Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Liver Int. 2013 Mar;33(3):368-74. doi: 10.1111/liv.12039. Epub 2013 Jan 14.
BACKGROUND/AIMS: Sepsis is a common complication of cirrhosis with a high mortality. Cirrhosis is associated with cardiac chronotropic and inotropic dysfunction, which is known as cirrhotic cardiomyopathy and might be linked to endotoxaemia. This study was aimed to explore the hypothesis that the inflammatory response induced by administration of low dose of lipopolysaccharide (LPS) exacerbates cardiac chronotropic dysfunction in cirrhotic rats; and if so, whether this is associated with altered cardiac toll-like receptor expression.
Cirrhosis was induced by surgical ligation of the bile duct in male Wister rats. Four weeks after bile duct ligation or sham surgery, the subjects were given intraperitoneal injection of either saline or LPS (0.1 mg/kg). Five hours after LPS injection, the atria were isolated and spontaneously beating rate and chronotropic responsiveness to β-adrenergic stimulation was assessed using standard organ bath. The expression of toll-like receptor 4 (TLR4) was assessed the atria using immunohistochemistry as well as quantitative RT-PCR.
LPS injection could induce a significant hypo-responsiveness to adrenergic stimulation in sham-operated rats. However, in cirrhotic rats, the chronotropic responses did not change after acute injection of LPS. Immunohistochemical study showed that TLR4 is mainly expressed in the myocardium in control atria and its expression is markedly decreased in myocardial layer following chronic bile duct ligation.
Our data showed that cirrhosis is associated with development of tolerance to cardiac chronotropic effect of LPS in rats and this might be caused by altered localization of TLR4 in myocardium.
背景/目的：败血症是肝硬化的常见并发症，死亡率很高。肝硬化与心脏变时和变力功能障碍有关，这被称为肝硬化性心肌病，可能与内毒素血症有关。本研究旨在探讨以下假设：给予低剂量脂多糖（LPS）诱导的炎症反应是否会加剧肝硬化大鼠的心脏变时功能障碍；如果是这样，这是否与心脏 toll 样受体表达的改变有关。
通过手术结扎胆管在雄性 Wister 大鼠中诱导肝硬化。在胆管结扎或假手术后 4 周，给予大鼠腹腔内注射生理盐水或 LPS（0.1mg/kg）。在 LPS 注射后 5 小时，分离心房并使用标准器官浴评估自发性跳动率和对β-肾上腺素刺激的变时反应。使用免疫组织化学和定量 RT-PCR 评估心房中 toll 样受体 4（TLR4）的表达。
LPS 注射可诱导假手术大鼠对肾上腺素刺激的反应明显降低。然而，在肝硬化大鼠中，急性 LPS 注射后，变时反应没有变化。免疫组织化学研究表明，TLR4 主要在对照组心房的心肌中表达，在慢性胆管结扎后心肌层中的表达明显降低。
我们的数据表明，肝硬化与大鼠 LPS 对心脏变时作用的耐受性发展有关，这可能是由于 TLR4 在心肌中的定位改变所致。
