Timothy R Billiar

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (732)3245.17 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: Myocytes are non-hemopoietic in origin and functionally essential in generating gastrointestinal motility. In endotoxemia, a rapid onset non-hemopoietic mechanism potently triggers early ileus in a TLR4/MyD88-dependent manner. Moreover, synergistically with hemopoietic cells, non-hemopoietic cells escalate late ileus via an IL-6 receptor-dependent inflammation-driven pathway. Herein, we therefore specifically investigated the role of myocytes in TLR4-triggered inflammation and ileus. Design: TLR4(+/+), TLR4(-/-), bmTLR4(+/+)/TLR4(-/-) chimera, SM22-Cre(-/-)TLR4(flox/flox) and selective myocyte TLR4-deficient (SM22-Cre(+/-)TLR4(flox/flox)) mice were injected intraperitoneally with purified lipopolysaccharide. SM22-driven Cre recombinase activity was selectively detected in cardiac, gastrointestinal and skeletal myocytes as well as vascular myocytes of small-sized vessels in a two-color fluorescent Cre reporter mouse. In contrast to non-hemopoietic TLR4-deficiency, deletion of myocyte TLR4 signaling prevented neither the endotoxin-induced suppression of spontaneous jejunal contractility in vitro nor early ileus in vivo at 6 h. Circulating plasma CSF3 was greatly elevated during endotoxemia, independent of myocyte TLR4 signaling or time. TLR4 activation of myocytes contributed significantly to an early enteric IL-6 mRNA induction and systemic IL-6 release, as well as to a late increase in circulating CXCL1 and IL 17. Consequently, inhibition of myocyte TLR4 signaling allowed functional recovery of motility by preventing inflammation-driven late ileus at 24 h. Direct TLR4 activation of myocytes is not responsible for non-hemopoietic-mediated early ileus. However, myocytes are proinflammatory cells that potently drive both enteric and systemic inflammation, subsequently fueling late mediator-triggered ileus. Specifically, the myocyte TLR4-dependent inflammatory signature of elevated plasma IL-6, CXCL1 and IL-17 is strongly associated with late rodent ileus. Copyright © 2014, American Journal of Physiology- Gastrointestinal and Liver Physiology.
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    ABSTRACT: Clinical research characterizing the mechanisms responsible for sex-based outcome differences after injury remains conflicting. Currently lacking is an understanding of the early sex hormone milieu of the injured patient and the effects these early hormone differences have on clinical outcomes and the innate immune response following injury. A prospective cohort study was performed over a 20-month period. Blunt injury patients requiring intensive care unit admission were enrolled. Samples were collected within 6 hours and at 24 hours after injury and were analyzed for total testosterone (TT) and estradiol concentrations. Outcomes of interest included multiple-organ failure (MOF; Marshall Multiple Organ Dysfunction Score [MODScore] > 5), nosocomial infection (NI), mortality, and serial cytokine/chemokine measurements. Multivariate logistic regression was used to determine the independent risks associated with early sex hormone measurements. In 288 prospectively enrolled patients, 69% were male, with a median Injury Severity Score (ISS) of 16 (interquartile range 10-21). Elevated TT levels at 6 hours were associated with elevated interleukin 6 levels and cytokine/chemokine measurements (18 of 24 measured). Rising TT levels were significantly associated with more than a fivefold and twofold higher independent risk of MOF and NI, respectively (odds ratio [OR], 5.2; p = 0.02; 95% confidence interval [CI], 1.2-22.3; and OR, 2.1; p = 0.03; 95% CI, 1.02-4.2). At 24 hours, TT levels were no longer associated with poor outcome, while estradiol levels were significantly associated with nearly a fourfold higher independent risk of MOF (OR, 3.9; p = 0.04, 95% CI, 1.05-13). Early elevations and increasing testosterone levels over initial 24 hours after injury are associated with an exaggerated inflammatory response and a significantly greater risk of MOF and NI. High estrogen levels at 24 hours are independently associated with an increased risk of MOF. The current analysis suggests that an early evolving testosterone to estrogen hormonal environment is associated with a significantly higher independent risk of poor outcome following traumatic injury. Prognostic/epidemiologic study, level II.
    Journal of Trauma and Acute Care Surgery 03/2015; 78(3):451-8. DOI:10.1097/TA.0000000000000550 · 2.50 Impact Factor
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    ABSTRACT: Abstract Hemorrhage and trauma induced coagulopathy remain major drivers of early preventable mortality in military and civilian trauma. Interest in the use of prehospital plasma in hemorrhaging patients as a primary resuscitation agent has grown recently. Trauma center-based damage control resuscitation using early and aggressive plasma transfusion has consistently demonstrated improved outcomes in hemorrhaging patients. Additionally, plasma has been shown to have several favorable immunomodulatory effects. Preliminary evidence with prehospital plasma transfusion has demonstrated feasibility and improved short-term outcomes. Applying state-of-the-art resuscitation strategies to the civilian prehospital arena is compelling. We describe here the rationale, design, and challenges of the Prehospital Air Medical Plasma (PAMPer) trial. The primary objective is to determine the effect of prehospital plasma transfusion during air medical transport on 30-day mortality in patients at risk for traumatic hemorrhage. This study is a multicenter cluster randomized clinical trial. The trial will enroll trauma patients with profound hypotension (SBP ≤ 70 mmHg) or hypotension (SBP 71-90 mmHg) and tachycardia (HR ≥ 108 bpm) from six level I trauma center air medical transport programs. The trial will also explore the effects of prehospital plasma transfusion on the coagulation and inflammatory response following injury. The trial will be conducted under exception for informed consent for emergency research with an investigational new drug approval from the U.S. Food and Drug Administration utilizing a multipronged community consultation process. It is one of three ongoing Department of Defense-funded trials aimed at expanding our understanding of the optimal therapeutic approaches to coagulopathy in the hemorrhaging trauma patient.
    Prehospital Emergency Care 02/2015; DOI:10.3109/10903127.2014.995851 · 1.81 Impact Factor
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    ABSTRACT: The intracellular protein HMGB1 is released from cells and acts as a damage-associated molecular pattern molecule during many diseases, including inflammatory bowel disease (IBD); however, the intracellular function of HMGB1 during inflammation is poorly understood. Here, we demonstrated that cytosolic HMGB1 regulates apoptosis by protecting the autophagy proteins beclin 1 and ATG5 from calpain-mediated cleavage during inflammation. Colitis in mice with an intestinal epithelial cell-specific Hmgb1 deletion and patients with IBD were both characterized by increased calpain activation, beclin 1 and ATG5 cleavage, and intestinal epithelial cell (IEC) death compared with controls. In vitro cleavage assays and studies of enteroids verified that HMGB1 protects beclin 1 and ATG5 from calpain-mediated cleavage events that generate proapoptotic protein fragments. Together, our results indicate that HMGB1 is essential for mitigating the extent and severity of inflammation-associated cellular injury by controlling the switch between the proautophagic and proapoptotic functions of beclin 1 and ATG5 during inflammation. Moreover, these studies demonstrate that HMGB1 is pivotal for reducing tissue injury in IBD and other complex inflammatory disorders.
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    ABSTRACT: Undertriage is a concern in geriatric patients. The National Trauma Triage Protocol (NTTP) recognized that systolic blood pressure (SBP) less than 110 mm Hg may represent shock in those older than 65 years. The objective was to evaluate the impact of substituting an SBP of less than 110 mm Hg for the current SBP of less than 90 mm Hg criterion within the NTTP on triage performance and mortality. Subjects undergoing scene transport in the National Trauma Data Bank (2010-2012) were included. The outcome of trauma center need was defined as Injury Severity Score (ISS) greater than 15, intensive care unit admission, urgent operation, or emergency department death. Geriatric (age > 65 years) and adult (age, 16-65 years) cohorts were compared. Triage characteristics and area under the curve (AUC) were compared between SBP of less than 110 mm Hg and SBP of less than 90 mm Hg. Hierarchical logistic regression was used to determine whether geriatric patients newly triaged positive under this change (SBP, 90-109 mm Hg) have a risk of mortality similar to those triaged positive with SBP of less than 90 mm Hg. There were 1,555,944 subjects included. SBP of less than 110 mm Hg had higher sensitivity but lower specificity in geriatric (13% vs. 5%, 93% vs. 99%) and adult (23% vs. 10%, 90% vs. 98%) cohorts. AUC was higher for SBP of less than 110 mm Hg individually in both geriatric and adult (p < 0.01) cohorts. Within the NTTP, the AUC was similar for SBP of less than 110 mm Hg and SBP of less than 90 mm Hg in geriatric subjects but was higher for SBP of less than 90 mm Hg in adult subjects (p < 0.01). Substituting SBP of less than 110 mm Hg resulted in an undertriage reduction of 4.4% with overtriage increase of 4.3% in the geriatric cohort. Geriatric subjects with SBP of 90 mm Hg to 109 mm Hg had an odds of mortality similar to those of geriatric patients with SBP of less than 90 mm Hg (adjusted odds ratio, 1.03; 95% confidence interval, 0.88-1.20; p = 0.71). SBP of less than 110 mm Hg increases sensitivity. SBP of less than 110 mm Hg has discrimination as good as that of SBP of less than 90 mm Hg, with superior improvements in undertriage relative to overtriage in geriatric patients. Geriatric patients newly triaged to be positive under this change have a risk of mortality similar to those under the current SBP criterion. This change in SBP criteria may be merited in geriatric patients, warranting further study to consider elevation to a Step 1 criterion in the NTTP. Diagnostic study, level IV.
    Journal of Trauma and Acute Care Surgery 02/2015; 78(2):352-359. DOI:10.1097/TA.0000000000000523 · 2.50 Impact Factor
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    ABSTRACT: Long-term outcomes following traumatic brain injury (TBI) correlate with initial head injury severity and other acute factors. Hospital-acquired pneumonia (HAP) is a common complication in TBI. Limited information exists regarding the significance of infectious complications on long-term outcomes after TBI. We sought to characterize risks associated with HAP on outcomes 5 years after TBI. This study involved data from the merger of an institutional trauma registry and the Traumatic Brain Injury Model Systems outcome data. Individuals with severe head injuries (Abbreviated Injury Scale [AIS] score ≥ 4) who survived to rehabilitation were analyzed. Primary outcome was Glasgow Outcome Scale-Extended (GOSE) at 1, 2, and 5 years. GOSE was dichotomized into low (GOSE score < 6) and high (GOSE score ≥ 6). Logistic regression was used to determine adjusted odds of low GOSE score associated with HAP after controlling for age, sex, head and overall injury severity, cranial surgery, Glasgow Coma Scale (GCS) score, ventilation days, and other important confounders. A general estimating equation model was used to analyze all outcome observations simultaneously while controlling for within-patient correlation. A total of 141 individuals met inclusion criteria, with a 30% incidence of HAP. Individuals with and without HAP had similar demographic profiles, presenting vitals, head injury severity, and prevalence of cranial surgery. Individuals with HAP had lower presenting GCS score. Logistic regression demonstrated that HAP was independently associated with low GOSE scores at follow-up (1 year: odds ratio [OR], 6.39; 95% confidence interval [CI], 1.76-23.14; p = 0.005) (2 years: OR, 7.30; 95% CI, 1.87-27.89; p = 0.004) (5-years: OR, 6.89; 95% CI, 1.42-33.39; p = 0.017). Stratifying by GCS score of 8 or lower and early intubation, HAP remained a significant independent predictor of low GOSE score in all strata. In the general estimating equation model, HAP continued to be an independent predictor of low GOSE score (OR, 4.59; 95% CI, 1.82-11.60; p = 0.001). HAP is independently associated with poor outcomes in severe TBI extending 5 years after injury. This suggests that precautions should be taken to reduce the risk of HAP in individuals with severe TBI. Prognostic study, level III.
    Journal of Trauma and Acute Care Surgery 02/2015; 78(2):396-402. DOI:10.1097/TA.0000000000000526 · 2.50 Impact Factor
  • Journal of Trauma and Acute Care Surgery 02/2015; 78(2):396-402. · 2.50 Impact Factor
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    ABSTRACT: Hemorrhage is the leading cause of survivable death in trauma. Resuscitation strategies including early red blood cell (RBC) transfusion have reduced this. Pre-trauma center (PTC) RBC transfusion is growing and preliminary evidence suggests improved outcomes. The study objective was to evaluate the association of PTC RBC transfusion with outcomes in air medical trauma patients.
    Journal of the American College of Surgeons 01/2015; DOI:10.1016/j.jamcollsurg.2015.01.006 · 4.45 Impact Factor
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    ABSTRACT: Craniofacial trauma is difficult to repair and presents a significant burden to the healthcare system. The inflammatory response following bone trauma is critical to initiate healing, serving to recruit inflammatory and progenitor cells and to promote angiogenesis. A role for inflammation in graft-induced bone regeneration has been suggested, but is still not well understood. The current study assessed the impact of Toll-like Receptor (TLR4) signaling on calvarial repair in the presence of morselized bone components. Calvarial defects in wildtype and global TLR4-/- knockout mouse strains were treated with fractionated bone components in the presence or absence of a TLR4 neutralizing peptide. Defect healing was subsequently evaluated over 28 days by micro-CT and histology. The matrix-enriched fraction of morselized bone stimulated calvarial bone repair comparably to intact bone graft, although the capacity for grafts to induce calvarial bone repair was significantly diminished by inhibition or genetic ablation of TLR4. Overall, our findings suggest that the matrix component of bone graft stimulates calvarial bone repair in a TLR4-dependent manner. These results support the need to better understand the role of inflammation in the design and implementation of strategies to improve bone healing.
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    ABSTRACT: Innate immune receptors for pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) orchestrate inflammatory responses to infection and injury. Secreted by activated immune cells or passively released by damaged cells, HMGB1 is subjected to redox modification that distinctly influences its extracellular functions. Previously, it was unknown how the TLR4 signalosome distinguished between HMGB1 isoforms. Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms. Using MD-2-deficient mice, as well as MD-2 silencing in macrophages, we show a requirement for HMGB1-dependent TLR4 signaling. By screening HMGB1 peptide libraries, we identified a tetramer (FSSE, designated P5779) as a specific MD-2 antagonist preventing MD-2-HMGB1 interaction and TLR4 signaling. P5779 does not interfere with lipopolysaccharide-induced cytokine/chemokine production, thus preserving PAMP-mediated TLR4-MD-2 responses. Furthermore, P5779 can protect mice against hepatic ischemia/reperfusion injury, chemical toxicity, and sepsis. These findings reveal a novel mechanism by which innate systems selectively recognize specific HMGB1 isoforms. The results may direct toward strategies aimed at attenuating DAMP-mediated inflammation while preserving antimicrobial immune responsiveness. © 2015 Yang et al.
    Journal of Experimental Medicine 01/2015; 212(1):5-14. DOI:10.1084/jem.20141318 · 13.91 Impact Factor
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    ABSTRACT: Proteolytic cleavage of the tumor necrosis factor (TNF) receptor (TNFR) from the cell surface contributes to anti-inflammatory responses and may be beneficial in reducing the excessive inflammation associated with multiple organ failure and mortality during sepsis. Using a clinically relevant mouse model of polymicrobial abdominal sepsis, we found that the production of inducible nitric oxide synthase (iNOS) in hepatocytes led to the cyclic guanosine monophosphate (cGMP)-dependent activation of the protease TACE (TNF-converting enzyme) and the shedding of TNFR. Furthermore, treating mice with a cGMP analog after the induction of sepsis increased TNFR shedding and decreased systemic inflammation. Similarly, increasing the abundance of cGMP with a clinically approved phosphodiesterase 5 inhibitor (sildenafil) also decreased markers of systemic inflammation, protected against organ injury, and increased circulating amounts of TNFR1 in mice with sepsis. We further confirmed that a similar iNOS-cGMP-TACE pathway was required for TNFR1 shedding by human hepatocytes in response to the bacterial product lipopolysaccharide. Our data suggest that increasing the bioavailability of cGMP might be beneficial in ameliorating the inflammation associated with sepsis. Copyright © 2015, American Association for the Advancement of Science.
    Science Signaling 01/2015; 8(361):ra11. DOI:10.1126/scisignal.2005548 · 7.65 Impact Factor
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    ABSTRACT: Objective: Evaluate the effect of US geographic region on outcomes of helicopter transport (HT) for trauma. Background: HT is an integral component of trauma systems. Evidence suggests that HT is associated with improved outcomes; however, no studies examine the impact of geographic variation on outcomes for HT. Methods: Retrospective cohort study of patients undergoing scene HT or ground transport in the National Trauma Databank (2009-2012). Subjects were divided by US census region. HT and ground transport subjects were propensity-score matched based on prehospital physiology and injury severity. Conditional logistic regression was used to evaluate the effect of HT on survival and discharge to home in each region. Region-level characteristics were assessed as potential explanatory factors. Results: A total of 193,629 pairs were matched. HT was associated with increased odds of survival and discharge to home; however, the magnitude of these effects varied significantly across regions (P < 0.01). The South had the greatest survival benefit (odds ratio: 1.44; 95% confidence interval: 1.39-1.49, P < 0.01) and the Northeast had the greatest discharge to home benefit (odds ratio: 1.29; 95% confidence interval: 1.18-1.41, P < 0.01). A subset of region-level characteristics influenced the effect of HT on each outcome, including helicopter utilization, injury severity, trauma center and helicopter distribution, trauma center access, traffic congestion, and urbanicity (P < 0.05). Conclusions: Geographic region impacts the benefits of HT in trauma. Variations in resource allocation partially account for outcome differences. Policy makers should consider regional factors to better assess and allocate resources within trauma systems to optimize the role of HT.
    Annals of Surgery 01/2015; DOI:10.1097/SLA.0000000000001047 · 7.19 Impact Factor
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    ABSTRACT: Although tissue-derived high mobility group box 1 (HMGB1) is involved in many aspects of inflammation and tissue injury after trauma, its role in trauma-induced immune suppression remains elusive. Using an established mouse model of peripheral tissue trauma, which includes soft tissue and fracture components, we report here that treatment with anti-HMGB1 monoclonal antibody ameliorated the trauma-induced attenuated T-cell responses and accumulation of CD11b(+)Gr-1(+) myeloid-derived suppressor cells in the spleens seen two days after injury. Our data suggest that HMGB1 released after tissue trauma contributes to signaling pathways that lead to attenuation of T-lymphocyte responses and enhancement of myeloid-derived suppressor cell expansion.
    Mediators of Inflammation 01/2015; 2015:458626. DOI:10.1155/2015/458626 · 2.42 Impact Factor
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    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.
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    ABSTRACT: Background: 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. Methods: In a cohort of 472 blunt trauma survivors studied over an 8-year period, 127 patients (27%) were diagnosed with NI versus 345 trauma patients without NI. To perform a pairwise, case-control study with 1:1 matching, 44 of the NI patients were compared with 44 no-NI trauma patients selected by matching patient demographics and injury characteristics. Plasma obtained upon admission and over time were assayed for 26 inflammatory mediators and analyzed for the presence of dynamic networks. Results: Significant differences in ICU length of stay (LOS), hospital LOS, and days on mechanical ventilation were observed in the NI patients versus no-NI patients. Although NI was not detected until day 7, multiple mediators were significantly elevated within the first 24 hours in patients who developed NI. Circulating inflammation biomarkers exhibited 4 distinct dynamic patterns, of which 2 clearly distinguish patients destined to develop NI from those who did not. Mediator network connectivity analysis revealed a higher, coordinated degree of activation of both innate and lymphoid pathways in the NI patients over the initial 24 hours. Conclusions: These studies implicate unique dynamic immune responses, reflected in circulating biomarkers that differentiate patients prone to persistent critical illness and infections following injury, independent of mechanism of injury, injury severity, age, or gender.
    Annals of Surgery 11/2014; DOI:10.1097/SLA.0000000000001001 · 7.19 Impact Factor
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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.
    The FASEB Journal 10/2014; 29(1). DOI:10.1096/fj.14-255992 · 5.48 Impact Factor
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    ABSTRACT: Objective(s): 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. Methods: A prospective cohort study was performed over a 24-month period. Bluntly injured patients requiring intensive care unit admission were enrolled, whereas patients with isolated brain and spinal cord injuries were excluded. Outcomes of interest included multiple organ failure (MOF, Marshall MOD score > 5) and mortality. Logistic regression was utilized to determine the independent risk of poor outcome associated with the IRAK-1 variant after controlling for important differences. Results: In an enrolled cohort of 321 patients, the IRAK-1 variant was common (12.5%). Patients with and without the variant were similar in age, injury severity, and 24hr blood transfusion. After controlling for important confounders, the IRAK1 variant was independently associated with more than eightfold (OR = 8.4, P = 0.005, 95% CI: 1.9-37.1) and 11-fold (OR = 11.8, P = 0.037, 95% CI: 1.1-121) greater risk of MOF and mortality, respectively. These differences were most prominent in men, whereas women heterozygous for the variant demonstrated worse outcome in a dose-dependent fashion. Conclusions: The IRAK1 polymorphism is a strong independent predictor of MOF and mortality postinjury and represents a common variant with prognostic potential. These data demonstrate the importance of TLR signaling postinjury and supports that a genetic mechanism may drive sex outcome differences postinjury.
    Annals of Surgery 10/2014; 260(4):698-705. DOI:10.1097/SLA.0000000000000918 · 7.19 Impact Factor
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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. DOI:10.1016/j.surg.2014.06.044 · 3.11 Impact Factor
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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.
    The Journal of Immunology 09/2014; 193(9). DOI:10.4049/jimmunol.1400899 · 5.36 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 09/2014; 60(3). DOI:10.1002/hep.27201 · 11.19 Impact Factor

Publication Stats

32k Citations
3,245.17 Total Impact Points


  • 1988–2015
    • University of Pittsburgh
      • • Department of Surgery
      • • Department of Medicine
      • • Department of Pediatrics
      Pittsburgh, Pennsylvania, United States
  • 2013
    • Guangzhou First People's Hospital
      Shengcheng, Guangdong, China
    • Stanford University
      • Stanford Genome Technology Center
      Palo Alto, CA, United States
  • 1992–2013
    • Childrens Hospital of Pittsburgh
      • Division of Newborn Medicine
      Pittsburgh, Pennsylvania, United States
  • 2012
    • University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 2005–2012
    • University of Bonn
      Bonn, North Rhine-Westphalia, Germany
  • 2011
    • Southern Medical University
      • Department of Pathophysiology
      Guangzhou, Guangdong Sheng, China
  • 2008
    • University of Helsinki
      • Transplantation Laboratory
      Helsinki, Uusimaa, Finland
  • 2002–2008
    • Kangwon National University
      • Department of Molecular and Cellular Biochemistry
      South Korea
    • Deutsches Herzzentrum München
      München, Bavaria, Germany
  • 2001
    • Baylor College of Medicine
      • Section of Infectious Diseases
      Houston, TX, United States
  • 2000
    • Carnegie Mellon University
      • Department of Biological Sciences
      Pittsburgh, PA, United States
  • 1998
    • University of Geneva
      Genève, Geneva, Switzerland
  • 1990–1998
    • Pittsburg State University
      Kansas, United States
  • 1996
    • National Institutes of Health
      • Laboratory of Human Carcinogenesis
      Bethesda, MD, United States
  • 1995
    • Montefiore Medical Center
      New York City, New York, United States
  • 1994–1995
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany
    • University of North Carolina at Chapel Hill
      • Department of Surgery
      Chapel Hill, NC, United States
  • 1993
    • Utah State University
      • Department of Chemistry and Biochemistry
      Logan, Ohio, United States
  • 1988–1989
    • University of Minnesota Duluth
      • Laboratory Medicine and Pathology
      Duluth, Minnesota, United States