Timothy R Billiar

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Are you Timothy R Billiar?

Claim your profile

Publications (796)3639.85 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Toll-like receptor 4 (TLR4) is a critical receptor involved in the sensing of Gram negative bacterial infection. However, the roles of TLR4 in sepsis are cell type specific. Dendritic cells (DC) are known to play a central role in microbial detection, alerting the immune system to the presence of infection and coordinating adaptive immune response. The goal of this study was to investigate the impact of DC-specific TLR4 signaling on host defense against intra-abdominal polymicrobial sepsis. Methods: C57BL/6, global Tlr4 knockout, cell specific knockout control, and CD11c-specific Tlr4(-/-) mice underwent cecal ligation and puncture (CLP). Results: Specific deletion of TLR4 on DC in mice improved survival and enhanced bacterial clearance. Deletion of TLR4 on DC was associated with lower circulating IL10, higher polymorphonuclear leukocytes (PMN) accumulation in the peritoneal cavity, and higher expression of chemokine (C-X-C motif) receptor 2 (CXCR2) on PMN after CLP. In vitro studies of DC and neutrophil cocultures confirmed that TLR4-dependent secretion of IL-10 from DC regulated neutrophil CXCR2 expression. Conclusions: Our data shed light on a previously unrecognized role for TLR4-signaling on DC in driving IL-10 secretion during sepsis, and through this pathway regulates PMN recruitment via suppression of CXCR2 expression.
    The Journal of Infectious Diseases 11/2015; DOI:10.1093/infdis/jiv562 · 6.00 Impact Factor
  • Hui Zhou · Meihong Deng · Melanie Scott · Matthew Neal · Jianguo Li · Timothy Billiar ·

    Critical care medicine 11/2015; 43(12 Suppl 1):269-270. DOI:10.1097/01.ccm.0000474902.81689.27 · 6.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: b>Significance: Traumatic injury elicits a complex, dynamic, multi-dimensional inflammatory response that is intertwined with complications such as multiple organ dysfunction and nosocomial infection. The complex interplay between inflammation and physiology in critical illness remains a challenge for translational research, including the extrapolation to human disease from animal models. Recent Advances: Over the past decade, we and others have attempted to decipher the bio-complexity of inflammation in these settings of acute illness, using computational models to improve clinical translation. In silico modeling has been suggested as a computationally-based framework for integrating data derived from basic biology experiments as well as preclinical and clinical studies. Critical Issues: Extensive studies in cells, mice, and human blunt trauma patients have led us to suggest: 1) that while an adequate level of inflammation is required for healing post-trauma, inflammation can be harmful when it becomes self-sustaining via a Damage-Associated Molecular Pattern (DAMP) / Toll-Like Receptor (TLR)-driven, feed-forward circuit; 2) that chemokines play a central regulatory role in driving either self-resolving or self-maintaining inflammation that drives the early activation of both classical innate and more recently-recognized lymphoid pathways; and 3) the presence of multiple thresholds and feedback loops which could significantly affect the propagation of inflammation across multiple body compartments. Future Directions: These insights from data-driven models into the primary drivers and interconnected networks of inflammation have been used to generate mechanistic computational models. Together, these models may be used to gain basic insights as well as serving to help define novel biomarkers and therapeutic targets.
    Antioxidants & Redox Signaling 11/2015; DOI:10.1089/ars.2015.6398 · 7.41 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Thrombosis and inflammation are intricately linked in several major clinical disorders, including disseminated intravascular coagulation and acute ischemic events. The damage-associated molecular pattern molecule high-mobility group box 1 (HMGB1) is upregulated by activated platelets in multiple inflammatory diseases; however, the contribution of platelet-derived HMGB1 in thrombosis remains unexplored. Here, we generated transgenic mice with platelet-specific ablation of HMGB1 and determined that platelet-derived HMGB1 is a critical mediator of thrombosis. Mice lacking HMGB1 in platelets exhibited increased bleeding times as well as reduced thrombus formation, platelet aggregation, inflammation, and organ damage during experimental trauma/hemorrhagic shock. Platelets were the major source of HMGB1 within thrombi. In trauma patients, HMGB1 expression on the surface of circulating platelets was markedly upregulated. Moreover, evaluation of isolated platelets revealed that HMGB1 is critical for regulating platelet activation, granule secretion, adhesion, and spreading. These effects were mediated via TLR4- and MyD88-dependent recruitment of platelet guanylyl cyclase (GC) toward the plasma membrane, followed by MyD88/GC complex formation and activation of the cGMP-dependent protein kinase I (cGKI). Thus, we establish platelet-derived HMGB1 as an important mediator of thrombosis and identify a HMGB1-driven link between MyD88 and GC/cGKI in platelets. Additionally, these findings suggest a potential therapeutic target for patients sustaining trauma and other inflammatory disorders associated with abnormal coagulation.
    Journal of Clinical Investigation 11/2015; DOI:10.1172/JCI81660 · 13.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Regionalized trauma care improves outcomes; however access to care is not uniform across the US. The objective was to evaluate whether geographic distribution of trauma centers correlates with injury mortality across state trauma systems. Methods: Level I/II trauma centers in the contiguous US were mapped. State-level age-adjusted injury fatality rates/100,000people were obtained and evaluated for spatial autocorrelation. Nearest neighbor ratios (NNR) were generated for each state. A NNR<1 indicates clustering, while NNR>1 indicates dispersion. NNR were tested for difference from random geographic distribution. Fatality rates and NNR were examined for correlation. Fatality rates were compared between states with trauma center clustering versus dispersion. Trauma center distribution and population density were evaluated. Spatial-lag regression determined the association between fatality rate and NNR, controlling for state-level demographics, population density, injury severity, trauma system resources, and socioeconomic factors. Results: Fatality rates were spatially autocorrelated (Moran's I=0.35, p<0.01). Nine states had a clustered pattern (median NNR 0.55, IQR 0.48-0.60), 22 had a dispersed pattern (median NNR 2.00, IQR 1.68-3.99), and 10 had a random pattern (median NNR 0.90, IQR 0.85-1.00) of trauma center distribution. Fatality rate and NNR were correlated (ρ=0.34, p=0.03). Clustered states had a lower median injury fatality rate compared to dispersed states (56.9 [IQR 46.5-58.9] versus 64.9 [IQR 52.5-77.1], p=0.04). Dispersed compared to clustered states had more counties without a trauma center that had higher population density than counties with a trauma center (5.7% versus 1.2%, p<0.01). Spatial-lag regression demonstrated fatality rates increased 0.02/100,000persons for each unit increase in NNR (p<0.01). Conclusions: Geographic distribution of trauma centers correlates with injury mortality, with more clustered state trauma centers associated with lower fatality rates. This may be a result of access relative to population density. These results may have implications for trauma system planning and requires further study to investigate underlying mechanisms. Level of evidence: IV, ecological study.
    10/2015; DOI:10.1097/TA.0000000000000902
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: Endoluminal vascular interventions such as angioplasty initiate a sterile inflammatory response resulting from local tissue damage. This response drives the development of intimal hyperplasia (IH) that, in turn, can lead to arterial occlusion. We hypothesized that the ubiquitous nuclear protein and damage-associated molecular pattern molecule, high-mobility group box 1 (HMGB1), is one of the endogenous mediators that activates processes leading to IH after endoluminal injury to the arterial wall. The aim of this study is to investigate whether approaches that reduce the levels of HMGB1 or inhibit its activity suppresses IH after arterial injury. Approach and results: Here, we show that HMGB1 regulates IH in a mouse carotid wire injury model. Induced genetic deletion or neutralization of HMGB1 prevents IH, monocyte recruitment, and smooth muscle cell growth factor production after endoluminal carotid artery injury. A specific inhibitor of HMGB1 myeloid differentiation factor 2-toll-like receptor 4 (TLR4) interaction, P5779, also significantly inhibits IH. HMGB1 deletion is mimicked in this model by global deletion of TLR4 and partially replicated by myeloid-specific deletion of TLR4 but not TLR2 or receptor for advanced glycation endproducts deletion. The specific HMGB1 isoform known to activate TLR4 signaling (disulfide HMGB1) stimulates smooth muscle cell to migrate and produce monocyte chemotactic protein 1/CCL2) via TLR4. Macrophages produce smooth muscle cell mitogens in response to disulfide HMGB1 also in a TLR4/myeloid differentiation primary response gene (88)/Trif-dependent manner. Conclusions: These findings place HMGB1 and its receptor, TLR4 as critical regulators of the events that drive the inflammation leading to IH after endoluminal arterial injury and identify this pathway as a possible therapeutic target to limit IH to attenuate damage-associated molecular pattern molecule-mediated vascular inflammatory responses.
    Arteriosclerosis Thrombosis and Vascular Biology 10/2015; DOI:10.1161/ATVBAHA.115.305789 · 6.00 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: The aim of this study was to develop and internally validate a triage score that can identify trauma patients at the scene who would potentially benefit from helicopter emergency medical services (HEMS). Summary background data: Although survival benefits have been shown at the population level, identification of patients most likely to benefit from HEMS transport is imperative to justify the risks and cost of this intervention. Methods: Retrospective cohort study of subjects undergoing scene HEMS or ground emergency medical services (GEMS) in the National Trauma Databank (2007-2012). Data were split into training and validation sets. Subjects were grouped by triage criteria in the training set and regression used to determine which criteria had a survival benefit associated with HEMS. Points were assigned to these criteria to develop the Air Medical Prehospital Triage (AMPT) score. The score was applied in the validation set to determine whether subjects triaged to HEMS had a survival benefit when actually transported by helicopter. Results: There were 2,086,137 subjects included. Criteria identified for inclusion in the AMPT score included GCS <14, respiratory rate <10 or >29, flail chest, hemo/pneumothorax, paralysis, and multisystem trauma. The optimal cutoff for triage to HEMS was ≥2 points. In subjects triaged to HEMS, actual transport by HEMS was associated with an increased odds of survival (AOR 1.28; 95% confidence interval [CI] 1.21-1.36, P < 0.01). In subjects triaged to GEMS, actual transport mode was not associated with survival (AOR 1.04; 95% CI 0.97-1.11, P = 0.20). Conclusions: The AMPT score identifies patients with improved survival following HEMS transport and should be considered in air medical triage protocols.
    Annals of surgery 10/2015; DOI:10.1097/SLA.0000000000001496 · 8.33 Impact Factor
  • [Show abstract] [Hide abstract]
    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 10/2015; DOI:10.1097/SLA.0000000000001047 · 8.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Adenosine deaminase acting on RNA 1 (ADAR1) is an essential protein for embryonic liver development. ADAR1 loss is embryonically lethal because of severe liver damage. Although ADAR1 is required in adult livers to prevent liver cell death, as demonstrated by liver-specific conditional knockout (LKO) mice, the mechanism remains elusive. We systematically analyzed ADAR1 LKO mice for liver damage. Differentiation genes and inflammatory pathways were examined in hepatic tissues from LKO and littermate controls. Inducible ADAR1 LKO mice were used to validate regulatory effects of ADAR1 on inflammatory cytokines. We found that ADAR1 LKO mice showed dramatic growth retardation and high mortality because of severe structural and functional damage to the liver, which showed overwhelming inflammation, cell death, fibrosis, fatty change, and compensatory regeneration. Simultaneously, ADAR1 LKO showed altered expression of key differentiation genes and significantly higher levels of hepatic inflammatory cytokines, especially type I interferons, which was also verified by inducible ADAR1 knockdown in primary hepatocyte cultures. We conclude that ADAR1 is an essential molecule for maintaining adult liver homeostasis and, in turn, morphological and functional integrity. It inhibits the production of type I interferons and other inflammatory cytokines. Our findings may provide novel insight in the pathogenesis of liver diseases caused by excessive inflammatory responses, including autoimmune hepatitis.
    American Journal Of Pathology 10/2015; DOI:10.1016/j.ajpath.2015.08.002 · 4.59 Impact Factor

  • 10/2015; 79(2):327.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Although survival benefits have been shown at the population level, it remains unclear what drives the outcome benefits for helicopter emergency medical services (HEMS) in trauma. Although speed is often cited as the vital factor of HEMS, we hypothesized a survival benefit would exist in the absence of a time savings over ground emergency medical services (GEMS). The objective was to examine the association of survival with HEMS compared with GEMS transport across similar prehospital transport times. Methods: We used a retrospective cohort of scene HEMS and GEMS transports in the National Trauma Databank (2007-2012). Propensity score matching was used to match HEMS and GEMS subjects on the likelihood of HEMS transport. Subjects were stratified by prehospital transport times in 5-minute increments. Conditional logistic regression determined the association of HEMS with survival across prehospital transport times strata controlling for confounders. Transport distance was estimated from prehospital transport times and average HEMS/GEMS transport speeds. Results: There were 155,691 HEMS/GEMS pairs matched. HEMS had a survival benefit over GEMS for prehospital transport times between 6 and 30 minutes. This benefit ranged from a 46% increase in odds of survival between 26 and 30 minutes (adjusted odds ratio [AOR], 1.46; 95% CI, 1.11-1.93; P < .01) to an 80% increase in odds of survival between 16 and 20 minutes (AOR, 1.80; 95% CI, 1.51-2.14; P < .01). This prehospital transport times window corresponds to estimated transport distance between 14.3 and 71.3 miles for HEMS and 3.3 and 16.6 miles for GEMS. Conclusion: When stratified by prehospital transport times, HEMS had a survival benefit concentrated in a window between 6 and 30 minutes. Because there was no time-savings advantage for HEMS, these findings may reflect care delivered by HEMS providers.
    Surgery 10/2015; DOI:10.1016/j.surg.2015.09.015 · 3.38 Impact Factor

  • Journal of the American College of Surgeons 10/2015; 221(4):S162-S163. DOI:10.1016/j.jamcollsurg.2015.07.389 · 5.12 Impact Factor
  • Mostafa H. Ramadan · Rosemary A. Hoffman · Timothy R. Billiar ·

    Journal of the American College of Surgeons 10/2015; 221(4):S160. DOI:10.1016/j.jamcollsurg.2015.07.383 · 5.12 Impact Factor
  • [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
  • [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    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; 21. DOI:10.2119/molmed.2014.00260 · 4.51 Impact Factor
  • [Show abstract] [Hide abstract]
    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; 63(4). DOI:10.1016/j.jhep.2015.05.030 · 11.34 Impact Factor

Publication Stats

38k Citations
3,639.85 Total Impact Points


  • 1988-2015
    • University of Pittsburgh
      • • Department of Surgery
      • • Department of Medicine
      Pittsburgh, Pennsylvania, United States
    • Washington University in St. Louis
      • Department of Surgery
      San Luis, Missouri, United States
  • 2014
    • UPMC
      Pittsburgh, Pennsylvania, United States
  • 1998-2014
    • Pittsburg State University
      Питсбург, Kansas, United States
    • University of Geneva
      Genève, Geneva, Switzerland
  • 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
  • 2006
    • Columbia University
      • Department of Surgery
      New York, New York, United States
  • 2005
    • University of Bonn
      Bonn, North Rhine-Westphalia, Germany
  • 2002
    • Kangwon National University
      • Department of Molecular and Cellular Biochemistry
      Shunsen, Gangwon, South Korea
  • 2001
    • Baylor College of Medicine
      • Section of Infectious Diseases
      Houston, Texas, 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
      North Carolina, United States
  • 1990
    • Cornell University
      Итак, New York, United States
  • 1988-1989
    • University of Minnesota Duluth
      • Laboratory Medicine and Pathology
      Duluth, Minnesota, United States