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 #
5P50GM049222-20
Application #
8678941
Study Section
Special Emphasis Panel (ZGM1-PPBC-5)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
20
Fiscal Year
2014
Total Cost
$334,141
Indirect Cost
$115,749
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Stahel, Philip F; Moore, Ernest E (2014) Peer review for biomedical publications: we can improve the system. BMC Med 12:179
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Chin, Theresa L; Moore, Ernest E; Moore, Hunter B et al. (2014) A principal component analysis of postinjury viscoelastic assays: clotting factor depletion versus fibrinolysis. Surgery 156:570-7
Wohlauer, M; Kobeiter, H; Desgranges, P et al. (2014) Inferior Mesenteric Artery Stenting as a Novel Treatment for Chronic Mesenteric Ischemia in Patients with an Occluded Superior Mesenteric Artery and Celiac Trunk. Eur J Vasc Endovasc Surg 27:e21-e23
Stringham, John R; Moore, Ernest E; Gamboni, Fabia et al. (2014) Mesenteric lymph diversion abrogates 5-lipoxygenase activation in the kidney following trauma and hemorrhagic shock. J Trauma Acute Care Surg 76:1214-21
Jones, Edward L; Stovall, Robert T; Jones, Teresa S et al. (2014) Intra-abdominal injury following blunt trauma becomes clinically apparent within 9 hours. J Trauma Acute Care Surg 76:1020-3
Dzieciatkowska, Monika; D'Alessandro, Angelo; Moore, Ernest E et al. (2014) Lymph is not a plasma ultrafiltrate: a proteomic analysis of injured patients. Shock 42:485-98
Gonzalez, E; Moore, E E; Moore, H B et al. (2014) Trauma-Induced Coagulopathy: An Institution's 35 Year Perspective on Practice and Research. Scand J Surg 103:89-103
Moore, Ernest E; Chin, Theresa L; Chapman, Michael C et al. (2014) Plasma first in the field for postinjury hemorrhagic shock. Shock 41 Suppl 1:35-8

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