Enamel matrix derivative limits the release of pro-inflammatory cytokines induced by lipopolysaccharide or peptidoglycan in human blood, suggesting that it has anti-inflammatory properties. We propose that this effect of EMD is, at least partly, secondary to an increase in the intracellular levels of cAMP in peripheral blood mononuclear cells.
The potencies of atracurium, vecuronium and pancuronium were compared using bolus injections and continuous infusions. The sizes of the bolus injections were based on previously determined cumulative dose-response relationships. Dose requirements for 90% and 50% sustained blockade were estimated by use of continuous infusion, and the corresponding plasma concentrations were measured for vecuronium and pancuronium. The effect of single bolus injections correlated well with the cumulative dose-responses, confirming relative potencies for atracurium, vecuronium and pancuronium of approximately 1:5:4. The maintenance doses (microgram kg-1 h-1) for 90% blockade were: atracurium 382.8, vecuronium 101.9, and pancuronium 36.9, making the relative dose requirements 10.4:2.8:1. The same dose ratio was found for atracurium and vecuronium at 50% blockade. This required about 60% of the doses needed for maintenance of 90% response. The relative potency of vecuronium and pancuronium in plasma was 1.1:1. The 25-75% recovery index was significantly shorter for vecuronium than for atracurium.
Several studies have implicated a role of peptidoglycan (PepG) as a pathogenicity factor in sepsis and organ injury, in part by initiating the release of inflammatory mediators. We wanted to elucidate the structural requirements of PepG to trigger inflammatory responses and organ injury. Injection of native PepG into anesthetized rats caused moderate but significant increases in the levels of alanine aminotransferase, aspartate aminotransferase, ␥-glutamyl transferase, and bilirubin (markers of hepatic injury and/or dysfunction) and creatinine and urea (markers of renal dysfunction) in serum, whereas PepG pretreated with muramidase to digest the glycan backbone failed to do this. In an ex vivo model of human blood, PepG containing different amino acids induced similar levels of the cytokines tumor necrosis factor alpha (TNF-␣), interleukin-6 (IL-6), IL-8, and IL-10, as determined by plasma analyses (enzyme-linked immunosorbent assay). Hydrolysis of the Staphylococcus aureus cross-bridge with lysostaphin resulted in moderately reduced release of TNF-␣, IL-6, IL-8, and IL-10, whereas muramidase digestion nearly abolished the ability to induce cytokine release and IL-6 mRNA accumulation in CD14؉ monocytes compared to intact PepG. However, additional experiments showed that muramidase-treated PepG synergized with lipopolysaccharide to induce TNF-␣ and IL-10 release in whole blood, despite its lack of inflammatory activity when administered alone. Based on these studies, we hypothesize that the structural integrity of the glycan chain of the PepG molecule is very important for the pathogenic effects of PepG. The amino acid composition of PepG, however, does not seem to be essential for the inflammatory properties of the molecule.
Infusion of the NO donor SNP in early endotoxaemia attenuates the detrimental effects of LPS on liver microcirculation, most probably by alleviating a relative deficit of NO at the microcirculatory level.
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