Effects of N-acetylcysteine and tirilazad mesylate on intestinal functional capillary density, leukocyte adherence, mesenteric plasma extravasation and cytokine levels in experimental endotoxemia in rats

摘要

Abstract. Introduction: The study’s objective was to determine the effects of the administration of N-acetylcysteine (NAC) andnof tirilazad mesylate (TM) on intestinal functional capillary density, mesenteric plasma extravasation, leukocyte adherence andnon cytokine release during experimental endotoxemia in rats.nMethods: In a prospective, randomized, controlled animal study, 80 male Wistar rats were examined in 2 test series. Bothnseries were divided into 4 groups. Group 1 served as control group (CON group). Group 2 (LPS group), group 3 (NAC group)nand group 4 (TM group) received endotoxin infusions (10 mg/kg over 2 h). In NAC group 150 mg/kg body weight NAC wasnadministered after the first 30 minutes of endotoxemia intravenously. In TMgroup, 10 mg/kg body weight TM was administerednafter the first 30 minutes of endotoxemia intravenously. Animals of the series 1 underwent studies of leukocyte adherence onnsubmucosal venular endothelium of the small bowel wall and intestinal functional capillary density (FCD) in the intestinalnmucosa and the circular as well as the longitudinal muscle layer by intravital fluorescence microscopy (IVM). Plasma levels ofninterleukin 1β (IL-1β), interferone γ (IFN-γ) and soluble intercellular adhesion molecule1 (s-ICAM 1) as well as white bloodncell count (WBC) were estimated. In the animals of the series 2 mesenteric plasma extravasation was determined by IVM andnplasma levels of tumor necrosis factor α (TNF-α), IL-4, IL-6, IL-10 and malondialdehyde (MDA) were estimated.nResults: After LPS administration, FCD in the villi intestinales was unchanged and in the longitudinal muscularis layer itnwas increased. There was no effect of NAC or TM administration on FCD.nAlthough the plasma extravasation was not significantly influenced by LPS administration, TM administration resulted in anlower plasma extravasation in the TM group compared to the other groups. After endotoxin challenge, the firmly adherencenof leukocytes to vascular endothelium as a parameter of leukocyte activation in endotoxemia was increased but NAC or TMnadministration had no influence on leukocyte adherence. The plasma levels of IL-1β, IL-6, IL-10, TNF-α, IFN-γ and sICAM-1nwere increased in the endotoxemic groups (LPS group, NAC group and TM group) and the WBC was decreased compared toncontrols. IL-4 levels were unchanged during observation period. Plasma MDA levels were not influenced by LPS administrationncompared to controls. The administration of NAC resulted in lower sICAM-1 and MDA levels compared to the LPS group. ThenIL-1β, IL-6, IL-10, TNF-α and IFN-γ plasma levels were not influenced by NAC or TM administration.nConclusions: In this posttreatment sepsis model in rats, NAC administration resulted in lower sICAM-1 and MDA levelsncompared to the LPS treated animals. TM administration reduced the plasma extravasation in this model.