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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
Hui Zhou, Meihong Deng, Yingjie Liu, Chenxuan Yang, Rosemary Hoffman, Jingjiao Zhou, Patricia A Loughran, Melanie J Scott, Matthew D Neal, Timothy R Billiar
Thrombocytopenia impairs host defense and hemostasis in sepsis. However, the mechanisms of how platelets regulate host defense are not fully understood. High-mobility group box 1 (HMGB1), a danger-associated molecular pattern protein, is released during infection and contributes to the pathogenesis of sepsis. Platelets express HMGB1, which is released on activation and has been shown to play a critical role in thrombosis, monocyte recruitment, and neutrophil extracellular trap (NET) production. However, the contribution of platelet HMGB1 to host defense is unknown...
March 27, 2018: Blood Advances
Dong-Keon Lee, Ji-Hee Kim, Joohwan Kim, Seunghwan Choi, MinSik Park, Wonjin Park, Suji Kim, Kyu-Sun Lee, Taesam Kim, Jiwon Jung, Yoon Kyung Choi, Kwon-Soo Ha, Moo-Ho Won, Timothy R Billiar, Young-Guen Kwon, Young-Myeong Kim
Regulated in development and DNA damage responses 1 (REDD-1), an inhibitor of mammalian target of rapamycin (mTOR), is induced by various cell stressors, including LPS, a major player in the pathogenesis of endotoxemic shock. However, the pathologic role of REDD-1 in endotoxemia is largely unknown. We found that LPS increased REDD-1 expression, nuclear transcription factor-κB (NF-κB) activation, and inflammation and that these responses were suppressed by REDD-1 knockdown and in REDD-1+/- macrophages. REDD-1 overexpression stimulated NF-κB-dependent inflammation without additional LPS stimulation...
August 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Dengming Lai, Jing Tang, Linsong Chen, Erica K Fan, Melanie J Scott, Yuehua Li, Timothy R Billiar, Mark A Wilson, Xiangming Fang, Qiang Shu, Jie Fan
Group 2 innate lymphoid cells (ILC2) are one of three subgroups of innate lymphoid cells (ILC1, ILC2, and ILC3), and the major ILC population detected in the lungs. The function of ILC2 in the regulation of lung inflammation remains unclear. In the current study, we explored an important role of ILC2 in protecting lung endothelial cell (EC) from pyroptosis in sepsis-induced acute lung inflammation and the underlying mechanism. Using a cecal ligation and puncture (CLP) mouse sepsis model, we demonstrated that IL-33, which is released in response to sepsis, acting through its receptor ST2 mediates ILC2 expansion in the lungs...
March 6, 2018: Cell Death & Disease
Joshua B Brown, Mark L Gestring, Christine M Leeper, Jason L Sperry, Andrew B Peitzman, Timothy R Billiar, Barbara A Gaines
BACKGROUND: Children suffering nonaccidental trauma (NAT) are at high risk of death. It is unclear whether markers of injury severity for trauma center/system benchmarking such as Injury Severity Score (ISS) adequately characterize this. Our objective was to evaluate mortality prediction of ISS in children with NAT compared with accidental trauma (AT). METHODS: Pediatric patients younger than 16 years from the Pennsylvania state trauma registry 2000 to 2013 were included...
October 2018: Journal of Trauma and Acute Care Surgery
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