Trauma, hemorrhage and blood resuscitation produce acute lung inflammation by inducing chemokine, cytokine and, and adhesive proteins. Up-regulating mechanisms depend on systemic signals that translocate gene-regulating, transcription factors (TFs), such as NF-kB into the nucleus. The genes expressed direct the adhesion, transmigration of leukocytes and phenotypic developments in the alveolar milieu. Hyperosmolarity (HOsm), appears to prevent inflammatory gene expression but the mechanisms and scope are unclear. Therapeutic hypertonic saline infusions during trauma-resuscitation, or inhaled as for cystic fibrosis, are well tolerated. We hypothesize that hyperosmolarity alters the nuclear translocation of selected transcription factors induced by inflammatory stimuli by promoting novel complexes. In this proposal period (2005-2010) we will first examine the traffic of TFs controlling prototypical alveolar cytokines and adhesive proteins that are modified by HOsm, and investigate complexes of these TFs, including those formed with importins. 1. Investigate HOsm altered translocation of the NF-KB and IKK family members, their HOsm altered cytoplasmic complexes and examine alternate complexes promoted by HOsm with IP-MS proteomics. 2. Since HOsm does not prohibit p65 Rel A translocation induced by IL-1 yet suppresses certain cytokines, we will examine translocation of other essential promoters of the IRF, C/EBP. and R/FLAT families and identify their HOsm altered partners. Next, to expand the inquiry beyond the known cytokines we will execute: 3. Gene array analyses, to guide bioinformatics queries for potential TFs. The goal is to gradually build up a library of TFs that do not translocate successfully during HOSm and identify their sequestering partners, (starting with NF-kB and IRF family members). Lastly, we will translate these bench experiments to asses the tolerability or benefit of nebulized HOsm in shocked animals and trauma patients. 4. Evaluate lung inflammation and TF translocation in traumatized Animal or Patients treated with inhaled HOsm. The information from Aims 1-3 will be used to interpret the molecular phenotypes and TF redistributions after treatments.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Special Emphasis Panel (ZGM1-PPBC-5)
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University of Colorado Denver
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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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