Journal ArticleDOI
HMG-1 as a Late Mediator of Endotoxin Lethality in Mice
Haichao Wang,Ona Bloom,Minghuang Zhang,Jaideep M. Vishnubhakat,Michael Ombrellino,Jiantu Che,Asia Frazier,Huan Yang,Svetlana Ivanova,Lyudmila V. Borovikova,Kirk R. Manogue,Eugen Faist,Edward Abraham,Jan Andersson,Ulf Andersson,Patricia E. Molina,Naji N. Abumrad,Andrew E. Sama,Kevin J. Tracey +18 more
Reads0
Chats0
TLDR
High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1, and showed increased serum levels after endotoxin exposure, suggesting that this protein warrants investigation as a therapeutic target.Abstract:
Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.read more
Citations
More filters
Journal ArticleDOI
Therapeutic approaches to innate immunity: severe sepsis and septic shock
Elias Lolis,Richard Bucala +1 more
TL;DR: In this article, the authors discuss selected pathophysiological mechanisms that might yield to therapeutic intervention, consider rationales for the resurrection of previously failed drugs, and highlight new targets that have shown promise in preclinical studies.
Journal ArticleDOI
Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury
Elena Arriazu,Xiaodong Ge,Xiaodong Ge,Tung-Ming Leung,Fernando Magdaleno,Fernando Magdaleno,Aritz Lopategi,Yongke Lu,Naoto Kitamura,Raquel Urtasun,Neil D. Theise,Daniel J. Antoine,Natalia Nieto,Natalia Nieto +13 more
TL;DR: Significant induction of osteopontin (OPN) and high-mobility group box-1 (HMGB1) in liver fibrosis is shown, which acts as a downstream alarmin driving collagen-I synthesis in HSCs.
Journal ArticleDOI
Risk stratification after paracetamol overdose using mechanistic biomarkers: results from two prospective cohort studies.
James W. Dear,Joanna I. Clarke,Ben Francis,Lowri Allen,Jonathan Wraight,Jasmine Shen,Paul I. Dargan,Paul I. Dargan,David M. Wood,David M. Wood,Jamie G. Cooper,Simon H. L. Thomas,Andrea L. Jorgensen,Munir Pirmohamed,B. Kevin Park,Daniel J. Antoine +15 more
TL;DR: Personalised treatment pathways could be developed by use of miR-122, HMGB1, and full-length K18 at hospital presentation for patient stratification in a prospective study supporting their use for hepatic safety assessment of new medicines.
Journal ArticleDOI
High-mobility group box 1 (HMGB1) as a master regulator of innate immunity
TL;DR: Evidence suggests that HMGB1 acts as a key molecule of innate immunity, downstream of persistent tissue injury, orchestrating inflammation, stem cell recruitment/activation, and eventual tissue remodeling.
Journal ArticleDOI
Heme oxygenase-1 mediates the anti-inflammatory effect of molecular hydrogen in LPS-stimulated RAW 264.7 macrophages
TL;DR: Molecular hydrogen exerts a regulating role in the release of pro- and anti-inflammatory cytokines in LPS-stimulated macrophages, and this effect is at least partly mediated by HO-1 expression and activation.
References
More filters
Journal ArticleDOI
Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene
Alexander Poltorak,Xiaolong He,Irina Smirnova,Mu Ya Liu,Christophe Van Huffel,Xin Du,Dale Birdwell,E. Alejos,M. Silva,Chris Galanos,Marina Freudenberg,Paola Ricciardi-Castagnoli,Betsy Layton,Bruce Beutler +13 more
TL;DR: The mammalian Tlr4 protein has been adapted primarily to subserve the recognition of LPS and presumably transduces the LPS signal across the plasma membrane.
Journal Article
Defective LPS signaling in C3 H/HeJ and C57 BL/10 ScCr mice: Mutations in Tlr4 Gene
Alexander Poltorak,Xiaolong He,Irina Smirnova,Mu Ya Liu,C. Van Huffel,Xin Du,Dale Birdwell,E. Alejos,M. Suva,Chris Galanos,Marina Freudenberg,Paola Ricciardi-Castagnoli,B. Layton,Bruce Beutler +13 more
Journal ArticleDOI
Shock and tissue injury induced by recombinant human cachectin.
Kevin J. Tracey,Bruce Beutler,Stephen F. Lowry,James P Merryweather,Stephen D. Wolpe,Ian W. Milsark,Robert J. Hariri,Thomas J. Fahey,Alejandro Zentella,J. D. Albert,G. Tom Shires,Anthony Cerami +11 more
TL;DR: It appears that a single protein mediator (cachectin) is capable of inducing many of the deleterious effects of endotoxin.
Journal ArticleDOI
Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia
Kevin J. Tracey,Kevin J. Tracey,Yuman Fong,David G. Hesse,Kirk R. Manogue,Annette T. Lee,George C. Kuo,Stephen F. Lowry,Anthony Cerami +8 more
TL;DR: Protection against shock, vital organ dysfunction, persistent stress hormone release and death was conferred by administration of antibodies 2 h before bacterial infusion, indicating that cachectin is a mediator of fatal bacteraemic shock and suggesting that antibodies against Cachectin offer a potential therapy of life-threatening infection.
Journal ArticleDOI
Detection of circulating tumor necrosis factor after endotoxin administration.
Hamish R. Michie,Kirk R. Manogue,David R. Spriggs,Arthur Revhaug,S. T. O'Dwyer,Charles A. Dinarello,Anthony Cerami,Sheldon M. Wolff,Douglas W. Wilmore +8 more
TL;DR: It is concluded that the response to endotoxin is associated with a brief pulse of circulating tumor necrosis factor and that the resultant responses are effected through the cyclooxygenase pathway.