Timothy R Billiar

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (679)2755.27 Total impact

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    ABSTRACT: Clinical research characterizing the mechanisms responsible for sex-based outcome differences postinjury remain conflicting. We sought to characterize an X chromosome-linked IRAK-1 (IL-1 receptor-associated kinase) polymorphism as an alternative mechanism responsible for sex differences postinjury. IRAK-1 is key intermediate in the toll-like receptor (TLR) pathway thought to drive inflammation postinjury.
    Annals of surgery. 10/2014; 260(4):698-705.
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    ABSTRACT: Cell death and inflammation are key pathologic responses of acute pancreatitis (AP), the leading cause of hospital admissions for gastrointestinal disorders. It is becoming increasingly clear that damage-associated molecular pattern molecules (DAMPs) play an important role in the pathogenesis of AP by linking local tissue damage to systemic inflammation syndrome. Endogenous DAMPs released from dead, dying, or injured cells initiate and extend sterile inflammation via specific pattern recognition receptors. Inhibition of the release and activity of DAMPs (e.g., high mobility group box 1, DNA, histones, and adenosine triphosphate) provides significant protection against experimental AP. Moreover, increased serum levels of DAMPs in patients with AP correlate with disease severity. These findings provide novel insight into the mechanism, diagnosis, and management of AP. DAMPs might be an attractive therapeutic target in AP.
    Molecular medicine (Cambridge, Mass.). 08/2014;
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    ABSTRACT: Hemorrhage and coagulopathy remain major drivers of early preventable mortality in military and civilian trauma. The development of trauma-induced coagulopathy and hyperfibrinolysis is associated with poor outcomes. Interest in the use of tranexamic acid (TXA) in hemorrhaging patients as an antifibrinolytic agent has grown recently. Additionally, several reports describe immunomodulatory effects of TXA that may confer benefit independent of its antifibrinolytic actions. A large trial demonstrated a mortality benefit for early TXA administration in patients at risk for hemorrhage; however, questions remain about the applicability in developed trauma systems and the mechanism by which TXA reduces mortality. We describe here the rationale, design, and challenges of the Study of Tranexamic Acid during Air Medical Prehospital transport (STAAMP) trial. The primary objective is to determine the effect of prehospital TXA infusion during air medical transport on 30-day mortality in patients at risk of traumatic hemorrhage. This study is a multicenter, placebo-controlled, double-blind, randomized clinical trial. The trial will enroll trauma patients with hypotension and tachycardia from 4 level I trauma center air medical transport programs. It includes a 2-phase intervention, with a prehospital and in-hospital phase to investigate multiple dosing regimens. The trial will also explore the effects of TXA on the coagulation and inflammatory response following injury. The trial will be conducted under exception for informed consent for emergency research and thus required an investigational new drug approval from the U.S. Food and Drug Administration as well as a community consultation process. It was designed to address several existing knowledge gaps and research priorities regarding TXA use in trauma.
    Prehospital Emergency Care 07/2014; · 1.86 Impact Factor
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    ABSTRACT: -Growing evidence indicates that the presence of TLR4 on platelets is a key regulator of platelet number and function. Platelets exposed to TLR4 agonists may serve to activate other cells such as neutrophils and endothelial cells in sepsis and other inflammatory conditions. The functional significance of platelet TLR4 in hemorrhagic shock, however, remains unexplored.
    Circulation Cardiovascular Genetics 07/2014; · 6.73 Impact Factor
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    ABSTRACT: Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed High-Mobility Group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhbitiors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localizationtion, structure, post-translational modification, and identifccation of additional partners will undoubtedly uncover additional secrets regarding HMGB1's multiple functions.
    Molecular Aspects of Medicine 07/2014; · 10.38 Impact Factor
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    ABSTRACT: Ideal triage uses simple criteria to identify severely injured patients. Glasgow Coma Scale motor (GCSm) may be easier for field use and was considered for the National Trauma Triage Protocol (NTTP). This study evaluated performance of the NTTP if GCSm is substituted for the current GCS score ≤ 13 criterion.
    The Journal of Trauma and Acute Care Surgery 07/2014; 77(1):95-102. · 2.35 Impact Factor
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    ABSTRACT: An excessive and uncontrolled systemic inflammatory response is associated with organ failure, immunodepression, and increased susceptibility to nosocomial infection following trauma. Interleukin-6 (IL-6) plays a particularly prominent role in the host immune response after trauma with hemorrhage. However, as a result of its pleiotropic functions, the effect of IL-6 in trauma and hemorrhage is still controversial. It remains unclear whether suppression of IL-6 after hemorrhagic shock and trauma will attenuate organ injury and immunosuppression. In this study, C57BL/6 mice were treated with anti-mouse-IL-6 monoclonal antibody (anti-IL-6 mAb) immediately prior to resuscitation in an experimental model combining hemorrhagic shock and lower extremity injury (HS+T). Interleukin-6 levels and signaling were transiently suppressed following administrations of anti-IL-6mAb following HS+T. This resulted in reduced lung and liver injury, as well as suppression in the levels of key inflammatory mediators including IL-10, KC, MCP-1, and MIP-1α at both 6 and 24h. Furthermore, the shift to Th2 cytokine production and suppressed lymphocyte response were partly prevented. These results demonstrate that IL-6 is not only a biomarker but also an important driver of injury-induced inflammation and immune suppression in mice. Rapid measurement of IL-6 levels in the early phase of post-injury care could be used to guide IL-6 based interventions.
    Shock (Augusta, Ga.) 06/2014; · 2.87 Impact Factor
  • Allan Tsung, Samer Tohme, Timothy R Billiar
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    ABSTRACT: High mobility group box 1 (HMGB1) was originally defined as a ubiquitous nuclear protein, but it was later determined that the protein has different roles both inside and outside of cells. Nuclear HMGB1 regulates chromatin structure and gene transcription, whereas cytosolic HMGB1 is involved in inflammasome activation and autophagy. Extracellular HMGB1 has drawn attention because it can bind to related cell signalling transduction receptors, such as the receptor for advanced glycation end-products, toll-like receptor (TLR)2, TLR4 and TLR9. It also participates in the development and progression of a variety of diseases. HMGB1 is actively secreted by stimulation of the innate immune system, and it is passively released by ischaemia or cell injury. This review focuses on the important role of HMGB1 in the pathogenesis of acute and chronic sterile inflammatory conditions. Strategies that target HMGB1 have been shown to significantly decrease inflammation in several disease models of sterile inflammation, and this may represent a promising clinical approach for treatment of certain conditions associated with sterile inflammation. This article is protected by copyright. All rights reserved.
    Journal of Internal Medicine 06/2014; · 6.46 Impact Factor
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    ABSTRACT: High mobility group box 1 (HMGB1) is an evolutionarily ancient protein that is present in one form or another in all eukaryotes. It fundamentally resides in the nucleus but translocates to the cytosol with stress and is subsequently released into the extracellular space. HMGB1 global knockout mice exhibit lethal hypoglycemia, whereas tissues and cells from conditional knockout or knockin mice are born alive without apparent significant functional deficit. An aberrant response to targeted stress in the liver, pancreas, heart, or myeloid cells is consistent with a protective role for HMGB1 in sustaining nuclear homeostasis and enabling other stress responses, including autophagy. Under some conditions, HMGB1 is not required for liver and heart function. Many challenges remain with respect to understanding the multiple roles of HMGB1 in health and disease.
    Molecular medicine (Cambridge, Mass.). 06/2014;
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    ABSTRACT: Sex-based outcome differences have been previously studied after thermal injury, with a higher risk of mortality being demonstrated in women. This is opposite to what has been found after traumatic injury. Little is known about the mechanisms and time course of these sex outcome differences after burn injury. A secondary analysis was performed using data from a prospective observational study designed to characterize the genetic and inflammatory response after significant thermal injury (2003-2010). Clinical outcomes were compared across sex (female vs male), and the independent risks associated with sex were determined using logistic regression analysis after controlling for important confounders. Stratified analysis across age and burn severity was performed, whereas Cox hazard survival curves were constructed to determine the time course of any sex differences found. During the time period of the study, 548 patients met inclusion criteria for the cohort study. Men and women were found to be similar in age, TBSA%, inhalation injury, and Acute Physiology and Chronic Health score. Regression analysis revealed that female sex was independently associated with over a 2-fold higher mortality after controlling for important confounders (odds ratio, 2.2; P = .049; 95% confidence interval, 1.01-4.8). The higher independent mortality risk for women was exaggerated and remained significant only in pediatric patients and demonstrated a dose-response relationship with increasing burn size (%TBSA). Survival analysis demonstrated early separation of female and male curves, and a greater independent risk of multiple organ failure was demonstrated in the pediatric cohort. The current results suggest that sex-based outcome differences may be different after thermal injury compared with traumatic injury and that the sex dimorphism may be exaggerated in patients with higher burn size and in those in the pediatric age group, with female sex being associated with poor outcome. These sex-based mortality differences occur early and may be a result of a higher risk of organ failure and early differences in the inflammatory response after burn injury. Further investigation is required to thoroughly characterize the mechanisms responsible for these divergent outcomes.
    Journal of burn care & research: official publication of the American Burn Association 05/2014; · 1.54 Impact Factor
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    ABSTRACT: Background and Rationale. Acetaminophen (APAP) toxicity is the most common cause of acute liver failure in industrialized countries. Understanding the mechanisms of APAP-induced liver injury as well as other forms of sterile liver injury is critical to improve the care of patients. Recent studies demonstrate that danger signaling and inflammasome activation play a role in APAP-induced injury. The purpose of these investigations was to test the hypothesis that benzyl alcohol (BA) is a therapeutic that protects against APAP-induced liver injury via modulation of danger signaling. Main Results. APAP-induced liver injury was dependent in part on TLR-9 and receptor for advanced glycation endproducts (RAGE) signaling. BA limited liver injury over a dose range of 135-540 µg/g body weight or when delivered as a pre-, concurrent, or post-APAP therapeutic. Furthermore, BA abrogated APAP-induced cytokines and chemokines as well as high mobility group box-1 release. Moreover, BA prevented APAP-induced inflammasome signaling as determined by IL-1β, IL-18 and caspase-1 cleavage in liver tissues. Interestingly, the protective effects of BA on limiting liver injury and inflammasome activation were dependent on TLR4 signaling, but not TLR2 or Cluster of differentiation 14 (CD14). Cell type specific knockouts of TLR4 were utilized in order to further determine the protective mechanisms of BA. These studies found that TLR4 expression specifically in myeloid cells (LyzCre-tlr4-/-) were necessary for the protective effects of BA. Conclusion: BA protects against APAP-induced acute liver injury and reduced inflammasome activation in a TLR4-dependent manner. BA may prove to be a useful adjunct in the treatment of APAP and other forms of sterile liver injury. (Hepatology 2014)
    Hepatology 05/2014; · 12.00 Impact Factor
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    ABSTRACT: To evaluate the association of pretrauma center (PTC) red blood cell (RBC) transfusion with outcomes in severely injured patients. Hemorrhage remains a major driver of mortality. Little evidence exists supporting PTC interventions to mitigate this. Blunt injured patients in shock arriving at a trauma center within 2 hours of injury were included from the Glue Grant database. Subjects were dichotomized by PTC RBC transfusion. Outcomes included 24-hour mortality, 30-day mortality, and trauma-induced coagulopathy [(TIC), admission international normalized ratio >1.5]. Cox regression and logistic regression determined the association of PTC RBC transfusion with outcomes. To address baseline differences, propensity score matching was used. Of 1415 subjects, 50 received PTC RBC transfusion. Demographics and injury severity score were similar. The PTC RBC group received 1.3 units of RBCs (median), and 52% were scene transports. PTC RBC transfusion was associated with a 95% reduction in odds of 24-hour mortality [odds ratio (OR) = 0.05; 95% confidence interval (CI), 0.01-0.48; P < 0.01], 64% reduction in the risk of 30-day mortality [hazard ratio = 0.36; 95% CI, 0.15-0.83; P = 0.02], and 88% reduction in odds of TIC (OR = 0.12; 95% CI, 0.02-0.79; P = 0.03). The matched cohort included 113 subjects (31% PTC RBC group). Baseline characteristics were similar. PTC RBC transfusion was associated with a 98% reduction in odds of 24-hour mortality (OR = 0.02; 95% CI, 0.01-0.69; P = 0.04), 88% reduction in the risk of 30-day mortality (hazard ratio = 0.12; 95% CI, 0.03-0.61; P = 0.01), and 99% reduction in odds of TIC (OR = 0.01; 95% CI, 0.01-0.95; P = 0.05). PTC RBC administration was associated with a lower risk of 24-hour mortality, 30-day mortality, and TIC in severely injured patients with blunt trauma, warranting further prospective study.
    Annals of surgery 03/2014; · 7.90 Impact Factor
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    ABSTRACT: A body of experimental evidence suggests that the female sex is associated with a lower risk of mortality after trauma-hemorrhage. However, controversy remains regarding the mechanism responsible for these differences and if basic science findings correspond to clinical differences. Racial disparities in trauma outcomes have also been increasingly described. Until now, research on the association between sex and trauma patient outcomes mainly focused on patients in Europe and the United States. Our research attempted to determine whether the female sex is associated with a survival advantage among severely injured Chinese trauma patients. A retrospective analysis of data derived from the Emergency Intensive Care Unit of the Shanghai Sixth People's Hospital Acute Trauma Center during 2010-2013 was performed to characterize differences in sex-based outcomes after severe blunt trauma. The patient study cohort (858 Asian subjects) was then stratified by age and injury severity (ISS). Crude and adjusted odds ratios (ORs) were calculated to evaluate the association between sex and nosocomial infection rate and hospitalized mortality, both overall and by age and ISS category subgroups. Among all trauma patients, females had a significantly lower risk of in-hospital mortality compared with males (OR, 0.41; 95% CI, 0.20 -0.85). This difference was most apparent for patients younger than 50 years old (OR, 0.31; 95% CI, 0.12-0.82) and the group with ISS scores ≥ 25 (OR, 0.39; 95% CI, 0.17 - 0.91). No differences in development of nosocomial infections between sexes were seen among the overall patient group and subgroups. This study revealed a statistically significant association between sex and mortality among severe blunt trauma patients, particularly those patients < 50 years old and with ISS scores ≥ 25. Women had significantly lower mortality than men after severe blunt trauma. These results highlight the important role of sex hormones and sex-based outcome differences following severe traumatic injury in the Chinese population.
    Shock (Augusta, Ga.) 03/2014; · 2.87 Impact Factor
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    ABSTRACT: Recent studies demonstrate a role for TLR4 in the pathogenesis of pulmonary hypertension (PH), however, the cell types involved in mediating the effects of TLR4 remain unknown. The objective of this study was to determine the contribution of TLR4 expressed on nonparenchymal cells to the pathogenesis of PH. TLR4 bone marrow chimeric mice revealed an equal contribution of TLR4 on nonparenchymal and parenchymal cells in the pathogenesis of PH as determined by measuring right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH). However, deletion of TLR4 from myeloid lineage cells had no effect on the development of PH since we found no difference in RVSP or RVH in WT vs. LysM-TLR4-/- mice. To explore the potential role of platelet TLR4 in the pathogenesis of PH, platelet specific TLR4-/- mice were generated (PF4-TLR4-/- mice). TLR4 -/- platelets from either global TLR4-/- or PF4-TLR4-/- mice were functional but failed to respond to lipopolysaccharide (LPS) demonstrating a lack of TLR4. PF4-TLR4-/- mice demonstrated significant protection from hypoxia-induced PH, including attenuated increases in RVSP and RVH, decreased platelet activation, and less pulmonary vascular remodeling. Deletion of TLR4 from platelets attenuated serotonin release after CH and LPS stimulated platelets released serotonin and promoted pulmonary artery smooth muscle cell proliferation in a serotonin-dependent manner. Our data demonstrate that TLR4 on platelets contributes to the pathogenesis of PH and further highlights the role of platelets in PH.
    Circulation Research 03/2014; · 11.86 Impact Factor
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    ABSTRACT: Blunt trauma and traumatic spinal cord injury induce systemic inflammation that contributes to morbidity. Dysregulated neural control of systemic inflammation postinjury is likely exaggerated in patients with traumatic spinal cord injury. We used in silico methods to discern dynamic inflammatory networks that could distinguish systemic inflammation in traumatic spinal cord injury from blunt trauma. Retrospective study. Tertiary care institution. Twenty-one severely injured thoracocervical traumatic spinal cord injury patients and matched 21 severely injured blunt trauma patients without spinal cord injury. None. Serial blood samples were obtained from days 1 to 14 postinjury. Twenty-four plasma inflammatory mediators were quantified. Statistical significance between the two groups was determined by two-way analysis of variance. Dynamic Bayesian network inference was used to suggest dynamic connectivity and central inflammatory mediators. Circulating interleukin-10 was significantly elevated in thoracocervical traumatic spinal cord injury group versus non-spinal cord injury group, whereas interleukin-1β, soluble interleukin-2 receptor-α, interleukin-4, interleukin-5, interleukin-7, interleukin-13, interleukin-17, macrophage inflammatory protein 1α and 1β, granulocyte-macrophage colony-stimulating factor, and interferon-γ were significantly reduced in traumatic spinal cord injury group versus non-spinal cord injury group. Dynamic Bayesian network suggested that post-spinal cord injury interleukin-10 is driven by inducible protein-10, whereas monocyte chemotactic protein-1 was central in non-spinal cord injury dynamic networks. In a separate validation cohorts of 356 patients without spinal cord injury and 85 traumatic spinal cord injury patients, individuals with plasma inducible protein-10 levels more than or equal to 730 pg/mL had significantly prolonged hospital and ICU stay and days on mechanical ventilator versus patients with plasma inducible protein-10 level less than 730 pg/mL. This is the first study to compare the dynamic systemic inflammatory responses of traumatic spinal cord injury patients versus patients without spinal cord injury, suggesting a key role for inducible protein-10 in driving systemic interleukin-10 and morbidity and highlighting the potential utility of in silico tools to identify key inflammatory drivers.
    Critical care medicine 02/2014; · 6.37 Impact Factor
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    ABSTRACT: The cellular cues that regulate the apoptosis of intestinal stem cells (ISCs) remain incompletely understood, yet may play a role in diseases characterized by ISC loss including necrotizing enterocolitis (NEC). Toll-like receptor-4 (TLR4) was recently found to be expressed on ISCs, where its activation leads to ISC apoptosis through mechanisms that remain incompletely explained. We now hypothesize that TLR4 induces endoplasmic reticulum (ER) stress within ISCs leading to their apoptosis in NEC pathogenesis, and that high ER stress within the premature intestine predisposes to NEC development. Using transgenic mice and cultured enteroids, we now demonstrate that TLR4 induces ER stress within Lgr5 (Leucine-rich repeat-containing-G-protein coupled-receptor-5)-positive ISCs, resulting in crypt apoptosis. TLR4 signaling within crypts was required, as crypt ER stress and apoptosis occurred in TLR4ΔIEC-OVER mice expressing TLR4 only within intestinal crypts and epithelium, but not TLR4ΔIEC mice lacking intestinal TLR4. TLR4-mediated ER stress and apoptosis of ISCs required PERK (Protein-kinase related-PKR-like ER-kinase), CHOP (C/EBP-homologous protein) and MyD88 (Myeloid-differentiation primary response-gene-88), but not ATF6 (activating-transcription factor-6), XBP1 (X-box-binding protein-1), or TRIF(TIR-domain-containing adapter-inducing interferon-β). Human and mouse NEC showed high crypt ER stress and apoptosis, while genetic inhibition of PERK or CHOP attenuated ER stress, crypt apoptosis, and NEC severity. Strikingly, using intra-gastric delivery into fetal mouse intestine, prevention of ER stress reduced TLR4-mediated ISC apoptosis and mucosal disruption. These findings identify a novel link between TLR4-induced ER stress and ISC apoptosis in NEC pathogenesis, and suggest that increased ER stress within the premature bowel predisposes to NEC development.
    Journal of Biological Chemistry 02/2014; · 4.65 Impact Factor
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    ABSTRACT: and The Inflammation and the Host Response to Injury Investigators Objective: To determine whether prehospital nonsteroidal anti-inflammatory drug (NSAID) use may lead to a reduced incidence of trauma-induced coag-ulopathy (TIC) in severely injured patients. Background: TIC is present in up to a quarter of severely injured trauma patients and is linked to worse outcomes after injury. Evidence linking TIC to inflammation has emerged; however, the mechanism behind this association is still under investigation. NSAIDs are commonly used anti-inflammatory drugs, but their effects on TIC and outcomes after injury are largely unex-plored. Methods: We performed a secondary analysis of the Inflammation and the Host Response to Injury Large Scale Collaborative Program (Glue Grant) data set. Prehospital medications and comorbidities were analyzed by logistic regression analysis for association with TIC as defined by laboratory (interna-tional normalized ratio >1.5) or clinical (transfusion >2 units of fresh frozen plasma or >1 pack of platelets in 6 hours) parameters. Results: Prehospital NSIAD use was independently associated with a 72% lower risk of TIC and was the only medication among 15 analyzed to retain significance in the model. Stepwise logistic regression also demonstrated that preadmission use of NSAIDs was independently associated with a 66% lower risk of clinically significant coagulopathy. These findings were independent of comorbid conditions linked to NSAID use. Conclusions: NSAID use before admission for severe injury is associated with a reduced incidence of TIC. These findings provide further evidence to a potential leak between TIC and inflammation. T rauma-induced coagulopathy (TIC) is a unique, endogenous coagulopathy that is present in as many as 25% of severely injured patients with major trauma independent of prehospital From the anticoagulation. 1 Early coagulopathy in trauma has recently been shown to be associated with a greater incidence of multiple-organ failure and nosocomial infection and substantially higher transfusion requirements. 2,3 Importantly, coagulopathy upon presentation to the emergency department has been associated with both early and late mortality. 3 Although TIC has been increasingly recognized as a crit-ical component of the pathophysiology of trauma and hemorrhagic shock, factors that predict the development of TIC remain largely unexplored. 4 The lack of ability to predict TIC makes the design of therapeutic interventions challenging, especially considering that TIC seems to develop rapidly and early after injury. Despite the significance of TIC, little is known about the patho-genesis of this perturbation in normal coagulation. Hyperfibrinolysis, factor V inhibition, and impaired platelet function, among others, have been implicated in the development of TIC. 5 Laboratory data and prospective analysis from severely injured trauma patients have linked the development of TIC to alterations in the thrombomodulin-protein C pathway and excessive activated protein C activation, re-sulting in impaired coagulation. 6–8 These data present a potential link between TIC and inflammation, which is a common finding in other conditions where both sterile (such as myocardial infarction) and pathogen-mediated (sepsis) diseases present with coagulopathy.
    Annals of Surgery 01/2014; · 6.33 Impact Factor
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    ABSTRACT: Impairment of autophagy has been associated with liver injury. TLR4-stimulation by LPS upregulates autophagy in hepatocytes, although the signaling pathways involved remain elusive. The objective of this study was to determine the signaling pathway leading to LPS-stimulated autophagy in hepatocytes. Cell lysates from livers of wild type (WT; C57BL/6) mice given LPS (5 mg/kg-IP) and hepatocytes from WT, TLR4ko, and MyD88ko mice treated with LPS (100 ng/mL) up to 24 h were collected. LC3II, p62/SQSTM1, Nrf2, and beclin1 levels were determined by immunoblot, immunofluorescence, and qPCR. Autophagy-like activation was measured by GFP-LC3-puncta formation and LC3II-expression. Beclin1, Nrf2, p62, MyD88, and TIRAP were knocked-down using siRNA. LC3II-expression increased in both liver and hepatocytes after LPS and was dependent on TLR4. Beclin1 expression did not increase after LPS in hepatocytes and beclin1-knockdown did not affect LC3II levels. In hepatocytes given LPS, expression of p62 increased and p62 colocalized with LC3. p62-knockdown prevented LC3II puncta formation. LPS-induced LC3II/p62-puncta also required MyD88/TIRAP signaling and localization of both Nrf2 and NF κ B transcription factors to the nucleus to upregulate p62-expression. Therefore, TLR4-activation by LPS in hepatocytes induces a p62-mediated, not beclin1-mediated, autophagy-like clearance pathway that is hepatoprotective by clearing aggregate-prone or misfolded proteins from the cytosol and preserving energy homeostasis under stress.
    BioMed research international. 01/2014; 2014:267350.
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    ABSTRACT: Increasing evidence suggests the important role of metabolic reprogramming in the regulation of the innate inflammatory response, but the underlying mechanism remains unclear. Here we provide evidence to support a novel role for the pyruvate kinase M2 (PKM2)-mediated Warburg effect, namely aerobic glycolysis, in the regulation of high-mobility group box 1 (HMGB1) release. PKM2 interacts with hypoxia-inducible factor 1α (HIF1α) and activates the HIF-1α-dependent transcription of enzymes necessary for aerobic glycolysis in macrophages. Knockdown of PKM2, HIF1α and glycolysis-related genes uniformly decreases lactate production and HMGB1 release. Similarly, a potential PKM2 inhibitor, shikonin, reduces serum lactate and HMGB1 levels, and protects mice from lethal endotoxemia and sepsis. Collectively, these findings shed light on a novel mechanism for metabolic control of inflammation by regulating HMGB1 release and highlight the importance of targeting aerobic glycolysis in the treatment of sepsis and other inflammatory diseases.
    Nature Communications 01/2014; 5:4436. · 10.02 Impact Factor
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    ABSTRACT: High mobility group box-1 (HMGB1) is an abundant chromatin associated nuclear protein and released into the extracellular milieu during liver ischemia/reperfusion (I/R), signaling the activation of pro-inflammatory cascades. Since the intracellular function of HMGB1 during the sterile inflammation of I/R is currently unknown, we sought to determine the role of intracellular HMGB1 in hepatocytes following liver I/R. When hepatocyte specific HMGB1 knockout (HMGB1-HC-KO) and control mice were subjected to a non-lethal warm liver I/R, it was found that HMGB1-HC-KO mice had significantly greater hepatocellular injury after I/R compared to control mice. Additionally, there was significantly greater DNA damage and decreased chromatin accessibility to repair with lack of HMGB1. Furthermore, lack of hepatocyte HMGB1 led to excessive poly (ADP-ribose) polymerase-1 (PARP-1) activation, exhausting NAD(+) and ATP stores, exacerbating mitochondrial instability and damage, and consequently leading to increased cell death. We found that this was also associated with significantly more oxidative stress in HMGB1-HC-KO mice compared to control. Increased nuclear instability led to a resultant increase in the release of histones with subsequently more inflammatory cytokine production and organ damage through the activation of TLR9. Conclusion: Therefore, the lack of HMGB1 within hepatocytes leads to the increased susceptibility to cellular death after oxidative stress conditions. (Hepatology 2013;).
    Hepatology 12/2013; · 12.00 Impact Factor

Publication Stats

24k Citations
2,755.27 Total Impact Points

Institutions

  • 1988–2014
    • University of Pittsburgh
      • • Department of Surgery
      • • School of Medicine
      • • Department of Orthopaedic Surgery
      Pittsburgh, Pennsylvania, United States
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
  • 2013
    • Heidelberg University
      Tiffin, Ohio, United States
    • Stanford University
      • Stanford Genome Technology Center
      Palo Alto, CA, United States
    • University Hospital RWTH Aachen
      • Department of Trauma and Reconstructive Surgery
      Aachen, North Rhine-Westphalia, Germany
  • 2011–2013
    • Southern Medical University
      • Department of Pathophysiology
      Guangzhou, Guangdong Sheng, China
  • 1992–2013
    • Childrens Hospital of Pittsburgh
      • Division of Newborn Medicine
      Pittsburgh, Pennsylvania, United States
  • 2012
    • University of Pennsylvania
      Philadelphia, Pennsylvania, United States
    • State University of New York Upstate Medical University
      • Department of Surgery
      Syracuse, NY, United States
  • 2011–2012
    • Massachusetts General Hospital
      • Department of Surgery
      Boston, MA, United States
  • 2005–2012
    • National and Kapodistrian University of Athens
      • • Division of Surgery V
      • • Department of Surgery
      Athens, Attiki, Greece
  • 2001–2012
    • University of Bonn
      Bonn, North Rhine-Westphalia, Germany
  • 1999–2008
    • Kangwon National University
      • • Department of Molecular and Cellular Biochemistry
      • • College of Medicine
      • • Department of Biochemistry
      South Korea
  • 2006
    • Beth Israel Deaconess Medical Center
      Boston, Massachusetts, United States
  • 2004
    • Chonbuk National University
      • College of Veterinary Medicine
      Seoul, Seoul, South Korea
  • 2001–2003
    • Wonkwang University
      Riri, North Jeolla, South Korea
  • 2001–2002
    • Deutsches Herzzentrum München
      München, Bavaria, Germany
  • 2000–2001
    • Baylor College of Medicine
      • • Section of Infectious Diseases
      • • Department of Medicine
      Houston, TX, United States
    • Carnegie Mellon University
      • Department of Biological Sciences
      Pittsburgh, PA, United States
  • 1996–2000
    • National Institutes of Health
      • Laboratory of Human Carcinogenesis
      Bethesda, MD, United States
  • 1998
    • University of Geneva
      Genève, Geneva, Switzerland
  • 1990–1998
    • Pittsburg State University
      Kansas, United States
  • 1995
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany
  • 1994
    • University of North Carolina at Chapel Hill
      • Department of Surgery
      Chapel Hill, NC, United States
  • 1988–1989
    • University of Washington Seattle
      • Department of Surgery
      Seattle, WA, United States