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Quan Liu, Gaelen K Dwyer, Yifei Zhao, Huihua Li, Lisa R Mathews, Anish Bhaswanth Chakka, Uma R Chandran, Jake A Demetris, John F Alcorn, Keven M Robinson, Luis A Ortiz, Bruce Pitt, Angus W Thomson, Ming-Hui Fan, Timothy R Billiar, Heth R Turnquist
Acute respiratory distress syndrome is an often fatal disease that develops after acute lung injury and trauma. How released tissue damage signals, or alarmins, orchestrate early inflammatory events is poorly understood. Herein we reveal that IL-33, an alarmin sequestered in the lung epithelium, is required to limit inflammation after injury due to an unappreciated capacity to mediate Foxp3+ Treg control of local cytokines and myeloid populations. Specifically, Il33-/- mice are more susceptible to lung damage-associated morbidity and mortality that is typified by augmented levels of the proinflammatory cytokines and Ly6Chi monocytes in the bronchoalveolar lavage fluid...
February 19, 2019: JCI Insight
Yue-Feng Xia, Jing Chang, Jin-Feng Yang, Wen Ouyang, Bruce Pitt, Timothy Billiar, Li-Ming Zhang
Mechanical ventilation may cause ventilator‑induced lung injury (VILI). Canonical Wnt signaling has been reported to serve an important role in the pathogenesis of VILI. Bioinformatics analysis revealed that canonical and non‑canonical Wnt signaling pathways were activated in VILI. However, the role of non‑canonical Wnt signaling in the pathogenesis of VILI remains unclear. The present study aimed to analyze the potential role of non‑canonical Wnt signaling in VILI pathogenesis. Lung injury was assessed via Evans blue albumin permeability and histological scoring, as well as by inflammatory cytokine expression and total protein concentration in bronchoalveolar lavage fluid...
January 17, 2019: International Journal of Molecular Medicine
A J Lamparello, R A Namas, G Constantine, T O McKinley, E Elster, Y Vodovotz, T R Billiar
Progress in the testing of therapies targeting the immune response following trauma, a leading cause of morbidity and mortality worldwide, has been slow. We propose that the design of interventional trials in trauma would benefit from a scheme or platform that could support the identification and implementation of prognostic strategies for patient stratification. Here, we propose a stratification scheme based on defined time periods or windows following the traumatic event. This 'time-window' model allows for the incorporation of prognostic variables ranging from circulating biomarkers and clinical data to patient-specific information such as gene variants to predict adverse short- or long-term outcomes...
January 9, 2019: Journal of Internal Medicine
Yiting Tang, Rui Zhang, Qianqian Xue, Ran Meng, Xiangyu Wang, Yanliang Yang, Lingli Xie, Xianzhong Xiao, Timothy R Billiar, Ben Lu
BACKGROUND: Caspase-11, a cytosolic receptor of bacterial endotoxin (lipopolysaccharide: LPS), mediates immune responses and lethality in endotoxemia and experimental sepsis. However, the upstream pathways that regulate caspase-11 activation in endotoxemia and sepsis are not fully understood. The aim of this study is to test whether TIR-domain-containing adapter-inducing interferon-β (TRIF) signaling is critical for caspase-11-dependent immune responses and lethality in endotoxemia. METHODS: Mice of indicated genotypes were subjected to endotoxemia or cecum ligation and puncture (CLP) and monitored daily by signs of a moribund state for lethality...
December 27, 2018: Molecular Medicine
Shenhai Gong, Zhengzheng Yan, Zhanguo Liu, Mengwei Niu, Heng Fang, Na Li, Chenyang Huang, Lei Li, Guiming Chen, Haihua Luo, Xiaojiao Chen, Hongwei Zhou, Jingjuan Hu, Wei Yang, Qiaobing Huang, Bernd Schnabl, Ping Chang, Timothy R Billiar, Yong Jiang, Peng Chen
Sepsis-induced liver injury is recognized as a key problem in intensive care units (ICUs). The gut microbiota has been touted as an important mediator of liver disease development; however, the precise roles of gut microbiota in regulating sepsis-induced liver injury are unknown. Here, we aimed to investigate the role of the gut microbiota in sepsis-induced liver injury and the underlying mechanism. Cecal ligation and puncture (CLP) was employed to induce polymicrobial sepsis and related liver injury. Fecal microbiota transplantation (FMT) was used to validate the roles of gut microbiota in these pathologies...
December 1, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Ashley J Lamparello, Rami A Namas, Othman Abdul-Malak, Yoram Vodovotz, Timothy R Billiar
BACKGROUND: Aging is accompanied by alterations in immune functions. How these changes translate into levels of circulating inflammatory mediators and network expression after severe trauma is not well characterized. To address this, we compared time-dependent changes in the levels of an extensive biomarker panel in cohorts of severely injured young and aged adults. STUDY DESIGN: Cohorts of young (18-30 years old, n=115) and aged (65-90 years old, n=101) blunt trauma patients admitted to the intensive care unit (ICU) with plasma sampled 3 times within the first 24 hours and daily from day (D)1 to D7 were assayed for 30 inflammatory biomarkers using Luminex™...
November 15, 2018: Journal of the American College of Surgeons
Xibing Ding, Yao Tong, Shuqing Jin, Zhixia Chen, Tunliang Li, Timothy R Billiar, Bruce R Pitt, Quan Li, Li-Ming Zhang
BACKGROUND: High tidal volume ventilation of healthy lungs or exacerbation of existing acute lung injury (ALI) by more moderate mechanical ventilation (MTV) produces ventilator-induced lung injury. It is less clear whether extrapulmonary sepsis sensitizes the lung to MTV. METHODS: We used a two-hit model of cecal ligation and puncture (CLP) followed 12 h later by MTV (10 ml/kg; 6 h) to determine whether otherwise noninjurious MTV enhances CLP-induced ALI by contrasting wildtype and TLR4-/- mice with respect to: alveolar-capillary permeability, histopathology and intrapulmonary levels of WNT-inducible secreted protein 1 (WISP1) and integrin β5; plasma levels of cytokines and chemokines (TNF-α, IL-6, MIP-2, MCP-1) and intrapulmonary neutrophil infiltration; and other inflammatory signaling via intrapulmonary activation of JNK, p38 and ERK...
November 16, 2018: Critical Care: the Official Journal of the Critical Care Forum
Ruben Zamora, Sebastian Korff, Qi Mi, Derek Barclay, Lukas Schimunek, Riccardo Zucca, Xerxes D Arsiwalla, Richard L Simmons, Paul Verschure, Timothy R Billiar, Yoram Vodovotz
Bacterial lipopolysaccharide (LPS) induces an acute inflammatory response across multiple organs, primarily via Toll-like receptor 4 (TLR4). We sought to define novel aspects of the complex spatiotemporal dynamics of LPS-induced inflammation using computational modeling, with a special focus on the timing of pathological systemic spillover. An analysis of principal drivers of LPS-induced inflammation in the heart, gut, lung, liver, spleen, and kidney to assess organ-specific dynamics, as well as in the plasma (as an assessment of systemic spillover), was carried out using data on 20 protein-level inflammatory mediators measured over 0-48h in both C57BL/6 and TLR4-null mice...
November 2018: PLoS Computational Biology
Meihong Deng, Yiting Tang, Wenbo Li, Xiangyu Wang, Rui Zhang, Xianying Zhang, Xin Zhao, Jian Liu, Cheng Tang, Zhonghua Liu, Yongzhuo Huang, Huige Peng, Lehui Xiao, Daolin Tang, Melanie J Scott, Qingde Wang, Jing Liu, Xianzhong Xiao, Simon Watkins, Jianhua Li, Huan Yang, Haichao Wang, Fangping Chen, Kevin J Tracey, Timothy R Billiar, Ben Lu
Caspase-11, a cytosolic endotoxin (lipopolysaccharide: LPS) receptor, mediates pyroptosis, a lytic form of cell death. Caspase-11-dependent pyroptosis mediates lethality in endotoxemia, but it is unclear how LPS is delivered into the cytosol for the activation of caspase-11. Here we discovered that hepatocyte-released high mobility group box 1 (HMGB1) was required for caspase-11-dependent pyroptosis and lethality in endotoxemia and bacterial sepsis. Mechanistically, hepatocyte-released HMGB1 bound LPS and targeted its internalization into the lysosomes of macrophages and endothelial cells via the receptor for advanced glycation end-products (RAGE)...
October 16, 2018: Immunity
Ronghua Wang, Yawen Li, Allan Tsung, Hai Huang, Qiang Du, Muqing Yang, Meihong Deng, Si Xiong, Xiju Wang, Liyong Zhang, David A Geller, Bin Cheng, Timothy R Billiar
The inducible nitric oxide synthase (iNOS) is associated with more aggressive solid tumors, including hepatocellular carcinoma (HCC). Notch signaling in cancer stem cells promotes cancer progression and requires Notch cleavage by ADAM (a disintegrin and metalloprotease) proteases. We hypothesized that iNOS/NO promotes Notch1 activation through TACE/ADAM17 activation in liver cancer stem cells (LCSCs), leading to a more aggressive cancer phenotype. Expression of the stem cell markers CD24 and CD133 in the tumors of patients with HCC was associated with greater iNOS expression and worse outcomes...
October 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
Han Yu, Pedro J Del Nido, Tal Geva, Chun Yang, Alexander Tang, Zheyang Wu, Rahul H Rathod, Xueying Huang, Kristen L Billiar, Dalin Tang
Patient-specific in vivo ventricle material parameter determination is important for cardiovascular investigations. A new cardiac magnetic image (CMR)-based modeling approach with different zero-load diastole and systole geometries was adopted to estimate right ventricle material parameter values for healthy and patients with Tetralogy of Fallot (TOF) and seeking potential clinical applications. CMR data were obtained from 6 healthy volunteers and 16 TOF patients with consent obtained. CMR-based RV/LV models were constructed using two zero-load geometries (diastole and systole, 2G model)...
September 10, 2018: International Journal of Cardiology
Xibing Ding, Shuqing Jin, Zhenzhen Shao, Li Xu, Zhuang Yu, Yao Tong, Zhixia Chen, Heth Turnquist, Bruce R Pitt, Timothy R Billiar, Li-Ming Zhang, Quan Li
Mechanical ventilation (MV) is frequently employed to manage respiratory failure in sepsis patients and is required for the surgical management of intra-abdominal sepsis. The impact of MV varies dramatically depending on tidal volume, with even moderate tidal volume (MTV) ventilation leading to ventilator-induced lung injury, whereas low tidal volume (LTV) ventilation protects against sepsis-induced ARDS. IL-33 is known to contribute to lung injury in sepsis and its release can be induced by mechanical stress...
September 5, 2018: Shock
Zhi-Gang Li, Melanie J Scott, Tomasz Brzóska, Prithu Sundd, Yue-Hua Li, Timothy R Billiar, Mark A Wilson, Ping Wang, Jie Fan
BACKGROUND: Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome (MODS) following pulmonary and systemic infection. Alveolar macrophages (AMϕ) are at the center of ALI pathogenesis. Emerging evidence has shown that cell-cell interactions in the lungs play an important regulatory role in the development of acute lung inflammation. However, the underneath mechanisms remain poorly addressed. In this study, we explore a novel function of lung epithelial cells (LEPCs) in regulating the release of exosomes from AMϕ following LPS stimulation...
July 30, 2018: Military Medical Research
Rajesh K Aneja, Alicia M Alcamo, Jessica Cummings, Vincent Vagni, Keri Feldman, Qingde Wang, C Edward Dixon, Timothy R Billiar, Patrick M Kochanek
High mobility group box 1 (HMGB1) is a prototypical danger-associated molecular pattern molecule that is considered a late mediator of neuro-inflammation after traumatic brain injury (TBI). Prior studies have suggested that targeting HMGB1 may lead to neuroprotective effects, but none of these studies have reported cognitive outcomes. We hypothesized that loss of HMGB1 before and after TBI would markedly attenuate post-traumatic brain edema, blood-brain barrier (BBB) permeability, improve functional deficits and long-term neuropathology versus control mice...
September 5, 2018: Journal of Neurotrauma
Jason L Sperry, Francis X Guyette, Joshua B Brown, Mark H Yazer, Darrell J Triulzi, Barbara J Early-Young, Peter W Adams, Brian J Daley, Richard S Miller, Brian G Harbrecht, Jeffrey A Claridge, Herb A Phelan, William R Witham, A Tyler Putnam, Therese M Duane, Louis H Alarcon, Clifton W Callaway, Brian S Zuckerbraun, Matthew D Neal, Matthew R Rosengart, Raquel M Forsythe, Timothy R Billiar, Donald M Yealy, Andrew B Peitzman, Mazen S Zenati
BACKGROUND: After a person has been injured, prehospital administration of plasma in addition to the initiation of standard resuscitation procedures in the prehospital environment may reduce the risk of downstream complications from hemorrhage and shock. Data from large clinical trials are lacking to show either the efficacy or the risks associated with plasma transfusion in the prehospital setting. METHODS: To determine the efficacy and safety of prehospital administration of thawed plasma in injured patients who are at risk for hemorrhagic shock, we conducted a pragmatic, multicenter, cluster-randomized, phase 3 superiority trial that compared the administration of thawed plasma with standard-care resuscitation during air medical transport...
July 26, 2018: New England Journal of Medicine
Vincent P Anto, Joshua B Brown, Andrew B Peitzman, Brian S Zuckerbraun, Matthew D Neal, Gregory Watson, Raquel Forsythe, Timothy R Billiar, Jason L Sperry
Background: Blunt cerebrovascular injuries (BCVI) are generally associated with high-energy injury mechanisms. Less is known regarding lower-energy injuries in elderly patients. We sought to determine the incidence of BCVI and characterize current BCVI screening practices and associated complications in elderly ground-level fall patients (EGLF, ≥ 65 years). We hypothesized that BCVI in EGLF patients would be clinically significant and screening would be less common. Methods: A retrospective study was performed utilizing the National Trauma Data Bank (NTDB, 2007-2014) and single institutional data...
2018: World Journal of Emergency Surgery: WJES
Wenjun Deng, Shan Zhu, Ling Zeng, Jiao Liu, Rui Kang, Minghua Yang, Lizhi Cao, Haichao Wang, Timothy R Billiar, Jianxin Jiang, Min Xie, Daolin Tang
Sepsis and septic shock are associated with life-threatening organ dysfunction caused by an impaired host response to infections. Although circadian clock disturbance impairs the early inflammatory response, its impact on post-septic immunosuppression remains poorly elucidated. Here, we show that Bmal1, a core circadian clock gene, plays a role in the regulation of host immune responses in experimental sepsis. Mechanistically, Bmal1 deficiency in macrophages increases PKM2 expression and lactate production, which is required for expression of the immune checkpoint protein PD-L1 in a STAT1-dependent manner...
July 10, 2018: Cell Reports
Rui Kang, Ling Zeng, Shan Zhu, Yangchun Xie, Jiao Liu, Qirong Wen, Lizhi Cao, Min Xie, Qitao Ran, Guido Kroemer, Haichao Wang, Timothy R Billiar, Jianxin Jiang, Daolin Tang
Sepsis is a life-threatening condition caused by pathogen infection and associated with pyroptosis. Pyroptosis occurs upon activation of proinflammatory caspases and their subsequent cleavage of gasdermin D (GSDMD), resulting in GSDMD N-terminal fragments that form membrane pores to induce cell lysis. Here, we show that antioxidant defense enzyme glutathione peroxidase 4 (GPX4) and its ability to decrease lipid peroxidation, negatively regulate macrophage pyroptosis, and septic lethality in mice. Conditional Gpx4 knockout in myeloid lineage cells increases lipid peroxidation-dependent caspase-11 activation and GSDMD cleavage...
July 11, 2018: Cell Host & Microbe
Xilin Chen, Mark L Gestring, Matthew R Rosengart, Andrew B Peitzman, Timothy R Billiar, Jason L Sperry, Joshua B Brown
BACKGROUND: Trauma is a time sensitive disease. Helicopter emergency medical services (HEMS) have shown benefit over ground emergency medical services (GEMS), which may be related to reduced prehospital time. The distance at which this time benefit emerges depends on many factors that can vary across regions. Our objective was to determine the threshold distance at which HEMS has shorter prehospital time than GEMS under different conditions. METHODS: Patients in the Pennsylvania trauma registry 2000 to 2013 were included...
July 2018: Journal of Trauma and Acute Care Surgery
Hui Xu, Jing Xu, Li Xu, Shuqing Jin, Heth R Turnquist, Rosemary Hoffman, Patricia Loughran, Timothy R Billiar, Meihong Deng
Sepsis is defined as infection with organ dysfunction due to a dysregulated immune response. The lung is one of the most vulnerable organs at the onset of sepsis. Interleukin (IL)-33 can be released by injured epithelial and endothelial cells in the lung and regulate immune activation and infiltration. Therefore, we postulated that IL-33 would contribute to the immune response in the lung during sepsis. Using the cecal ligation and puncture (CLP) sepsis model, we show here that IL-33 contributes significantly to both sepsis-induced inflammation in the lung and systemic inflammatory response in the early phase of sepsis...
October 2018: Immunology and Cell Biology
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