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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
2P50GM049222-17A1
Application #
8117343
Study Section
Special Emphasis Panel (ZGM1-PPBC-5 (TR))
Project Start
Project End
Budget Start
2011-09-22
Budget End
2012-05-31
Support Year
17
Fiscal Year
2011
Total Cost
$362,866
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Lawson, Peter J; Moore, Hunter B; Moore, Ernest E et al. (2017) Preoperative thrombelastography maximum amplitude predicts massive transfusion in liver transplantation. J Surg Res 220:171-175
Moore, Frederick A; Moore, Ernest E; Billiar, Timothy R et al. (2017) The role of NIGMS P50 sponsored team science in our understanding of multiple organ failure. J Trauma Acute Care Surg 83:520-531
Stettler, Gregory R; Moore, Ernest E; Moore, Hunter B et al. (2017) Platelet adenosine diphosphate receptor inhibition provides no advantage in predicting need for platelet transfusion or massive transfusion. Surgery 162:1286-1294
Moore, Hunter B; Moore, Ernest E; Chapman, Michael P et al. (2017) Viscoelastic Tissue Plasminogen Activator Challenge Predicts Massive Transfusion in 15 Minutes. J Am Coll Surg 225:138-147
Clendenen, Nathan; Nunns, Geoffrey R; Moore, Ernest E et al. (2017) Hemorrhagic shock and tissue injury drive distinct plasma metabolome derangements in swine. J Trauma Acute Care Surg 83:635-642
Sauaia, Angela; Moore, Frederick A; Moore, Ernest E (2017) Postinjury Inflammation and Organ Dysfunction. Crit Care Clin 33:167-191
Slaughter, Anne L; Nunns, Geoffrey R; D'Alessandro, Angelo et al. (2017) The Metabolopathy of Tissue Injury, Hemorrhagic Shock and Resuscitation in a Rat Model. Shock :
Silliman, Christopher C; Kelher, Marguerite R; Khan, Samina Y et al. (2017) Supernatants and lipids from stored red blood cells activate pulmonary microvascular endothelium through the BLT2 receptor and protein kinase C activation. Transfusion 57:2690-2700
Reisz, Julie A; Slaughter, Anne L; Culp-Hill, Rachel et al. (2017) Red blood cells in hemorrhagic shock: a critical role for glutaminolysis in fueling alanine transamination in rats. Blood Adv 1:1296-1305
D?Alessandro, Angelo; Moore, Hunter B; Moore, Ernest E et al. (2017) Plasma succinate is a predictor of mortality in critically injured patients. J Trauma Acute Care Surg 83:491-495

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