Endotoxin (ETX) can be a lethal agent, but it also can be used to prime cells, organs, or animals to resist a subsequent injury. Though this state of protection has an undefined mechanism, it is highly conserved in that one priming stimulus protects against another, and that diverse stimuli appear to induce the expression of a common pattern of genes. We hypothesize that multiple types of priming stimuli can each therapeutically prime cells or tissues by causing the expression of a common program of genes which is related to protection from subsequent injury. We will address this hypothesis at the organ level (isolated heart, gut ischemia models) and gene levels by characterizing the program of tissue gene expression of early response genes, heat shock proteins, anti-oxidant enzymes, growth factors, and fetal program genes in response to a range of pathologic and physiologic stimuli. This programmed response will be localized within organs by in situ mRNA and protein hybridizations. Models of tissue gene injection and subsequent gene manipulation should allow mechanistic investigations of the preceding characterization. Results to date suggest a conserved genomic response mimicking the fetal state to stimuli which have in common the protein synthesis dependent induction of protection. Skeletal muscles injected with a promoter/reporter gene construct show expression of the injected gene. Finally, initial experiments suggest some parallels between rat and human myocardial gene expressions after similar stimuli. Knowledge gained from these proposed basic investigations should lead to improved clinical treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM049222-04
Application #
5212233
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
1996
Total Cost
Indirect Cost
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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