Recently, the gut has been invoked as the central organ promoting the environment conducive for multi-organ failure (MOF). Following effective resuscitation, critically injured patients typically enter a hypermetabolic state. A secondary insult during this vulnerable period appears to be responsible for precipitating clinical MOF. We have developed a sequential insult rodent model to investigate the possible mechanisms involved in postinjury MOF. Our preliminary data suggests that limited gut ischemia/reperfusion I/R, (45 min SMA occlusion), followed by low dose endotoxin (2.5 mg/Kg IP) will produce MOF. Moreover, our animal work to date indicates a) the neutrophil (PMN) is an integral effector, b) xanthine oxidase (XO) mechanisms promote PMN mediated injury, c) phospholipase A2 (PLA2) is a proximal step in this exaggerated inflammatory process, and d) PLA2 blockade, even initiated after gut ischemia, attenuates organ failure thereby suggesting clinical relevance. Based on these findings, our working hypothesis is: postinjury gut I/R promotes remote organ injury by serving as a priming bed for circulating PMN's that are related to PLA2 activation.
Our specific aims are: 1. Does limited gut I/R (45 min SMA occlusion) produce lung injury (125I albumin leak, histology) and liver injury (125I albumin leak bile production, systemic ketone body ratio (KBR), histology)? 2. Does low dose endotoxin (2.5 mg/Kg) produce lung and liver injury? 3. Does limited gut I/R followed by low dose endotoxin synergistically produce lung and liver injury? 4. Do neutrophils (PMN's) have a mechanistic role in this sequential insult model myeloperoxidase (MPO), histology, PMN CD18/CD11b receptor blockade (R17 antibody)? 5. Does gut I/R prime circulating PMN's for superoxide production (FMLP)? 6. Is phospholipase A2 (PLA2) activation involved mechanistically with gut I/R induced PMN priming (PLA2 inhibition (quinacrine), platelet activating factor (PAF) blockade (WEB 2170)? 7. Does PLA2 inhibition abrogate lung and liver injury in this synergistic model? 8. Is there a therapeutic window (postischemia) that offers clinical relevance for PLA2 inhibition in the injured patient? Our ultimate goal is to decouple obligatory postinjury gut I/R from initiating MOF.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM049222-03
Application #
3734976
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
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
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

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