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.

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National Institute of General Medical Sciences (NIGMS)
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University of Colorado Denver
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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
Loi, Michele M; Kelher, Marguerite; Dzieciatkowska, Monika et al. (2018) A comparison of different methods of red blood cell leukoreduction and additive solutions on the accumulation of neutrophil-priming activity during storage. Transfusion 58:2003-2012
Nemkov, Travis; Sun, Kaiqi; Reisz, Julie A et al. (2018) Hypoxia modulates the purine salvage pathway and decreases red blood cell and supernatant levels of hypoxanthine during refrigerated storage. Haematologica 103:361-372
Stettler, Gregory R; Sumislawski, Joshua J; Moore, Ernest E et al. (2018) Citrated kaolin thrombelastography (TEG) thresholds for goal-directed therapy in injured patients receiving massive transfusion. J Trauma Acute Care Surg 85:734-740
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

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