Following injury/stress cardiac output is diverted, provoking spanchnic hypoperfusion. Although our Trauma Center could not identify portal venous bacterial/endotoxin in trauma patients (bacterial translocation), we do propose that the post-injury splanchnic circulation serves as a """"""""priming bed"""""""" for circulating neutrophils. Post-injury shock renders the injured patient (with projects IA and IC) at risk for MOF by 1) priming circulating PMN's for cytotoxicity (CD11b/CD18 expression, endothelial, superoxide production, degranulation, cytokine release) and 2) activating microvascular endothelium (Projects VI and VIII) for primed PMN adherence (E-selection ICAM-1). Traditional anti- neutrophil and anti-cytokine (Project VII) therapies have proven disappointing. Two years ago we proposed to prevent the ischemic gut from """"""""priming"""""""" PMN's and thus provoking inflammation/MOF by intervening at the level of intracellular PMN signaling. In this current application, we wish to extend these observations and now propose gut phospholipase A2 as a proximal inflammatory signal that activates P38 MAP kinase inducing both 1) PMN """"""""priming"""""""" and 2) distant organ endothelial expression of contraligands for primed neutrophils. We also postulate that receptor dependent P38 MAP kinase activation requires cytoskeletal remodeling (with Project VIII) and that hyperosmolar resuscitation (osmolar stress) promotes actin depolymerization/restructuring that prevents PMN priming by inhibiting P38 MAPK activation. Consequently, we hypothesize that hyperosmolar resuscitation of the injured patient with attenuate systemic PMN priming and reduce neutrophil adherence to endovasculature, thus reducing the incidence of MOF. Elucidation of the link between intracellular signals and cytoskeletal trafficking may suggest novel interventions into the modification of PMN:endovascular responses in disease hyperinflammatory syndromes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM049222-10
Application #
6585992
Study Section
Project Start
2002-04-01
Project End
2003-03-31
Budget Start
Budget End
Support Year
10
Fiscal Year
2002
Total Cost
$186,685
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Nunns, Geoffrey R; Moore, Ernest E; Stettler, Gregory R et al. (2018) Empiric transfusion strategies during life-threatening hemorrhage. Surgery 164:306-311
Slaughter, Anne L; Nunns, Geoffrey R; D'Alessandro, Angelo et al. (2018) The Metabolopathy of Tissue Injury, Hemorrhagic Shock, and Resuscitation in a Rat Model. Shock 49:580-590
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

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