We postulate that mitochondrial oxidative metabolism determines restoration of high energy stores and organ function after traumatic stress sites. Mitochondrial dysfunction leads to impaired energy production, stimulates oxidant induced inflammation and promotes apoptosis. Inflammatory agents important in post-traumatic stress includes mediators such as lysophospholipids (LPC) (with projects IV-Moore and project V-Meng) and tumor necrosis alpha (TNF-alpha) (with project VII-Harken). Not only can these mediators induce mitochondrial dysfunction, but we propose that dysregulated mitochondrial themselves initiate the inflammatory cascade. Multi-system organ dysfunction (MOD) is associated with impaired oxygen consumption (with project IA-Offner). We have reported that severely injured patients who develop MOD exhibit an early decoupling of the redox state of mitochondrial cytochrome a, a3 (cytochrome c oxidase) from tissue oxyhemoglobin. This decoupling of mitochondrial respiration is associated with the production of cellular oxidants and provides evidence of an inherent defect in mitochondrial electron transport after severe traumatic injury. Our preliminary studies suggest that mitochondrial electron transport can be therapeutically manipulated in post-traumatic stress states, resulting in reduced oxidant production, inflammatory mediator generation and improving organ function. Yet, the capacity for mitochondria to respond to therapeutic maneuvers may be influenced by inherent alterations in mitochondrial structure and distribution (with project VIII-Banerjee). Further, the mitochondrial genome is a target of oxidative damage which may lead to the development of irreversible injury and the perpetuation of dysfunction (with project IB-Johnson). Global Hypothesis: Post-traumatic stressors (ischemia, hypoxia, inflammation) decouple cytochrome c oxidase from tissue oxyhemoglobin, alter mitochondrial morphology, distribution, electron transport and membrane potential. Therapies designed to stabilize cytochrome c oxidase and to prevent mitochondrial morphologic alterations will modulate oxidant signaling, hyperinflammation and optimize in vivo mitochondrial respiration during post-traumatic stress.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM049222-10
Application #
6585988
Study Section
Special Emphasis Panel (ZGM1)
Project Start
2002-04-01
Project End
2003-03-31
Budget Start
Budget End
Support Year
10
Fiscal Year
2002
Total Cost
$158,272
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
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
Kuldanek, Susan; Silliman, Christopher C (2018) Mortality after red blood cell transfusions from previously pregnant donors: complexities in the interpretation of large data. J Thorac Dis 10:648-652
Nunns, Geoffrey R; Moore, Ernest E; Stettler, Gregory R et al. (2018) Empiric transfusion strategies during life-threatening hemorrhage. Surgery 164:306-311

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