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  • DISEASE  (2)
  • COMPLEX  (1)
  • DNA  (1)
  • PROTEIN  (1)
  • 1
    Keywords: IN-VITRO ; IN-VIVO ; PATHWAY ; VITRO ; DISEASE ; PROTEIN ; SURGERY ; MICE ; ACTIVATION ; COMPLEX ; MECHANISM ; cytokines ; PLASMA ; RAGE ; inflammation ; INJURY ; signaling ; CYTOKINE ; GENOTYPE ; toll-like receptor 4 ; INVESTIGATE ; sepsis ; TLR2 ; toll-like receptor 2 ; HMGB-1 ; HMGB1 ; host defense ; receptor for advanced glycation end products
    Abstract: High-mobility group box 1 (HMGB-1) has been reported as a "late" proinflammatory mediator in sepsis. In vitro data have shown that HMGB-1 can induce activation of intracellular signaling pathways via interaction with at least three pattern recognition receptors: Toll-like receptor (TLR) 2, TLR-4, and the receptor for advanced glycation end products (RAGE). The objective of this study was to investigate the role of these receptors in the in vivo response to HMGB-1. Therefore, we first performed a time-series experiment with wild-type (Wt) mice. High-mobility group box 1 induced time-dependent elevations of TNF-alpha, IL-6, monocyte chemoattractant protein 1, and thrombin-antithrombin complex levels in peritoneal lavage fluid and plasma. This inflammatory reaction was accompanied by a prominent and sustained rise in neutrophil counts in the peritoneal cavity. We next administered HMGB-1 to Wt, TLR-2(-/-), TLR-4(-/-), and RAGE(-/-) mice. All genotypes showed similar plasma levels of TNF-alpha, IL-6, IL-10, and thrombin-antithrombin complex at 2 h after intraperitoneal injection of HMGB-1. Compared with Wt mice, both TLR-4(-/-) and RAGE(-/-) mice displayed lower TNIF-alpha and IL-6 concentrations and lower neutrophil numbers in their peritoneal lavage fluid. In contrast, TLR-2(-/-) mice showed increased levels of TNF-alpha and IL-6 in their peritoneal cavity relative to Wt mice. These data indicate that HMGB-1 induces release of cytokines, activation of coagulation, and neutrophil recruitment in vivo via a mechanism that at least in part depends on TLR-4 and RAGE
    Type of Publication: Journal article published
    PubMed ID: 19218854
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  • 2
    Abstract: Statins, which are effective lipid-lowering drugs, also possess anti-inflammatory potential. However, circulating lipoproteins may also play a protective role during acute inflammatory diseases because of their ability to bind bacterial toxins. Low cholesterol levels have been reported in inflammatory conditions, and plasma cholesterol concentrations inversely correlate with severity and clinical outcome in septic patients. It is thus paradoxical that statins, which drastically reduce circulating cholesterol levels, should be beneficial in patients with inflammatory disease who are already hypocholesterolemic. We investigated the effect of simvastatin on LPS-induced nuclear factor kappa B (NF-kappa B) activation, TNF release, and mortality in guinea pigs, an animal model with a lipoprotein profile and pattern similar to humans. In the present study, simvastatin reduced circulating total and low-density lipoprotein cholesterol levels by 68% and 76%, respectively, and LPS-induced mortality from 73% to 20%. This reduction was accompanied by a significant reduction of NF-kappa B activation in the liver tissue, splenocytes, and plasma TNF levels by about 80%, 50%, and 77%, respectively. Our data suggest that simvastatin, despite lowering circulating low-density lipoprotein cholesterol, decreased LPS toxicity by reduction of NF-kappa B activation and subsequent release of TNF by modulating 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and therefore deserves consideration as a possible adjuvant therapy in acute inflammatory disease
    Type of Publication: Journal article published
    PubMed ID: 19008785
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  • 3
    Shock 21 (), 1- 
    Keywords: DNA ; SURGERY ; DISEASE ; microarray ; microarrays ; CARE ; antibodies ; antibody ; vascular disease ; VASCULAR-DISEASE ; antibody microarray
    Type of Publication: Meeting abstract published
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