UNLABELLED:Endothelial dysfunction drives vascular derangement and organ failure associated with sepsis. However, the consequences of sepsis on liver sinusoidal endothelial function are largely unknown. Statins might improve microvascular dysfunction in sepsis. The present study explores liver vascular abnormalities and the effects of statins in a rat model of endotoxemia. For this purpose, lipopolysaccharide (LPS) or saline was given to: (1) rats treated with placebo; (2) rats treated with simvastatin (25 mg/kg, orally), given at 3 and 23 hours after LPS/saline challenge; (3) rats treated with simvastatin (25 mg/kg/24 h, orally) from 3 days before LPS/saline injection. Livers were isolated and perfused and sinusoidal endothelial function was explored by testing the vasodilation of the liver circulation to increasing concentrations of acetylcholine. The phosphorylated endothelial nitric oxide synthase (PeNOS)/endothelial nitric oxide synthase (eNOS) ratio was measured as a marker of eNOS activation. LPS administration induced an increase in baseline portal perfusion pressure and a decrease in vasodilation to acetylcholine (sinusoidal endothelial dysfunction). This was associated with reduced eNOS phosphorylation and liver inflammation. Simvastatin after LPS challenge did not prevent the increase in baseline portal perfusion pressure, but attenuated the development of sinusoidal endothelial dysfunction. Treatment with simvastatin from 3 days before LPS prevented the increase in baseline perfusion pressure and totally normalized the vasodilating response of the liver vasculature to acetylcholine and reduced liver inflammation. Both protocols of treatment restored a physiologic PeNOS/eNOS ratio. CONCLUSION:LPS administration induces intrahepatic endothelial dysfunction that might be prevented by simvastatin, suggesting that statins might have potential for liver protection during endotoxemia.

译文

未加标签:内皮功能障碍可导致败血症相关的血管紊乱和器官衰竭。然而,败血症对肝窦窦内皮功能的影响在很大程度上尚不清楚。他汀类药物可能会改善败血症中的微血管功能障碍。本研究探讨了内毒素血症大鼠模型中的肝血管异常和他汀类药物的作用。为此,将脂多糖(LPS)或盐水给予以下动物:(1)用安慰剂治疗的大鼠; (2)在LPS /盐水刺激后3和23小时给予辛伐他汀(25mg / kg,口服)治疗的大鼠; (3)从LPS /盐水注射前3天开始,用辛伐他汀(25 mg / kg / 24 h,口服)治疗的大鼠。分离并灌注肝脏,并通​​过测试肝循环的血管舒张作用以增加乙酰胆碱的浓度来探索正弦内皮功能。测量磷酸化内皮一氧化氮合酶(PeNOS)/内皮一氧化氮合酶(eNOS)的比率作为eNOS活化的标志。 LPS给药引起基线门静脉灌注压力增加,乙酰胆碱(正弦血管内皮功能障碍)的血管舒张减少。这与减少的eNOS磷酸化和肝脏炎症有关。 LPS刺激后的辛伐他汀不能阻止基线门静脉灌注压力的升高,但可以减轻正弦血管内皮功能障碍的发展。 LPS前3天开始用辛伐他汀治疗可防止基线灌注压力增加,并使肝血管对乙酰胆碱的血管舒张反应完全正常化,并减轻肝脏炎症。两种治疗方案均恢复了生理性PeNOS / eNOS比率。
结论:LPS给药可引起辛伐他汀可预防肝内内皮功能障碍,这表明他汀类药物可能在内毒素血症期间具有保护肝脏的潜能。

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