Postinjury multiple organ failure is the net result of the dysfunctional immune response to injury characterized by an early hyperactive innate system. Acute lung injury (ALI) is the first clinical manifestation of organ failure, followed by renal and hepatic dysfunction. The gut has been invoked as the "motor of MOF", and mesenteric lymph is recognized as the mechanistic link between splanchnic ischemia and distant organ dysfunction. But the specific mediators remain to be defined. Current evidence suggests the lipid fraction of post-shock mesenteric lymph (PSML) is central in the etiology of ALI. Specifically, our recent work indicates that 5-lipoxygenase (5-LO) products are essential, but proteins may have an important role. Elucidating these mediators is critical In translating our current knowledge to new therapeutic strategies at the bedside. Our specific research aims (abbreviated) are: 1) to determine if 5-lipoxygenase activity is necessary for PSML to provoke acute lung injury by examining a) mesenteric lymph diversion (MLD) in rats, b) pretreatment of rats with 5-LO inhibitors, c) knock out mice, d) 5-LO metabolites in BALF and pleural fluid of severely injured patients with ALI / ARDS;2) to determine if T/HS activates 5-LO in the gut, thereby producing metabolites in PSML that mediate ALI by a) infusing rat PSML into naive rats from donor rats, pretreatedt with 5-LO inhibitors, monitoring for increases in 5-LO metabolites and ALI, b) incubating PMNs, HMVECs, alveolar macrophages, and type II pneumocytes with PSML and LTB4/ LTC4 receptor antagonists to produce proinflammatory activation, c) examining 5-LO metabolites in PSML following T/HS in rats, d) examining 5-LO metabolites in the mesenteric lymph of severely injured patients;and 3) to determine if T/HS activates 5-lipoxygenase in the lung by a) infusing isotope labeled (d8)AA into MLD T/HS rat lung to generate (d8)LTB{4}and produce ALI, b) cross-transfusing PSML from T/HS rats, pretreated with a PLA{2} inhibitor (to eliminate AA) or 5-LO inhibitor, into naive rats and measuring 5-LO metabolites in BALF and assessing for ALI, c) locating 5-LO pathway components in the lung versus infiltrating hematological cells (PMNs and platelets) following T/HS +/- MLD, d) determining if elevated alpha-enolase, elevated major urinary protein, or the depletion of antiproteases in PSML stimulates 5-LO activity in cultured PMNs, HMVECs, alveolar macrophages and type II pneumocytes, e) proteomics analysis of human lymph to identify relevant lipid carriers and 5-LO activators.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM049222-20
Application #
8678939
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
$507,211
Indirect Cost
$131,358
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

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