Traumatic injury involving shock, tissue injury, fracture and transfusion, releases circulating factors (such as TNFalpha, IL-1 and IPS) that promote systemic hyper-inflammation. These agents immediately activate signaling receptors on circulating leukocytes, endothelium and vascular cells, thereby priming or altering these cell-types, and their subsequent responses. The initial phase of signaling by ligand activated receptor from the plasma membrane surface, is mediated by second messengers, ion-fluxes, and protein phosphorylation occurring within minutes. Activated receptors recruit adaptor proteins often coordinated with change in Ca++ and local membrane composition. A series of assembly events forms clustered signaling complexes that build-up multi-domain protein scaffolds which simultaneously conduct endocytosis and activate kinase modules such as MAPKs and IKK. These modules cause many sustained changes to the transcriptome, thereby affecting all subsequent cellular responses for hours or days, including cell-cycling or apoptosis. In leukocytes, MAPK modules regulate pro-inflammatory actions: superoxide secretion, and degranulation in neutrophils, synthesis and release of cytokines and chemokines. In vascular endothelial and smooth muscle cells, NF-kB and AP-1 upregulate expression of leuko-adhesive proteins, promoting inflammation and leak. Cell biologists have known that that clathrin-mediated endocytosis (CME) can be blocked by hypertonicity and primary amines block (by affecting endosome assembly or disrupting its maturation). In several transformed cells, interfering with CME prevents MAPK or NF-kB signaling by bioactive mediators (such as catechols, lipids and TNFalpha). However, it is unclear how the different stages of CME processing regulates kinase signaling by internalized receptors in mammalian, especially human, cells. Further, would the results in primary cells reflect inflammatory signaling in animal models? Remarkably, advances in resuscitation suggest that hypertonicity has additional advantages for preventing pro-inflammatory priming. Separately, some primary amines and microtubule effectors appear promising for inflammation control. In this proposal we assess whether suppressing endocytosis affects postendocytotic signaling for a permuted list of culpable agents and cells. If so, could the mechanisms suggest improvements or alternatives?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM049222-14
Application #
7413749
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
14
Fiscal Year
2007
Total Cost
$343,273
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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
Reisz, Julie A; Wither, Matthew J; Moore, Ernest E et al. (2018) All animals are equal but some animals are more equal than others: Plasma lactate and succinate in hemorrhagic shock-A comparison in rodents, swine, nonhuman primates, and injured patients. J Trauma Acute Care Surg 84:537-541
Stettler, Gregory R; Moore, Ernest E; Nunns, Geoffrey R et al. (2018) Rotational thromboelastometry thresholds for patients at risk for massive transfusion. J Surg Res 228:154-159
Nunns, Geoffrey R; Stringham, John R; Gamboni, Fabia et al. (2018) Trauma and hemorrhagic shock activate molecular association of 5-lipoxygenase and 5-lipoxygenase-Activating protein in lung tissue. J Surg Res 229:262-270
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

Showing the most recent 10 out of 291 publications