Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J et al.. HMG-1 as a late mediator of endotoxin lethality in mice. Science 285: 248-251

University of Colorado, Denver, Colorado, United States
Science (Impact Factor: 33.61). 08/1999; 285(5425):248-51. DOI: 10.1126/science.285.5425.248
Source: PubMed


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.

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    • "Recently , in humans and mice , extracellular his - tones have been shown to be involved in death associ - ated with a variety of pathologies including acute sepsis and injury ( Xu et al . , 2009 , 2011 ) . Moreover , histones are lethal when injected into mice ( Xu et al . , 2011 ) , and serum appears to protect against histone cytotoxic - ity ( Wang et al . , 1999 ) . Several serum proteins have demonstrated the ability to bind to histones , and work by Abrams et al . ( 2013 ) demonstrated that C - reactive protein ( CRP ) binds to and neutralizes histone toxic - ity . Therefore , we hypothesize that histone cytotoxicity contributes to the severity of BRDC and that cattle ex - hibit varying degre"
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    ABSTRACT: Bovine respiratory disease complex (BRDC) is the leading cause of morbidity and mortality in feedlot cattle. Significant inflammation and lesions are often observed in lungs of infected cattle. During acute inflammatory responses, histones contribute to mortality in rodents and humans and serum proteins can protect against histone-induced cytotoxicity. We hypothesized that cattle experiencing chronic or fatal cases of BRDC have reduced ability to protect against cytotoxic effects of histones. Serum samples were collected from 66 bull calves at the time of normal feedlot processing procedures. Animals were retrospectively assigned to groups consisting of calves never treated for BRDC (control [CONT]; = 10), calves treated with antimicrobials once for BRDC (1T; = 16), calves treated twice for BRDC (2T; = 13), calves treated 3 times for BRDC (3T; = 14), or calves treated 4 times for BRDC (4T; = 13). Samples were also collected each time animals received antimicrobial treatment; animals within a group were further sorted by calves that recovered and calves that died to test histone cytotoxicity. Bovine kidney cells were cultured in duplicate in 96-well plates and exposed to 0 or 50 μg/mL of total histones for 18 h with 1% serum from each animal. Cell viability was assessed by the addition of resazurin for 6 h followed by fluorescent quantification. Fluorescent values from serum alone were subtracted from values obtained for histone treatment for each animal. Serum from CONT, 1T, and 2T at initial processing all exhibited a similar ( > 0.10) response to histone treatment with fluorescent values of -312 ± 557, -1,059 ± 441, and -975 ± 489, respectively. However, 3T and 4T demonstrated an impaired capacity ( < 0.05) to protect against histones (-2,778 ± 471 and -3,026 ± 489) at initial processing when compared to the other groups. When sorted by mortality within group, calves that were treated twice and recovered (-847 ± 331) demonstrated a greater ( < 0.05) protective capacity than calves that were treated twice and died (-2,264 ± 412), indicating that calves that contract BRDC and ultimately die might have reduced protective capacity against histone cytotoxicity. Results suggest that calves that require multiple treatments for BRDC have reduced ability to protect against cytotoxicity of histones. Understanding the primary mechanism responsible for protecting against histone cytotoxicity could lead to improved identification of animals susceptible to severe cases of BRDC, improved focus and use of available resources, or better treatments for severe cases of BRDC.
    Journal of Animal Science 04/2015; 93(4):1841. DOI:10.2527/jas.2014-8334 · 2.11 Impact Factor
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    • "Further structural analysis is required to reveal the disulfide HMGB1-binding site on MD-2. HMGB1-neutralizing antibodies are protective against sterile injury (Tsung et al., 2005), and agents capable of inhibiting HMGB1 release or its extracellular activities (Wang et al., 1999; Yang et al., 2004) also confer protection against sepsis. "
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    ABSTRACT: Innate immune receptors for pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) orchestrate inflammatory responses to infection and injury. Secreted by activated immune cells or passively released by damaged cells, HMGB1 is subjected to redox modification that distinctly influences its extracellular functions. Previously, it was unknown how the TLR4 signalosome distinguished between HMGB1 isoforms. Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms. Using MD-2-deficient mice, as well as MD-2 silencing in macrophages, we show a requirement for HMGB1-dependent TLR4 signaling. By screening HMGB1 peptide libraries, we identified a tetramer (FSSE, designated P5779) as a specific MD-2 antagonist preventing MD-2-HMGB1 interaction and TLR4 signaling. P5779 does not interfere with lipopolysaccharide-induced cytokine/chemokine production, thus preserving PAMP-mediated TLR4-MD-2 responses. Furthermore, P5779 can protect mice against hepatic ischemia/reperfusion injury, chemical toxicity, and sepsis. These findings reveal a novel mechanism by which innate systems selectively recognize specific HMGB1 isoforms. The results may direct toward strategies aimed at attenuating DAMP-mediated inflammation while preserving antimicrobial immune responsiveness. © 2015 Yang et al.
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    • "HMGB1 translocation and expression were increased in both the ischemic and nonischemic lobes during the late phase, which was likely to have been induced by circulatory mediators released from the ischemic lobes. HMGB1 release to extracellular space has been demonstrated to occur in two different ways: one way is active secretion by activated macrophages, neutrophils and endothelial cells (Ito et al. 2007; Mullins et al. 2004; Wang et al. 1999), the other is a passive process in which HMGB1 diffuses to extracellular space when cells are undergoing necrosis (Bell et al. 2006; Rovere-Querini et al. 2004; Scaffidi et al. 2002). Liver non-parenchymal cells, including Kupffer cells and sinusoidal endothelium cells, are activated during liver I/R. "

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