A5042022202- Trauma, Hemostasis, Coagulopathy, Resuscitation
- Immune Response and Inflammation
- Sepsis Diagnosis and Treatment
- Traumatic Brain Injury and Neurovascular Disturbances
- Trauma and Emergency Care Studies
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- NF-κB Signaling Pathways
- Cardiac Arrest and Resuscitation
- Blood Coagulation and Thrombosis Mechanisms
- Acute Kidney Injury Research
- Cell Adhesion Molecules Research
- Respiratory Support and Mechanisms
- Heme Oxygenase-1 and Carbon Monoxide
- Erythrocyte Function and Pathophysiology
- ZnO doping and properties
- Hemoglobin structure and function
- Neonatal Health and Biochemistry
- Protease and Inhibitor Mechanisms
- Renal function and acid-base balance
- Alcohol Consumption and Health Effects
- Abdominal Trauma and Injuries
- Indoor Air Quality and Microbial Exposure
- Animal testing and alternatives
- Proteoglycans and glycosaminoglycans research
- Barrier Structure and Function Studies
University of Colorado Denver
2014-2024
University of Colorado Anschutz Medical Campus
2005-2024
University of Gour Banga
2024
Denver Health Medical Center
2015-2023
The Medical Center of Aurora
2023
The Ohio State University
2023
Scripps Health
2023
Vitalant
2023
Scripps Institution of Oceanography
2023
Scripps (United States)
2023
Abstract Although oxidative stress has been thought to play a general role in the activation of NF-κB, involvement reactive oxygen species (ROS) facilitating nuclear translocation NF-κB neutrophils not described. In addition, mechanisms by which ROS modulate transcriptional activity response Toll-like receptor 4 (TLR4)-dependent signaling are well characterized. To examine these issues, oxidant-dependent events downstream TLR4 were investigated stimulated with LPS. Pretreatment antioxidants...
BACKGROUND Trauma-induced coagulopathy (TIC) is associated with a fourfold increased risk of mortality. Hyperfibrinolysis component TIC, but its mechanism poorly understood. Plasminogen activation inhibitor (PAI-1) degradation by activated protein C has been proposed as for deregulation the plasmin system in hemorrhagic shock, other settings ischemia, tissue plasminogen activator (tPA) shown to be elevated. We hypothesized that hyperfibrinolysis TIC not result PAI-1 driven an increase tPA,...
High mobility group box 1 (HMGB1) is a novel late mediator of inflammatory responses that contributes to endotoxin-induced acute lung injury and sepsis-associated lethality. Although frequent complication severe blood loss, the contribution HMGB1 organ system dysfunction in this setting has not been investigated. In study, was detected pulmonary endothelial cells macrophages under baseline conditions. After hemorrhage, addition positively staining macrophages, neutrophils expressing were...
Abstract Neutrophils are critical initiators and effectors of the innate immune system express Toll-like receptor 2 (TLR2) TLR4. Although signaling through pathways involving phosphoinositide 3-kinase (PI3-K) downstream kinase Akt (protein B) plays a central role in modulating neutrophil chemotaxis superoxide generation response to engagement G protein-coupled receptors, importance these kinases affecting inflammatory responses neutrophils stimulated TLR2 has not been examined. In...
Reactive oxygen species (ROS), including hydrogen peroxide (H 2 O ), are generated in increased amounts pathological, biological processes and can play a role signal transduction. Neutrophils often accumulate acute inflammatory reactions, at sites where elevated concentrations of ROS present. have been demonstrated to participate the activation intracellular signaling pathways, those involved modulating nuclear accumulation transcriptional activity NF-κB. However, affecting such events...
BACKGROUND Complement activation after trauma promotes hemostasis but is associated with increased morbidity and mortality. However, the specific pathways downstream mediators remain unclear. Recently, anaphylatoxin C4a has been shown to bind thrombin receptors. While plasma-based resuscitation modify endotheliopathy of trauma, it may provide complement zymogens that fuel ongoing inflammatory cascades. We sought characterize injury effect fresh frozen plasma (FFP) on this response....
Abstract Urokinase plasminogen activator (uPA) is a serine protease that catalyzes the conversion of to plasmin. In addition, uPA has been shown have proinflammatory properties, particularly in potentiating lipopolysaccharide (LPS)-induced neutrophil responses. To explore mechanisms by which exerts these effects, we examined ability specific domains increase cytokine expression murine and human neutrophils stimulated with LPS. Whereas addition intact cultured LPS increased mRNA protein...
Summary Plasminogen activator inhibitor-1 (PAI-1), a member of the serine protease inhibitor superfamily, modulates fibrinolysis by interacting with proteolytic mediators, including urokinase plasminogen (uPA). Although roles uPA and PAI-1 in plasmin generation degradation fibrin are well known, recent evidence also suggests that they can participate acute inflammatory conditions involve neutrophil activation. In present experiments, we found addition to LPS-stimulated neutrophils resulted...
Hypertonic saline (HTS) has been used intravenously to reduce organ dysfunction following injury and as an inhaled therapy for cystic fibrosis lung disease. The role mechanism of HTS inhibition was explored in the TNFα IL-1β stimulation pulmonary epithelial cells. Hyperosmolar (HOsm) media (400 mOsm) inhibited production select cytokines stimulated by at level mRNA translation, synthesis release. In A549 cells, HOsm I-κBα phosphorylation, NF-κB translocation into nucleus nuclear binding....
ABSTRACT Background: Severe injury can provoke systemic processes that lead to organ dysfunction, and hemolysis of both native transfused red blood cells (RBCs) may contribute. Hemolysis release erythrocyte proteins, such as hemoglobin arginase-1, the latter with potential disrupt arginine metabolism limit physiologic NO production. We aimed quantify in trauma patients measure association severity, transfusions, outcomes. Methods: Blood was collected from injured at a level I center enrolled...
Abstract The SHIP converts phosphatidylinositol 3,4,5 triphosphate to phosphatidyl 3,4 biphosphate. has negative regulatory functions on PI3K-dependent signaling pathways, which occupy important roles in modulating neutrophil functions. We used neutrophils from transgenic SHIP−/− and SHIP+/+ mice that were stimulated with peptidoglycan (PGN) examine the role of TLR2-induced activation. demonstrated significantly increased activation kinase Akt after exposure PGN. Release cytokines...
Trauma/hemorrhagic shock is a complex physiological phenomenon that leads to dysregulation of many molecular pathways. For over decade, hypertonic saline (HTS) has been used as an alternative resuscitation fluid in the setting trauma/hemorrhagic shock. In addition restoring circulating volume within vascular space, studies have shown positive immunomodulatory effect HTS. Targeted HTS affects transcription several pro-inflammatory cytokines by inhibiting NF-κB–IκB pathway model cell lines and...
Lysophosphatidylcholines (lysoPCs) are effective polymorphonuclear neutrophil (PMN) priming agents implicated in transfusion-related acute lung injury (TRALI). LysoPCs cause ligation of the G2A receptor, cytosolic Ca2+ flux, and activation Hck. We hypothesize that lysoPCs induce Hck-dependent protein kinase C (PKC), resulting phosphorylation membrane translocation 47 kDa phagocyte oxidase (p47phox). PMNs, human or murine, were primed with smeared onto slides examined by digital microscopy...
Introduction: Severely injured patients develop a dysregulated inflammatory state characterized by vascular endothelial permeability, which contributes to multiple organ failure. To date, however, the mediators of and mechanisms for this permeability are not well established. Endothelial in other states such as sepsis is driven primarily overactivation RhoA GTPase. We hypothesized that tissue injury shock drive after trauma increased activation leading break down tight adherens junctions....
BACKGROUND Activated Protein C (aPC) plays dual roles after injury, driving both trauma-induced coagulopathy (TIC) by cleaving, and thus inactivating, factors Va VIIIa depressing fibrinolysis while also mediating an inflammomodulatory milieu via protease activated receptor-1 (PAR-1) cytoprotective signaling. Because of this role, it represents ideal target for study therapeutics trauma. A known aPC variant, 3K3A-aPC, has been engineered to preserve activity retaining minimal anticoagulant...
Glypican 1 (GPC1) is a heparan sulphate proteoglycan cell membrane protein. It implicated in driving cancers of the breast, brain, pancreas, and prostate; however, its role esophagogastric cancer (EGAC) remains unexplored. The aim study was to investigate elucidate molecular mechanistic GPC1 human EGAC.Thirty tissue 120 microarray sections EGAC were evaluated with Anti-GPC1 immunohistochemistry. Loss gain function performed using lentivirus transfection lines. Mechanistically,...
Uncontrolled inflammatory responses underlie the etiology of acute lung injury and distress respiratory syndrome, most common late complications in trauma, leading cause death under age 59. Treatment with HTS decreases clinical trials, rat models trauma hemorrhagic shock inflammation cell lines, although mechanisms underlying these are still incompletely understood. Transcriptomics (RNaseq), proteomics, U-13C-glucose tracing metabolomics experiments were performed to investigate cellular...
Objective: Advanced mass spectrometry methods were leveraged to analyze both proteomics and metabolomics signatures in plasma upon controlled tissue injury hemorrhagic shock – isolated or combined - a swine model, followed by correlation viscoelastic measurements of coagulopathy via thrombelastography. Summary Background Data: TI HS cause distinct molecular changes animal models trauma patients. However, the contribution trauma, leading preventable mortality this patient population remains...
The coagulopathy of traumatic brain injury (TBI) remains poorly understood. Contradictory descriptions highlight the distinction between systemic and local coagulation, with hypercoagulability despite intracranial hypocoagulopathy. This perplexing coagulation profile has been hypothesized to be due tissue factor release. objective this study was assess TBI patients undergoing neurosurgical procedures. We hypothesize that dura violation is associated higher conversion a hypercoagulable unique...
Platelets are well known for their roles in hemostasis, but they also play a key role thromboinflammatory pathways by regulating endothelial health, stimulating angiogenesis, and mediating host defense through both contact dependent independent signaling. When activated, platelets degranulate releasing multiple active substances. We hypothesized that the soluble environment formed trauma platelet releasates (TPR) attenuates thromboinflammation via mitigation of induced permeability...