Timothy R Billiar

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (782)3574.37 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: We sought to examine the association between the clinical outcomes and the early, dynamic, systemic acute inflammatory response in the setting of major bone/soft tissue injury. Methods: From a cohort of 472 blunt trauma survivors, two stringently matched cohorts were derived: 32 patients who had a severe extremity injury (AIS ≥ 3) following blunt trauma (18 males and 14 females; age: 52.5 ± 3.1; ISS: 21.5 ± 1.5) and 30 trauma patients with mild/moderate extremity injury (AIS < 3; 15 males and 15 females; age: 53 ± 2.4; ISS: 22.4 ± 1.4). Serial blood samples (3 samples within the first 24 h and then from days 1 to 7 post- injury) were assayed for multiple inflammation mediators. Two-Way ANOVA was used to compare groups, and Dynamic Bayesian Network (DyBN) analysis to infer network connectivity. Results: ICU length of stay [LOS], total LOS, days on mechanical ventilation, Marshall MODScore, as well admission lactate and CPK were significantly altered in AIS ≥ 3 group. Plasma levels of IL-6, IL-8, MIG, IP-10, and MCP-1 were significantly elevated in the AIS ≥ 3 group, while plasma levels of IL-7, Eotaxin, and MIP- 1α were significantly elevated in the AIS < 3 group over the 7 days post-injury. DyBN inference suggested a different core chemokine-based network upstream of mediators including IL-6 and IL-10. Conclusion: Our results suggest that severe extremity/soft tissue injury can drive a differential inflammation program including multiple chemokines that affect systemic IL-6 and IL-10, in a manner associated with worse clinical outcomes as compared to mild/moderate soft tissue injury.
    Shock (Augusta, Ga.) 09/2015; 44 Suppl 2:10. DOI:10.1097/01.shk.0000472034.95062.1e · 3.05 Impact Factor
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    ABSTRACT: Extracellular HMGB1 (disulfide form), via activation of Toll-Like-Receptor (TLR4)-dependent signaling, is a strong driver of pathologic inflammation in both acute and chronic conditions. Identification of selective inhibitors of HMGB1-TLR4 signaling could offer novel therapies that selectively target proximal endogenous activators of inflammation. A cell-based screening strategy led us to identify first generation HIV-protease inhibitors (PI) as potential inhibitors of HMGB1-TLR4 driven cytokine production. Here we report, that the first-generation HIV-PI saquinavir (SQV), as well as a newly identified mammalian protease inhibitor STO33438 (334), potently block disulfide HMGB1 induced TLR4 activation, as assayed by the production of TNF-α by human monocyte-derived macrophages (THP-1). We further report on the identification of mammalian cathepsin V, a protease, as a novel target of these inhibitors. Cellular as well as recombinant protein studies show that the mechanism of action involves a direct interaction between cathepsin V with TLR4 and its adaptor protein MyD88. Treatment with SQV, 334, or the known cathepsin inhibitor SID26681509 (SID) significantly improved survival in murine models of sepsis and reduced liver damage following warm liver I/R, models both characterized by strong HMGB1-TLR4 driven pathology. The current study demonstrates a novel role for cathepsin V in TLR4 signaling and implicates cathepsin V as a novel target for first-generation HIV-PI compounds. The identification of cathepsin V as a target to block HMGB1-TLR4 driven inflammation could allow for a rapid transition of the discovery from the bench to the bedside.
    Molecular Medicine 09/2015; DOI:10.2119/molmed.2015.00197 · 4.51 Impact Factor
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    ABSTRACT: Sepsis is the host's deleterious systemic inflammatory response to microbial infections. Here we report an essential role for the oestrogen sulfotransferase (EST or SULT1E1), a conjugating enzyme that sulfonates and deactivates estrogens, in sepsis response. Both the caecal ligation and puncture (CLP) and lipopolysaccharide models of sepsis induce the expression of EST and compromise the activity of oestrogen, an anti-inflammatory hormone. Surprisingly, EST ablation sensitizes mice to sepsis-induced death. Mechanistically, EST ablation attenuates sepsis-induced inflammatory responses due to compromised oestrogen deactivation, leading to increased sepsis lethality. In contrast, transgenic overexpression of EST promotes oestrogen deactivation and sensitizes mice to CLP-induced inflammatory response. The induction of EST by sepsis is NF-κB dependent and EST is a NF-κB-target gene. The reciprocal regulation of inflammation and EST may represent a yet-to-be-explored mechanism of endocrine regulation of inflammation, which has an impact on the clinical outcome of sepsis.
    Nature Communications 08/2015; 6:7979. DOI:10.1038/ncomms8979 · 11.47 Impact Factor
  • Journal of Trauma and Acute Care Surgery 08/2015; 79(2):327. DOI:10.1097/TA.0000000000000717 · 2.74 Impact Factor
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    ABSTRACT: We propose an exploratory clinical study, the first of its kind to our knowledge, to determine the safety and potential clinical benefit of the combination of the HIV protease inhibitors (HIV-PIs) saquinavir and ritonavir (SQV+RIT) in patients with idiopathic pulmonary arterial hypertension (IPAH). This study is based on evidence that (1) HIV-PIs can improve pulmonary hemodynamics in experimental models; (2) both Toll-like receptor 4 and high-mobility group box 1 (HMGB1) participate in the pathogenesis of experimental pulmonary hypertension; and (3) a high-throughput screen for inhibitors of HMGB1-induced macrophage activation yielded HIV-PIs as potent inhibitors of HMGB1-induced cytokine production. In this proposed open-label, pre-post study, micro, low, and standard doses of SQV+RIT will be given to IPAH patients for 14 days. Patients will receive follow-up for the next 14 days. The primary outcome to be evaluated is change in HMGB1 level from baseline at 14 days. The secondary outcome is changes in tumor necrosis factor α, interleukin 1β, interleukin 6, C-reactive protein, pulmonary arterial pressure based on echocardiography parameters and New York Heart Association/World Health Organization functional class, and Brog dyspnea scale index from baseline at 14 days. Other secondary measurements will include N-terminal pro-brain natriuretic peptide, atrial natriuretic peptide, and 6-minute walk distance. We propose that SQV+RIT treatment will improve inflammatory disorders and pulmonary hemodynamics in IPAH patients. If the data support a potentially useful therapeutic effect and suggest that SQV+RIT is safe in IPAH patients, the study will warrant further investigation. (ClinicalTrials.gov identifier: NCT02023450.).
    07/2015; 5(3):000-000. DOI:10.1086/682426
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    ABSTRACT: Toll-like receptors (TLRs) play an important role in regulating muscle regeneration and angiogenesis in response to ischemia. TLR2 knockout mice exhibit pronounced skeletal muscle necrosis and abnormal vessel architecture following femoral artery ligation, suggesting that TLR2 signaling is protective during ischemia. TLR4, an important receptor in inflammatory signaling, has been shown to regulate TLR2 expression in other systems. We hypothesize that a similar relationship between TLR4 and TLR2 may exist in hindlimb ischemia in which TLR4 upregulates TLR2, a mediator of angiogenesis and perfusion recovery. We examined the expression of TLR2 in unstimulated and in TLR agonist treated endothelial cells (ECs). TLR2 expression, low in control ECs, was upregulated by lipopolysaccharide, the danger signal high mobility group box-1, and hypoxia in a TLR4-dependent manner. Endothelial tube formation on matrigel as well as EC permeability was assessed as in vitro measures of angiogenesis. Time-lapse imaging demonstrated that ECs lacking TLR4 formed more tubes while TLR2 knockdown ECs exhibited attenuated tube formation. TLR2 also mediated EC permeability, an initial step during angiogenesis, in response to HMGB1 which is released by cells during hypoxic injury. In vivo, ischemia-induced upregulation of TLR2 required intact TLR4 signaling which mediated systemic inflammation as measured by local and systemic IL-6 levels. Similar to our in vitro findings, vascular density and limb perfusion were both enhanced in the absence of TLR4 signaling, but not if TLR2 was deleted. These findings indicate that TLR2, in the absence of TLR4, improves angiogenesis and perfusion recovery in response to ischemia.
    Molecular Medicine 07/2015; DOI:10.2119/molmed.2014.00260 · 4.51 Impact Factor
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    ABSTRACT: Fatty acid binding protein 4 (FABP4) has been known as a mediator of inflammatory response in the macrophages and adipose tissue, but its hepatic function is poorly understood. The goal of this study is to investigate the role of FABP4 in liver ischemia/reperfusion (I/R), a clinical condition involves both hypoxia and inflammation. To examine the I/R regulation of FABP4, mice were subjected to I/R surgery before being measured for FABP4 gene expression. Both loss-of-function (by using a pharmacological FABP4 inhibitor) and gain-of-function (by adenoviral overexpression of FABP4) were used to determine the functional relevance of FABP4 expression and its regulation during I/R. To determine the hypoxia responsive regulation of FABP4, primary mouse hepatocytes were exposed to hypoxia. The FABP4 gene promoter was cloned and its regulation by hypoxia inducible factor 1α (HIF-1α) was characterized by luciferase reporter gene, electrophoretic mobility shift, and chromatin immunoprecipitation assays. We found that the hepatic expression of FABP4 was markedly induced by I/R. At the functional level, pharmacological inhibition of FABP4 alleviated the I/R injury, whereas adenoviral overexpression of FABP4 sensitized mice to I/R injury. We also showed that exposure of primary hepatocytes to hypoxia or transgenic overexpression of HIF-1α in the mouse liver was sufficient to induce the expression of FABP4. Our promoter analysis established FABP4 as a novel transcriptional target of HIF-1α. FABP4 is a hypoxia inducible gene that sensitizes mice to liver I/R injury. FABP4 may represent a novel therapeutic target, and FABP4 inhibitors may be used as therapeutic agents to manage hepatic I/R injury. Copyright © 2015. Published by Elsevier B.V.
    Journal of Hepatology 06/2015; DOI:10.1016/j.jhep.2015.05.030 · 11.34 Impact Factor
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    ABSTRACT: Clinical outcomes following trauma depend on the extent of injury and the host's response to injury, along with medical care. We hypothesized that dynamic networks of systemic inflammation manifest differently as a function of injury severity in human blunt trauma. From a cohort of 472 blunt trauma survivors studied following IRB approval, three Injury Severity Score (ISS) sub-cohorts were derived after matching for age and gender: Mild ISS (49 patients [33 males, 16 females; age 42±1.9; ISS 9.5±0.4]); Moderate ISS: (49 patients [33 males, 16 females; age 42±1.9; ISS 19.9±0.4]) and Severe ISS: (49 patients [33 males, 16 females; age 42±2.5; ISS 33±1.1]). Multiple inflammatory mediators were assessed in serial blood samples. Dynamic Bayesian Network (DyBN) inference was utilized to infer causal relationships based on probabilistic measures. ICU length of stay [LOS], total LOS, days on mechanical ventilation, Marshall Multiple Organ Dysfunction Score, prevalence of pre-hospital hypotension and nosocomial infection, as well admission lactate and base deficit were elevated as a function of ISS. Multiple circulating inflammatory mediators were significantly elevated in Severe ISS vs. Moderate or Mild ISS over both the first 24 h and out to 7 days post-injury. Moderate and Mild ISS. DyBN suggested that IL-6 production in Severe ISS was affected by MCP-1/CCL2, MIG/CXCL9, and IP-10/CXCL10; by MCP-1/CCL2 and MIG/CXCL9 in Moderate ISS; and by MIG/CXCL9 alone in Mild ISS over 7 d post-injury. ISS correlates linearly with morbidity, prevalence of infection, and early systemic inflammatory connectivity of chemokines to IL-6.
    Shock (Augusta, Ga.) 05/2015; 44(2). DOI:10.1097/SHK.0000000000000395 · 3.05 Impact Factor
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    ABSTRACT: Hemorrhagic shock followed by fluid resuscitation (HS/R) triggers an inflammatory response and causes pulmonary inflammation that can lead to acute lung injury (ALI). Hydrogen, a therapeutic gas, has potent cytoprotective, antiinflammatory, and antioxidant effects. This study examined the effects of inhaled hydrogen on ALI caused by HS/R. Rats were subjected to hemorrhagic shock by withdrawing blood to lower blood pressure followed by resuscitation with shed blood and saline to restore blood pressure. After HS/R, the rats were maintained in a control gas of similar composition to room air or exposed to 1.3% hydrogen. HS/R induced ALI, as demonstrated by significantly impaired gas exchange, congestion, edema, cellular infiltration, and hemorrhage in the lungs. Hydrogen inhalation mitigated lung injury after HS/R, as indicated by significantly improved gas exchange and reduced cellular infiltration and hemorrhage. Hydrogen inhalation did not affect hemodynamic status during HS/R. Exposure to 1.3% hydrogen significantly attenuated the upregulation of the messenger RNAs for several proinflammatory mediators induced by HS/R. Lipid peroxidation was reduced significantly in the presence of hydrogen, indicating antioxidant effects. Hydrogen, administered through inhalation, may exert potent therapeutic effects against ALI induced by HS/R and attenuate the activation of inflammatory cascades. Copyright © 2015 Elsevier Inc. All rights reserved.
    Surgery 05/2015; 158(2). DOI:10.1016/j.surg.2015.03.038 · 3.38 Impact Factor
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    ABSTRACT: Trauma-induced critical illness is driven by acute inflammation, and elevated systemic interleukin-6 (IL-6) after trauma is a biomarker of adverse outcomes. We constructed a multicompartment, ordinary differential equation model that represents a virtual trauma patient. Individual-specific variants of this model reproduced both systemic inflammation and outcomes of 33 blunt trauma survivors, from which a cohort of 10,000 virtual trauma patients was generated. Model-predicted length of stay in the intensive care unit, degree of multiple organ dysfunction, and IL-6 area under the curve as a function of injury severity were in concordance with the results from a validation cohort of 147 blunt trauma patients. In a subcohort of 98 trauma patients, those with high-IL-6 single-nucleotide polymorphisms (SNPs) exhibited higher plasma IL-6 levels than those with low IL-6 SNPs, matching model predictions. Although IL-6 could drive mortality in individual virtual patients, simulated outcomes in the overall cohort were independent of the propensity to produce IL-6, a prediction verified in the 98-patient subcohort. In silico randomized clinical trials suggested a small survival benefit of IL-6 inhibition, little benefit of IL-1β inhibition, and worse survival after tumor necrosis factor-α inhibition. This study demonstrates the limitations of extrapolating from reductionist mechanisms to outcomes in individuals and populations and demonstrates the use of mechanistic simulation in complex diseases. Copyright © 2015, American Association for the Advancement of Science.
    Science translational medicine 04/2015; 7(285):285ra61. DOI:10.1126/scitranslmed.aaa3636 · 15.84 Impact Factor
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    ABSTRACT: Estrogen sulfotransferase (EST) regulates estrogen homeostasis by sulfonating and deactivating estrogens. Liver ischemia and reperfusion (I/R) involves both hypoxia during the ischemic phase and oxidative damage during the reperfusion phase. In this report, we showed that the expression of EST was markedly induced by I/R. Mechanistically, oxidative stress-induced activation of Nrf2 was responsible for the EST induction, which was abolished in Nrf2-/- mice. EST is a direct transcriptional target of Nrf2. In the female mice, the I/R responsive induction of EST compromised estrogen activity. EST ablation attenuated the I/R injury as a result of decreased estrogen deprivation, whereas this benefit was abolished upon ovariectomy. The effect of EST ablation was sex-specific, because the EST-/- males showed heightened I/R injury. Reciprocally, both estrogens and EST regulate the expression and activity of Nrf2. Estrogen deprivation by ovariectomy abolished the I/R responsive Nrf2 accumulation, whereas the compromised estrogen deprivation in EST-/- mice was associated with an increased Nrf2 accumulation. Our results suggested a novel I/R responsive feedback mechanism to limit the activity of Nrf2, in which Nrf2 induces the expression of EST, which subsequently increases estrogen deactivation and limits the estrogen responsive activation of Nrf2. Inhibition of EST, at least in females, may represent an effective approach to manage hepatic I/R injury. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 04/2015; 290(23). DOI:10.1074/jbc.M115.642124 · 4.57 Impact Factor
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    ABSTRACT: The mechanisms that lead to the development of remote lung injury after trauma remain unknown, although a central role for the gut in the induction of lung injury has been postulated. We hypothesized that the development of remote lung injury after trauma/hemorrhagic shock requires activation of TLR4 in the intestinal epithelium, and we sought to determine the mechanisms involved. We show that trauma/hemorrhagic shock caused lung injury in wild-type mice, but not in mice that lack TLR4 in the intestinal epithelium, confirming the importance of intestinal TLR4 activation in the process. Activation of intestinal TLR4 after trauma led to increased endoplasmic reticulum (ER) stress, enterocyte apoptosis, and the release of circulating HMGB1, whereas inhibition of ER stress attenuated apoptosis, reduced circulating HMGB1, and decreased lung injury severity. Neutralization of circulating HMGB1 led to reduced severity of lung injury after trauma, and mice that lack HMGB1 in the intestinal epithelium were protected from the development of lung injury, confirming the importance of the intestine as the source of HMGB1, whose release of HMGB1 induced a rapid protein kinase C ζ-mediated internalization of surface tight junctions in the pulmonary epithelium. Strikingly, the use of a novel small-molecule TLR4 inhibitor reduced intestinal ER stress, decreased circulating HMGB1, and preserved lung architecture after trauma. Thus, intestinal epithelial TLR4 activation leads to HMGB1 release from the gut and the development of lung injury, whereas strategies that block upstream TLR4 signaling may offer pulmonary protective strategies after trauma. Copyright © 2015 by The American Association of Immunologists, Inc.
    The Journal of Immunology 04/2015; 194(10). DOI:10.4049/jimmunol.1402490 · 4.92 Impact Factor
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    ABSTRACT: Unlabelled: Innate immunity plays a crucial role in the response to sterile inflammation such as liver ischemia/reperfusion (I/R) injury. The initiation of liver I/R injury results in the release of damage-associated molecular patterns, which trigger an innate immune and inflammatory cascade through pattern recognition receptors. Neutrophils are recruited to the liver after I/R and contribute to organ damage and innate immune and inflammatory responses. Formation of neutrophil extracellular traps (NETs) has been recently found in response to various stimuli. However, the role of NETs during liver I/R injury remains unknown. We show that NETs form in the sinusoids of ischemic liver lobes in vivo. This was associated with increased NET markers, serum level of myeloperoxidase-DNA complexes, and tissue level of citrullinated-histone H3 compared to control mice. Treatment with peptidyl-arginine-deiminase 4 inhibitor or DNase I significantly protected hepatocytes and reduced inflammation after liver I/R as evidenced by inhibition of NET formation, indicating the pathophysiological role of NETs in liver I/R injury. In vitro, NETs increase hepatocyte death and induce Kupffer cells to release proinflammatory cytokines. Damage-associated molecular patterns, such as High Mobility Group Box 1 and histones, released by injured hepatocytes stimulate NET formation through Toll-like receptor (TLR4)- and TLR9-MyD88 signaling pathways. After neutrophil depletion in mice, the adoptive transfer of TLR4 knockout or TLR9 knockout neutrophils confers significant protection from liver I/R injury with a significant decrease in NET formation. In addition, we found inhibition of NET formation by the peptidyl-arginine-deiminase 4 inhibitor and that DNase I reduces High Mobility Group Box 1 and histone-mediated liver I/R injury. Conclusion: Damage-associated molecular patterns released during liver I/R promote NET formation through the TLR signaling pathway. Development of NETs subsequently exacerbates organ damage and initiates inflammatory responses during liver I/R. (Hepatology 2015;62:600-614.
    Hepatology 04/2015; 62(2). DOI:10.1002/hep.27841 · 11.06 Impact Factor
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    ABSTRACT: To define the impact of prehospital hypotension on the dynamic, systemic acute inflammatory response to blunt trauma. Retrospective study. Tertiary care institution. Twenty-two hypotensive blunt trauma patients matched with 28 normotensive blunt trauma patients. None. From a cohort of 472 blunt trauma survivors studied following institutional review board approval, two stringently matched subcohorts were derived. Twenty-two patients who sustained prehospital hypotension following blunt trauma (15 males and 7 females; age, 45 ± 3.8; Injury Severity Score, 20.7 ± 1.8) were matched with 28 normotensive trauma patients (20 males and 8 females; age, 46.1 ± 2.5; Injury Severity Score, 20.8 ± 1.3). Serial blood samples (three samples within the first 24 hr and then from days 1 to 7 postinjury) were assessed for 24 inflammatory mediators using Luminex, and No2-/No3- was measured using the nitrate reductase/Griess assay. Two-way analysis of variance was used to compare groups. Dynamic Bayesian Network inference was used to infer causal relationships based on probabilistic measures. Statistically significant differences were observed in ICU length of stay, total length of stay, days on mechanical ventilator, and Marshall Multiple Organ Dysfunction score between hypotensive and normotensive patients. Shock markers (shock index, pH, lactate, and base deficit) were significantly altered in hypotensive patients. Plasma levels of chemokines (monocyte chemotactic protein-1/CCL2, inducible protein-10/CXCL10, macrophage inflammatory protein-1α/CCL3, and interleukin-8/CCL8) and cytokines (interleukin-6, interleukin-10, interleukin-17, granulocyte-macrophage colony-stimulating factor, interleukin-1β, and interleukin-7) as well as soluble interleukin-2 receptor-α were significantly elevated over the first 7 days postinjury in the hypotensive versus normotensive patients. Dynamic Bayesian Network suggested that the chemokines monocyte chemotactic protein-1/CCL2 and monokine induced by gamma interferon/CXCL9 in the hypotensive and normotensive patients, respectively, affect plasma interleukin-6 levels differentially in the initial 24 hours postinjury. Studies in stringently matched patient cohorts suggest that an episode of prehospital hypotension post trauma leads to early, dynamic reprogramming of systemic inflammation (including differential upstream regulation of interleukin-6), which is associated with worse outcomes.
    Critical care medicine 03/2015; 43(7). DOI:10.1097/CCM.0000000000000964 · 6.31 Impact Factor
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    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.
    AJP Gastrointestinal and Liver Physiology 03/2015; 308(10):ajpgi.00211.2014. DOI:10.1152/ajpgi.00211.2014 · 3.80 Impact Factor
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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 · 2.74 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; 19(3). DOI:10.3109/10903127.2014.995851 · 1.76 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.
    Journal of Clinical Investigation 02/2015; 125(3). DOI:10.1172/JCI76344 · 13.22 Impact Factor
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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 · 2.74 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 · 2.74 Impact Factor

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  • 1988–2015
    • University of Pittsburgh
      • • Department of Surgery
      • • Department of Medicine
      Pittsburgh, Pennsylvania, United States
  • 2014
    • UPMC
      Pittsburgh, Pennsylvania, United States
  • 1990–2014
    • Pittsburg State University
      Питсбург, Kansas, United States
    • Cornell University
      Итак, New York, United States
  • 1993–2013
    • Childrens Hospital of Pittsburgh
      • Division of Newborn Medicine
      Pittsburgh, Pennsylvania, United States
  • 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
  • 2006
    • Columbia University
      • Department of Surgery
      New York, New York, United States
  • 2005
    • University of Bonn
      Bonn, North Rhine-Westphalia, Germany
  • 2001
    • Baylor College of Medicine
      • Section of Infectious Diseases
      Houston, Texas, United States
  • 1998
    • University of Geneva
      Genève, Geneva, Switzerland
  • 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
      North Carolina, United States
  • 1988–1989
    • University of Minnesota Duluth
      • Laboratory Medicine and Pathology
      Duluth, Minnesota, United States