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
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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
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Release of chromatin protein HMGB1 by necrotic cells triggers inflammation
TL;DR: It is reported that Hmgb1-/- necrotic cells have a greatly reduced ability to promote inflammation, which proves that the release of HMGB1 can signal the demise of a cell to its neighbours, and cells undergoing apoptosis are programmed to withhold the signal that is broadcast by cells that have been damaged or killed by trauma.
Journal ArticleDOI
The pathophysiology and treatment of sepsis.
TL;DR: This review examines evolving concepts of sepsis and discusses new and potential therapies, including therapy with activated protein C, stringent control of blood glucose, and early goal-directed therapy to treat cellular oxygen deficit.
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Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin
Lyudmila V. Borovikova,Svetlana Ivanova,Minghuang Zhang,Huan Yang,Galina I. Botchkina,Linda R. Watkins,Haichao Wang,Naji N. Abumrad,John W. Eaton,Kevin J. Tracey +9 more
TL;DR: Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock.
Journal ArticleDOI
The inflammatory reflex
TL;DR: The discovery that cholinergic neurons inhibit acute inflammation has qualitatively expanded understanding of how the nervous system modulates immune responses, and the opportunity now exists to apply this insight to the treatment of inflammation through selective and reversible 'hard-wired' neural systems.
Journal ArticleDOI
Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation.
Hong Wang,Man Yu,Mahendar Ochani,C A Amella,Mahira Tanovic,Seenu Susarla,Jianhua Li,Haichao Wang,Huan Yang,Luis Ulloa,Yousef Al-Abed,Christopher J. Czura,Kevin J. Tracey +12 more
TL;DR: It is reported that the nicotinic acetylcholine receptor α7 subunit is essential for inhibiting cytokine synthesis by the cholinergic anti-inflammatory pathway.
References
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TL;DR: The structural and functional relationships between the proteins are examined, their signature† and common features of their target DNA elements are described, suggesting that the target DNA sequences share a common structural element.
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TL;DR: This brief review provides a framework for discussing current approaches being used to determine the cellular localization and function of the high mobility group chromosomal (HMG) proteins.
Journal Article
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Daniel G. Remick,Robert M. Strieter,Mark K. Eskandari,D. T. Nguyen,M. Genord,C. L. Raiford,Steven L. Kunkel +6 more
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Journal ArticleDOI
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Joseph F. Maher,Daniel Nathans +1 more
TL;DR: It is demonstrated that high-affinity binding uses two or three appropriately spaced AT tracts as a single multivalent binding site, which has implications for binding to regulatory elements such as the interferon beta enhancer, TATA boxes, and serum response elements.