103:361-372
Stettler, Gregory R; Sumislawski, Joshua J; Moore, Ernest E et al. (2018) Citrated kaolin thrombelastography (TEG) thresholds for goal-directed therapy in injured patients receiving massive transfusion. J Trauma Acute Care Surg 85:734-740
Coleman, Julia R; Moore, Ernest E; Chapman, Michael P et al. (2018) Rapid TEG efficiently guides hemostatic resuscitation in trauma patients. Surgery 164:489-493
Banerjee, Anirban; Silliman, Christopher C; Moore, Ernest E et al. (2018) Systemic hyperfibrinolysis after trauma: a pilot study of targeted proteomic analysis of superposed mechanisms in patient plasma. J Trauma Acute Care Surg 84:929-938
Moore, Ernest E; Moore, Hunter B; Chapman, Michael P et al. (2018) Goal-directed hemostatic resuscitation for trauma induced coagulopathy: Maintaining homeostasis. J Trauma Acute Care Surg 84:S35-S40
Reisz, Julie A; Wither, Matthew J; Moore, Ernest E et al. (2018) All animals are equal but some animals are more equal than others: Plasma lactate and succinate in hemorrhagic shock-A comparison in rodents, swine, nonhuman primates, and injured patients. J Trauma Acute Care Surg 84:537-541
Stettler, Gregory R; Moore, Ernest E; Nunns, Geoffrey R et al. (2018) Rotational thromboelastometry thresholds for patients at risk for massive transfusion. J Surg Res 228:154-159
Nunns, Geoffrey R; Stringham, John R; Gamboni, Fabia et al. (2018) Trauma and hemorrhagic shock activate molecular association of 5-lipoxygenase and 5-lipoxygenase-Activating protein in lung tissue. J Surg Res 229:262-270
Moore, Hunter B; Moore, Ernest E; Chapman, Michael P et al. (2018) Plasma-first resuscitation to treat haemorrhagic shock during emergency ground transportation in an urban area: a randomised trial. Lancet 392:283-291

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