Burn and Shock Trauma Institute

Anderson, United States

Burn and Shock Trauma Institute

Anderson, United States
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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 4 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.


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.


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.


Li X.,Loyola University Chicago | Li X.,Alcohol Research Program | Li X.,Burn and Shock Trauma Institute | Akhtar S.,Loyola University Chicago | And 11 more authors.
Journal of Burn Care and Research | Year: 2011

This study characterized the inflammatory response after burn injury and determined whether ethanol (EtOH) intoxication at the time of burn injury influences this response. To accomplish this, male mice were gavaged with EtOH (2.9 g/kg) 4 hours before 12 to 15% TBSA sham or burn injury. Mice were killed on day 1 after injury; blood, small intestine, lung, and liver were collected to measure interleukin (IL)-6, IL-10, IL-18, and Monocyte chemotactic protein-1 (MCP-1) levels. In addition, neutrophil infiltration, myeloperoxidase activity, and edema formation were also measured in the small intestine, lung, and liver. There was no difference in the inflammatory markers in the small intestine, lung, and liver in mice receiving either sham or burn injury alone except IL-6 that was increased in all four tissue compartments after burn injury alone. However, when compared with EtOH or burn injury alone, EtOH combined with burn injury resulted in a significant increase in cytokines, neutrophil infiltration, myeloperoxidase activity, and edema in the small intestine, liver, and lung tissue. Furthermore, a significant increase in IL-6 and MCP-1 was observed in circulation after EtOH intoxication and burn injury compared with either EtOH intoxication or burn injury alone; no other cytokines were detected in circulation. These findings suggest that acute EtOH intoxication exacerbates the inflammatory response after burn injury. Copyright © 2011 by the American Burn Association.


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.


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.


Curtis B.J.,Loyola University Chicago | Curtis B.J.,Burn and Shock Trauma Institute | Plichta J.K.,Loyola University Chicago | Plichta J.K.,Burn and Shock Trauma Institute | And 7 more authors.
Life Sciences | Year: 2012

Aim: To characterize how nicotinic acetylcholine receptors (nAChRs) influence epidermal barrier function and recovery following prolonged stress or direct nAChR activation or antagonism. Main methods: Mice were subjected to psychological stress or treated topically with nAChR agonist or antagonist for 3 days. We assessed barrier permeability and recovery by measuring transepidermal water loss (TEWL) before and after barrier disruption. In parallel, we analyzed the production and localization of several epidermal cornified envelope proteins in mouse skin and in human EpiDerm™ organotypic constructs stimulated with a nAChR agonist (nicotine) and/or a nAChR selective antagonist (α-bungarotoxin). Key findings: We determined that psychological stress in mice impairs barrier permeability function and recovery, an effect that is reversed by application of the α7 selective nAChR antagonist, α-bungarotoxin (Bung). In the absence of stress, both topical nicotine or Bung treatment alone impaired barrier permeability. We further observed that stress, topical nicotine, or topical Bung treatment in mice influenced the abundance and/or localization of filaggrin, loricrin, and involucrin. Similar alterations in these three major cornified envelope proteins were observed in human EpiDerm™ cultures. Significance: Perceived psychological stress and nicotine usage can both initiate or exacerbate several dermatoses by altering the cutaneous permeability barrier. Modulation of nAChRs by topical agonists or antagonists may be used to improve epidermal barrier function in skin diseases associated with defects in epidermal barrier permeability. © 2012 Elsevier Inc.


PubMed | Burn and Shock Trauma Institute
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2011

Ubiquitin, a post-translational protein modifier inside the cell, functions as a CXC chemokine receptor (CXCR) 4 agonist outside the cell. However, the structural determinants of the interaction between extracellular ubiquitin and CXCR4 remain unknown. Utilizing C-terminal truncated ubiquitin and ubiquitin mutants, in which surface residues that are known to interact with ubiquitin binding domains in interacting proteins are mutated (Phe-4, Leu-8, Ile-44, Asp-58, Val-70), we provide evidence that the ubiquitin-CXCR4 interaction follows a two-site binding mechanism in which the hydrophobic surfaces surrounding Phe-4 and Val-70 are important for receptor binding, whereas the flexible C terminus facilitates receptor activation. Based on these findings and the available crystal structures, we then modeled the ubiquitin-CXCR4 interface with the RosettaDock software followed by small manual adjustments, which were guided by charge complementarity and anticipation of a conformational switch of CXCR4 upon activation. This model suggests three residues of CXCR4 (Phe-29, Phe-189, Lys-271) as potential interaction sites. Binding studies with HEK293 cells overexpressing wild type and CXCR4 after site-directed mutagenesis confirm that these residues are important for ubiquitin binding but that they do not contribute to the binding of stromal cell-derived factor 1. Our findings suggest that the structural determinants of the CXCR4 agonist activity of ubiquitin mimic the typical structure-function relationship of chemokines. Furthermore, we provide evidence for separate and specific ligand binding sites on CXCR4. As exogenous ubiquitin has been shown to possess therapeutic potential, our findings are expected to facilitate the structure-based design of new compounds with ubiquitin-mimetic actions on CXCR4.


PubMed | Burn and Shock Trauma Institute
Type: Journal Article | Journal: The Journal of surgical research | Year: 2011

Here, we report the novel observation that natural killer T (NKT) cells contribute to the cutaneous wound repair process. Using an excisional wound model in wild-type versus NKT cell-deficient mice, this report shows that when NKT cells are absent, initial wound closure is markedly accelerated. We report here for the first time that NKT cells are a significant constituent of early wound inflammation and that they regulate the local production of a key subset of neutrophil and monocyte/macrophage chemokines, as well as TGF-1 content and collagen deposition. Together, our findings support the concept that NKT cells regulate the early inflammatory and fibroproliferative phases of nonpathologic healing wounds, positioning the NKT cell as an attractive potential therapeutic target for modulation of impaired wound healing.

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