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https://www.readbyqxmd.com/read/30314759/the-endotoxin-delivery-protein-hmgb1-mediates-caspase-11-dependent-lethality-in-sepsis
#1
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
https://www.readbyqxmd.com/read/30297396/inos-promotes-cd24-cd133-liver-cancer-stem-cell-phenotype-through-a-tace-adam17-dependent-notch-signaling-pathway
#2
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 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/30217422/patient-specific-in-vivo-right-ventricle-material-parameter-estimation-for-patients-with-tetralogy-of-fallot-using-mri-based-models-with-different-zero-load-diastole-and-systole-morphologies
#3
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
https://www.readbyqxmd.com/read/30192340/the-il-33-st2-pathway-contributes-to-ventilator-induced-lung-injury-in-septic-mice-in-a-tidal-volume-dependent-manner
#4
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
https://www.readbyqxmd.com/read/30056803/lung-epithelial-cell-derived-il-25-negatively-regulates-lps-induced-exosome-release-from-macrophages
#5
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
https://www.readbyqxmd.com/read/30045665/lack-of-benefit-on-brain-edema-blood-brain-barrier-permeability-or-cognitive-outcome-in-global-inducible-high-mobility-group-box-1-knockout-mice-despite-tissue-sparing-after-experimental-traumatic-brain-injury
#6
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
https://www.readbyqxmd.com/read/30044935/prehospital-plasma-during-air-medical-transport-in-trauma-patients-at-risk-for-hemorrhagic-shock
#7
RANDOMIZED CONTROLLED TRIAL
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
https://www.readbyqxmd.com/read/29997683/blunt-cerebrovascular-injury-in-elderly-fall-patients-are-we-screening-enough
#8
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
https://www.readbyqxmd.com/read/29996098/the-circadian-clock-controls-immune-checkpoint-pathway-in-sepsis
#9
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
https://www.readbyqxmd.com/read/29937272/lipid-peroxidation-drives-gasdermin-d-mediated-pyroptosis-in-lethal-polymicrobial-sepsis
#10
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
https://www.readbyqxmd.com/read/29787553/logistics-of-air-medical-transport-when-and-where-does-helicopter-transport-reduce-prehospital-time-for-trauma
#11
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
https://www.readbyqxmd.com/read/29672927/interleukin-33-contributes-to-ilc2-activation-and-early-inflammation-associated-lung-injury-during-abdominal-sepsis
#12
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...
April 19, 2018: Immunology and Cell Biology
https://www.readbyqxmd.com/read/29563120/platelet-hmgb1-is-required-for-efficient-bacterial-clearance-in-intra-abdominal-bacterial-sepsis-in-mice
#13
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
https://www.readbyqxmd.com/read/29547704/redd-1-aggravates-endotoxin-induced-inflammation-via-atypical-nf-%C3%AE%C2%BAb-activation
#14
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
https://www.readbyqxmd.com/read/29511181/group-2-innate-lymphoid-cells-protect-lung-endothelial-cells-from-pyroptosis-in-sepsis
#15
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
https://www.readbyqxmd.com/read/29462080/characterizing-injury-severity-in-nonaccidental-trauma-does-injury-severity-score-miss-the-mark
#16
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
https://www.readbyqxmd.com/read/29462003/toll-like-receptor-4-signaling-licenses-the-cytosolic-transport-of-lipopolysaccharide-from-bacterial-outer-membrane-vesicles
#17
Lan Gu, Ran Meng, Yiting Tang, Kai Zhao, Fang Liang, Rui Zhang, Qianqian Xue, Fangping Chen, Xianzhong Xiao, Huadong Wang, Haichao Wang, Timothy R Billiar, Ben Lu
Outer membrane vesicles (OMVs), released by variety of bacteria, are membrane-enclosed entities enriched in microbial components, toxins and virulent factors. OMVs could deliver lipopolysaccharide (LPS) into the cytosol of host cells and subsequently activate caspase-11, which critically orchestrates immune responses and mediates septic shock. Though it is known that caspase-11 is activated by intracellular LPS, how OMVs deliver LPS into the cytosol remains largely unknown. Here we show that the activation of toll like receptor 4 (TLR4), a LPS receptor on the cytoplasmic membrane, licenses macrophages to transport LPS from OMVs into the cytosol through TIR domain-containing adaptor-inducing interferon-β (TRIF)...
February 16, 2018: Shock
https://www.readbyqxmd.com/read/29461394/diagnosis-and-management-of-polytraumatized-patients-with-severe-extremity-trauma
#18
Todd O McKinley, Greg E Gaski, Yoram Vodovotz, Benjamin T Corona, Timothy R Billiar
Multiply injured patients with severe extremity trauma are at risk of acute systemic complications and are at high risk of developing longer term orthopaedic complications including soft-tissue infection, osteomyelitis, posttraumatic osteoarthritis, and nonunion. It is becoming increasingly recognized that injury magnitude and response to injury have major jurisdiction pertaining to patient outcomes and complications. The complexities of injury and injury response that affect outcomes present opportunities to apply precision approaches to understand and quantify injury magnitude and injury response on a patient-specific basis...
March 2018: Journal of Orthopaedic Trauma
https://www.readbyqxmd.com/read/29446653/cgas-mediated-autophagy-protects-the-liver-from-ischemia-reperfusion-injury-independently-of-sting
#19
Zhao Lei, Meihong Deng, Zhongjie Yi, Qian Sun, Richard A Shapiro, Hongbo Xu, Tunliang Li, Patricia A Loughran, John E Griepentrog, Hai Huang, Melanie J Scott, Feizhou Huang, Timothy R Billiar
Liver ischemia-reperfusion (I/R) injury occurs through induction of oxidative stress and release of damage-associated molecular patterns (DAMPs), including cytosolic DNA released from dysfunctional mitochondria or from the nucleus. Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) is a cytosolic DNA sensor known to trigger stimulator of interferon genes (STING) and downstream type 1 interferon (IFN-I) pathways, which are pivotal innate immune system responses to pathogen. However, little is known about the role of cGAS/STING in liver I/R injury...
June 1, 2018: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/29443859/overresuscitation-with-plasma-is-associated-with-sustained-fibrinolysis-shutdown-and-death-in-pediatric-traumatic-brain-injury
#20
Christine M Leeper, Matthew D Neal, Timothy R Billiar, Jason L Sperry, Barbara A Gaines
BACKGROUND: Elevated International Normalized Ratio (INR) is a marker of poor outcome but not necessarily bleeding or clinical coagulopathy in injured children. Conversely, children with traumatic brain injury (TBI) tend to be hypercoagulable based on rapid thromboelastography (rTEG) parameters. Many clinicians continue to utilize INR as a treatment target. METHODS: Prospective observational study of severely injured children age < 18 with rTEG on arrival and daily thereafter for up to 7 days...
July 2018: Journal of Trauma and Acute Care Surgery
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