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Shock, United States

Baker T.A.,Burn and Shock Trauma Institute | Romero J.,Burn and Shock Trauma Institute | Bach H.H.,Burn and Shock Trauma Institute | Strom J.A.,Florida College | And 3 more authors.
Critical Care Medicine | Year: 2012

OBJECTIVE: To determine whether treatment with the CXC chemokine receptor 4 agonist ubiquitin results in beneficial effects in a polytrauma model consisting of bilateral femur fractures plus blunt chest trauma (Injury Severity Score 18-25). DESIGN: Treatment study. SETTING: Research laboratory. SUBJECTS: Seventeen Yorkshire pigs. INTERVENTIONS: Intravenous injection of 1.5 mg/kg ubiquitin or albumin (control) at 60 mins after polytrauma. MEASUREMENTS AND MAIN RESULTS: Anesthetized, mechanically ventilated pigs underwent polytrauma, followed by a simulated 60-min shock phase. At the end of the shock phase, ubiquitin or albumin were administered and animals were resuscitated to a mean arterial blood pressure of 70 mm Hg until t = 420 mins. After intravenous ubiquitin, ubiquitin plasma concentrations increased 16-fold to 2870 ± 1015 ng/mL at t = 90 mins and decreased with t1/2 = 60 mins. Endogenous plasma ubiquitin increased two-fold in the albumin group with peak levels of 359 ± 210 ng/mL. Plasma levels of the cognate CXC chemokine receptor 4 ligand stromal cell-derived factor-1α were unchanged in both groups. Ubiquitin treatment reduced arterial lactate levels and prevented a continuous decrease in arterial oxygenation, which occurred in the albumin group during resuscitation. Wet weight to dry weight ratios of the lung contralateral from the injury, heart, spleen and jejunum were lower with ubiquitin. With ubiquitin treatment, tissue levels of Interleukin-8, Interleukin-10, Tumor Necrosis Factor α, and stromal cell-derived factor-1α were reduced in the injured lung and of Interleukin-8 in the contralateral lung, respectively. CONCLUSIONS: Administration of exogenous ubiquitin modulates the local inflammatory response, improves resuscitation, reduces fluid shifts into tissues, and preserves arterial oxygenation after blunt polytrauma with lung injury. This study further supports the notion that ubiquitin is a promising protein therapeutic and implies CXC chemokine receptor 4 as a drug target after polytrauma. Copyright © 2012 by the Society of Critical Care. Source

Saini V.,Burn and Shock Trauma Institute | Marchese A.,Loyola University Chicago | Majetschak M.,Burn and Shock Trauma Institute | Majetschak M.,Loyola University Chicago
Journal of Biological Chemistry | Year: 2010

Ubiquitin is one of the most highly conserved proteins in eukaryotes and plays major biological roles as a post-translational protein modifier. Ubiquitin is also a natural constituent of plasma, and several lines of evidence suggest that extracellular ubiquitin is an immune modulator with anti-inflammatory properties. In addition, ubiquitin treatment has been shown to limit inflammation and reduce organ injury in various disease models and species in vivo. However, its mechanism of action is unknown. Here we show that extracellular ubiquitin is a natural CXC chemokine receptor 4 (CXCR4 and CD184) agonist. Extracellular ubiquitin promotes intracellular Ca2+ flux and reduces cAMP levels through a G protein-coupled receptor that signals via a Gαi/o protein in THP1 cells. Toll-like receptor 4 stimulation reduces ubiquitin-binding sites, which enabled identification of four Gαi/o PCRs as ubiquitin receptor candidates. Over-expression of candidate genes in HEK293 cells, gene silencing in THP1 cells, competition binding, and signaling studies with the CXCR4 agonist stromal cell-derived factor-1α (chemokine (CXC motif) ligand 12) and inhibitor AMD3100 identifyCXCR4 as a functional ubiquitin receptor. Our finding uncovers a fundamentally new aspect of the role of ubiquitin in biology, has implications for the understanding of CXCR4-mediated events, and is expected to facilitate development of new therapeutic avenues for a variety of diseases. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Baker T.A.,Burn and Shock Trauma Institute | Romero J.,Burn and Shock Trauma Institute | Bach H.H.,Burn and Shock Trauma Institute | Strom J.A.,Jacksonville University | And 3 more authors.
Critical Care Medicine | Year: 2012

OBJECTIVE: To define systemic release kinetics of a panel of cytokines and heat shock proteins in porcine polytrauma/hemorrhage models and to evaluate whether they could be useful as early trauma biomarkers. DESIGN: Prospective observational study. SETTING: Research laboratory. SUBJECTS: Twenty-one Yorkshire pigs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pigs underwent polytrauma (femur fractures/lung contusion, P), hemorrhage (mean arterial pressure 25-30 mm Hg, H), polytrauma plus hemorrhage (P/H), or sham procedure (S). Plasma was obtained at baseline, in 5- to 15-min intervals during a 60-min shock period without intervention, and in 60- to 120-min intervals during fluid resuscitation for up to 300 min. Plasma was assayed for interleukin-1β, interleukin-4, interleukin-5, interleukin-6, interleukin-8, interleukin-10, interleukin-12/interleukin-23p40, interleukin-13, interleukin-17, interleukin-18, interferonγ, transforming growth factor-β, tumor necrosis factor-α, heat shock protein 40, heat shock protein 70, and heat shock protein 90 by enzyme-linked immunosorbent assay. All animals after S, P, and H survived (n = 5/group). Three of six animals after P/H died. Interleukin-10 increased during shock after P and this increase was attenuated after H. Tumor necrosis factor-α increased during the shock period after P, H, and also after S. P/H abolished the systemic interleukin-10 and tumor necrosis factor-α release and resulted in 20% to 30% increased levels of interleukin-6 during shock. As fluid resuscitation was initiated, tumor necrosis factor-α and interleukin-10 levels decreased after P, H, and P/H; heat shock protein 70 increased after P; and interleukin-6 levels remained elevated after P/H and also increased after P and S. CONCLUSIONS: Differential regulation of the systemic cytokine release after polytrauma and/or hemorrhage, in combination with the effects of resuscitation, can explain the variability and inconsistent association of systemic cytokine/heat shock protein levels with clinical variables in trauma patients. Insults of major severity (P/H) partially suppress the systemic inflammatory response. The plasma concentrations of the measured cytokines/heat shock proteins do not reflect injury severity or physiological changes in porcine trauma models and are unlikely to be able to serve as useful trauma biomarkers in patients. Copyright © 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins. Source

Biju P.G.,University of Arkansas for Medical Sciences | Garg S.,University of Arkansas for Medical Sciences | Wang W.,University of Arkansas for Medical Sciences | Choudhry M.A.,Burn and Shock Trauma Institute | And 3 more authors.
Shock | Year: 2012

Sepsis is the leading cause of mortality in intensive care units. Early detection and intervention are critical to prevent death. The acute radiation syndrome is characterized by damage of the gastrointestinal and hematopoietic systems. Translocation of intestinal microflora combined with immune system compromise may lead to septicemia and death. This work examined the utility of procalcitonin, a clinical sepsis biomarker, in a mouse model of radiation toxicity. C57/BL6 mice were exposed to total body irradiation (TBI). Intestinal mucosal permeability was measured in vivo, and liver bacterial load and plasma levels of procalcitonin (PCT), lipopolysaccharide (LPS), and LPS-binding protein were measured at baseline and at 3.5, 7, and 10 days after TBI. The value of early PCT in predicting subsequent lethality was determined by receiver operating characteristic analysis. Four days after TBI, a dose-dependent increase in permeability of the intestinal mucosa was observed, whereas bacterial translocation was present from day 7 onward. There was a high positive correlation between bacterial translocation and all sepsis biomarkers, with PCT exhibiting the strongest correlation. Moreover, plasma PCT levels were elevated already from day 3.5 onward, whereas LPS was elevated from day 7 and LPS-binding protein only 10 days after TBI. Receiver operating characteristic analysis revealed that PCT levels measured 3.5 days after TBI predicted lethality at 10 days. These data demonstrate the value of PCT as an early biomarker in radiation-induced bacteremia for mouse studies and suggest that clinical results from other septic conditions may apply to postradiation septicemia in humans. © 2012 by the Shock Society. Source

Davis C.S.,Burn and Shock Trauma Institute | Albright J.M.,Burn and Shock Trauma Institute | Carter S.R.,Burn and Shock Trauma Institute | Ramirez L.,Burn and Shock Trauma Institute | And 3 more authors.
Journal of Burn Care and Research | Year: 2012

This prospective study aims to address mortality in the context of the early pulmonary immune response to burn and inhalation injury. The authors collected bronchoalveolar lavage fluid from 60 burn patients within 14 hours of their injury when smoke inhalation was suspected. Clinical and laboratory parameters and immune mediator profiles were compared with patient outcomes. Patients who succumbed to their injuries were older (P = .005), had a larger % TBSA burn (P < .001), and required greater 24-hour resuscitative fluids (P = .002). Nonsurvivors had lower bronchoalveolar lavage fluid concentrations of numerous immunomodulators, including C5a, interleukin (IL)-1β, IL-1RA, IL-8, IL-10, and IL-13 (P < .05 for all). Comparing only those with the highest Baux scores to account for the effects of age and % TBSA burn on mortality, nonsurvivors also had reduced levels of IL-2, IL-4, granulocyte colony-stimulating factor, interferon-γ, macrophage inflammatory protein-1β, and tumor necrosis factor-α (P < .05 for all). The apparent pulmonary immune hyporesponsiveness in those who died was confirmed by in vitro culture, which revealed that pulmonary leukocytes from nonsurvivors had a blunted production of numerous immune mediators. This study demonstrates that the early pulmonary immune response to burn and smoke inhalation may be attenuated in patients who succumb to their injuries. Copyright © 2012 by the American Burn Association. Source

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