Timothy R Billiar

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (691)2846.34 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Pathophysiological conditions that lead to the release of the prototypic damage-associated molecular pattern molecule high mobility group box-1 (HMGB1) also result in activation of poly (ADP-ribose) polymerase (now known as ADP-ribosyl transferases (ARTD))-1 or PARP1. Persistent activation of PARP1 promotes energy failure and cell death. The role of poly(ADP-ribosyl)ation in HMGB1 release has been previously explored; however, PARP1 is a versatile enzyme and performs several other functions including cross-talk with another nicotinamide adenine dinucleotide (NAD(+)) dependent member of the Class III histone deacetylases (HDACs)-sirtuin-1 (SIRT1). Previously, it has been shown that the hyperacetylation of HMGB1 is a seminal event prior to its secretion, a process that is also dependent on HDACs. Therefore, in this study, we seek to determine if PARP1 inhibition alters LPS-mediated HMGB1 hyperacetylation and subsequent secretion due to its effect on SIRT1.We demonstrate in an in vitro model that LPS treatment leads to hyperacetylated HMGB1with concomitant reduction in nuclear HDAC activity. Treatment with PARP1 inhibitors mitigates the LPS-mediated reduction in nuclear HDAC activity and decreases HMGB1 acetylation. By utilizing an NAD(+) based mechanism, PARP1 inhibition increases the activity of SIRT1. Consequently, there is an increased nuclear retention and decreased extracellular secretion of HMGB1. We also demonstrate that PARP1 physically interacts with SIRT1. Further confirmation of this data was obtained in a murine model of sepsis i.e., administration of PJ-34, a specific PARP1 inhibitor, led to decreased serum HMGB1 concentrations in mice subjected to CLP as compared to untreated mice. In conclusion, our study provides new insights in understanding the molecular mechanisms of HMGB1 secretion in sepsis.
    Molecular medicine (Cambridge, Mass.). 12/2014;
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    ABSTRACT: Severe traumatic injury can lead to immune dysfunction that renders trauma patients susceptible to nosocomial infections (NI) and prolonged intensive care unit (ICU) stays. We hypothesized that early circulating biomarker patterns following trauma would correlate with sustained immune dysregulation associated with NI and remote organ failure.
    Annals of surgery. 11/2014;
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    ABSTRACT: Trauma/hemorrhagic shock is associated with morbidity and mortality due to dysregulated inflammation, which is driven in part by monocytes/macrophages stimulated by injury-induced release of damage-associated molecular pattern (DAMP) molecules. MRP8/MRP14 is an endogenous DAMP involved in various inflammatory diseases, though its mechanism of action is unclear. Circulating MRP8/MRP14 levels in human blunt trauma nonsurvivors were significantly lower than those of survivors (P < 0.001). Human monocytic THP-1 cells stimulated with MRP8/MRP14 expressed the chemokine IFN-γ inducible protein 10 (IP-10)/CXCL10. Circulating IP-10 levels in human blunt trauma patients were correlated positively with MRP8/MRP14 levels (r = 0.396, P < 0.001), and were significantly lower in trauma nonsurvivors than in survivors (P < 0.001). We therefore sought to determine the mechanisms by which MRP8/MRP14 stimulates IP-10 in monocytes/macrophages, and found that induction of IP-10 by MRP8/MRP14 required Toll-like receptor 4 and TRIF but not MyD88. Full induction of IP-10 by MRP8/MRP14 required synergy between the transcription factors NF-κB and IFN regulatory factor 3 (IRF3). The receptor for IP-10 is CXCR3, and MRP8/MRP14-induced chemotaxis of CXCR3(+) cells was dependent on the production of IP-10 in monocytes/macrophages. Furthermore, in vivo study with a mouse trauma/hemorrhagic shock model showed that administration of neutralizing antibody against MRP8 prevented activation of NF-κB and IRF3 as well as IP-10 production. Thus, the current study identified a novel signaling mechanism that controls IP-10 expression in monocytes/macrophages by MRP8/MRP14, which may play an important role in injury-induced inflammation.-Wang, J., Vodovotz, Y., Fan, L., Li, Y., Liu, Z., Namas, R., Barclay, D., Zamora, R., Billiar, T. R., Wilson, M. A., Fan, J., Jiang, Y. Injury-induced MRP8/MRP14 stimulates IP-10/CXCL10 in monocytes/macrophages.
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 10/2014;
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    ABSTRACT: Many institutions now use empiric full-body computed tomography (CT) as a standard step in the initial workup of stable trauma patients. Recent data suggest that these scans may reveal unexpected injuries and improve survival in patients with polytrauma. However, patients who are unstable on presentation are often taken to the operating room (OR) without CT. Many of these patients undergo empiric full-body CTs after being stabilized in the OR, yet few data exist regarding how often early postoperative CT reveals unexpected injuries within compartments that have been explored surgically. Thus, the objective of this study was to determine if empiric abdominal/pelvic (ABD) CT after emergent trauma laparotomies are likely to reveal missed injuries requiring urgent management and improve patient management compared with clinical judgment alone.
    Surgery 10/2014; 156(4):979-87. · 3.37 Impact Factor
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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: Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome after hemorrhagic shock (HS) resulting from major surgery and trauma. The increased susceptibility in HS patients to the development of ALI suggests not yet fully elucidated mechanisms that enhance proinflammatory responses and/or suppress anti-inflammatory responses in the lung. Alveolar macrophages (AMϕ) are at the center of the pathogenesis of ALI after HS. We have previously reported that HS-activated polymorphonuclear neutrophils (PMNs) interact with macrophages to influence inflammation progress. In this study, we explore a novel function of PMNs regulating AMϕ anti-inflammatory mechanisms involving autophagy. Using a mouse "two-hit" model of HS/resuscitation followed by intratracheal injection of muramyl dipeptide, we demonstrate that HS initiates high mobility group box 1/TLR4 signaling, which upregulates NOD2 expression in AMϕ and sensitizes them to subsequent NOD2 ligand muramyl dipeptide to augment lung inflammation. In addition, upregulated NOD2 signaling induces autophagy in AMϕ, which negatively regulates lung inflammation through feedback suppression of NOD2-RIP2 signaling and inflammasome activation. Importantly, we further demonstrate that HS-activated PMNs that migrate in alveoli counteract the anti-inflammatory effect of autophagy in AMϕ, possibly through NAD(P)H oxidase-mediated signaling to enhance I-κB kinase γ phosphorylation, NF-κB activation, and nucleotide-binding oligomerization domain protein 3 inflammasome activation, and therefore augment post-HS lung inflammation. These findings explore a previously unidentified complexity in the mechanisms of ALI, which involves cell-cell interaction and receptor cross talk.
    Journal of immunology (Baltimore, Md. : 1950). 09/2014;
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    ABSTRACT: Type I IFNs play central roles in innate immunity; however, overproduction of IFN can lead to immunopathology. In this study, we demonstrate that adenosine deaminase acting on RNA 1 (ADAR1), an RNA-editing enzyme induced by IFN, is essential for cells to avoid inappropriate sensing of cytosolic RNA in an inducible knockout cell model-the primary mouse embryo fibroblast derived from ADAR1 lox/lox and Cre-ER mice as well as in HEK293 cells. ADAR1 suppresses viral and cellular RNA detection by retinoic acid-inducible gene I (RIG-I) through its RNA binding rather than its RNA editing activity. dsRNA binds to both ADAR1 and RIG-I, but ADAR1 reduces RIG-I RNA binding. In the absence of ADAR1, cellular RNA stimulates type I IFN production without viral infection or exogenous RNA stimulation. Moreover, we showed in the ADAR1-inducible knockout mice that ADAR1 gene disruption results in high-level IFN production in neuronal tissues-the hallmark of Aicardi-Goutières syndrome, a heritable autoimmune disease recently found to be associated with ADAR1 gene mutations. In summary, this study found that ADAR1 limits cytosolic RNA sensing by RIG-I through its RNA binding activity; therefore, ADAR1 suppresses type I IFN production stimulated by viral and cellular RNAs. These results explain why loss of ADARA1 causes IFN induction and also indicates a mechanism for the involvement of ADAR1 in autoimmune diseases such as Aicardi-Goutières syndrome.
    The Journal of Immunology 08/2014; · 5.52 Impact Factor
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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

Publication Stats

26k Citations
2,846.34 Total Impact Points

Institutions

  • 1988–2014
    • University of Pittsburgh
      • • Department of Surgery
      • • School of Medicine
      • • Department of Orthopaedic Surgery
      Pittsburgh, Pennsylvania, 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