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 #
5P50GM049222-18
Application #
8382283
Study Section
Special Emphasis Panel (ZGM1-PPBC-5)
Project Start
2012-06-01
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
18
Fiscal Year
2012
Total Cost
$366,276
Indirect Cost
$126,880
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Slaughter, Anne L; D'Alessandro, Angelo; Moore, Ernest E et al. (2016) Glutamine metabolism drives succinate accumulation in plasma and the lung during hemorrhagic shock. J Trauma Acute Care Surg 81:1012-1019
D'Alessandro, Angelo; Moore, Hunter B; Moore, Ernest E et al. (2016) Plasma First Resuscitation Reduces Lactate Acidosis, Enhances Redox Homeostasis, Amino Acid and Purine Catabolism in a Rat Model of Profound Hemorrhagic Shock. Shock 46:173-82
Kelher, Marguerite R; McLaughlin, Nathan J D; Banerjee, Anirban et al. (2016) LysoPCs induce Hck- and PKCδ-mediated activation of PKCγ causing p47phox phosphorylation and membrane translocation in neutrophils. J Leukoc Biol :
Moore, Hunter B; Moore, Ernest E; Burlew, Clay C et al. (2016) Establishing Benchmarks for Resuscitation of Traumatic Circulatory Arrest: Success-to-Rescue and Survival among 1,708 Patients. J Am Coll Surg 223:42-50
Moore, Hunter B; Moore, Ernest E; Liras, Ioannis N et al. (2016) Acute Fibrinolysis Shutdown after Injury Occurs Frequently and Increases Mortality: A Multicenter Evaluation of 2,540 Severely Injured Patients. J Am Coll Surg 222:347-55
Chapman, Michael P; Moore, Ernest E; Moore, Hunter B et al. (2016) Overwhelming tPA release, not PAI-1 degradation, is responsible for hyperfibrinolysis in severely injured trauma patients. J Trauma Acute Care Surg 80:16-23; discussion 23-5
D'alessandro, Angelo; Nemkov, Travis; Moore, Hunter B et al. (2016) Metabolomics of trauma-associated death: shared and fluid-specific features of human plasma vs lymph. Blood Transfus 14:185-94
Nemkov, Travis; D'Alessandro, Angelo; Hansen, Kirk C (2015) Three-minute method for amino acid analysis by UHPLC and high-resolution quadrupole orbitrap mass spectrometry. Amino Acids 47:2345-57
Chapman, Michael P; Moore, Ernest E; Chin, Theresa L et al. (2015) Combat: Initial Experience with a Randomized Clinical Trial of Plasma-Based Resuscitation in the Field for Traumatic Hemorrhagic Shock. Shock 44 Suppl 1:63-70
D'Alessandro, Angelo; Nemkov, Travis; Kelher, Marguerite et al. (2015) Routine storage of red blood cell (RBC) units in additive solution-3: a comprehensive investigation of the RBC metabolome. Transfusion 55:1155-68

Showing the most recent 10 out of 244 publications