辛伐他汀预防急性肝硬化和门静脉高压症大鼠慢性肝功能衰

StephenW

Simvastatin Prevents Progression of Acute on Chronic Liver Failure in Rats With Cirrhosis and Portal Hypertension
Dinesh Mani Tripathi∗
, Marina Vilaseca∗
, Erica Lafoz
, Héctor Garcia-Calderó
, Gabriela Viegas Haute
, Anabel Fernández-Iglesias
, Jarbas Rodrigues de Oliveira
, Juan Carlos García-Pagán
, Jaime Bosch'Correspondence information about the author Jaime Bosch§, Email the author Jaime Bosch
, Jordi Gracia-Sancho'
Background & Aims

Cirrhosis and its clinical consequences can be aggravated by bacterial infections, ultimately leading to the development of acute on chronic liver failure (ACLF), characterized by acute decompensation, organ failure, and high mortality within 28 days. Little is known about cellular and molecular mechanisms We developed a sepsis-associated preclinical model of ACLF to facilitat studies of pathogenesis and evaluate the protective effects of simvastatin.
Methods

Male Wistar rats inhaled CCl4 until they developed cirrhosis (at 10 weeks) or cirrhosis with ascites (at 15–16 weeks). Male Sprague-Dawley rats received bile-duct ligation for 28 days or intraperitoneal thioacetamide for 10 weeks to induce cirrhosis. After Induction of cirrhosis, some rats received a single injection of lipopolysaccharide (LPS) to induce ACLF; some were given simvastatin or vehicle (control) 4 hours or 24 hours before induction of ACLF. We collected data on changes in hepatic and systemic hemodynamics, hepatic Microvascular phenotype and function, and survival times. Liver tissues and plasma were collected and analyzed by immunoblots, quantitative polymerase chain reaction, immuno(fluoro)histochemistry and immunoassays.
Results

Administration of LPS aggravated portal hypertension in rats with cirrhosis by increasing the severity of intrahepatic microvascular dysfunction, exacerbating hepatic inflammation, increasing oxidative stress, and recruiting hepatic stellate cells and neutrophils. Rats with cirrhosis given LPS had significant shorter survival times than rats with cirrhosis given Simvastatin appears to increase hepatic sinusoidal function and reduce portal hypertension and markers of inflammation and oxidation. The drug is reduced levels of transaminases, total bilirubin, and ammonia, as well As LPS-mediated activation of hepatic stellate cells in liver tissues of rats with cirrhosis.
Conclusions

In studies of rats with cirrhosis, we found administration of LPS to promote development of ACLF, aggravating the complications of chronic liver disease and decreasing survival times. Simvastatin reduced LPS-induced inflammation and liver damage in rats with ACLF, supporting its use in treatment of Patients with advanced chronic liver disease.

StephenW

辛伐他汀预防急性肝硬化和门静脉高压症大鼠慢性肝功能衰竭的进展
Dinesh Mani Tripathi *
，Marina Vilaseca *
，Erica Lafoz
，HéctorGarcia-Calderó
，Gabriela Viegas Haute
，AnabelFernández-Iglesias
，贾巴斯罗德里格斯德奥利维拉
，JuanCarlosGarcía-Pagán
，Jaime Bosch'关于作者Jaime Bosch的相关信息，请发送电子邮件给作者Jaime Bosch
，Jordi Gracia-Sancho'
背景与目的

细菌感染可加重肝硬化及其临床后果，最终导致急性慢性肝功能衰竭（ACLF）的发展，其特征为急性失代偿，器官衰竭和28天内的高死亡率。关于细胞和分子机制知之甚少我们开发了一种与败血症相关的ACLF临床前模型，以促进发病机制的研究并评估辛伐他汀的保护作用。
方法

雄性Wistar大鼠吸入CCl4直至它们发展为肝硬化（10周）或肝硬化腹水（15-16周）。雄性Sprague-Dawley大鼠接受胆管结扎28天或腹膜内硫代乙酰胺10周以诱导肝硬化。在诱导肝硬化后，一些大鼠接受单次注射脂多糖（LPS）以诱导ACLF;一些人在诱导ACLF前4小时或24小时给予辛伐他汀或载体（对照）。我们收集了肝脏和全身血流动力学，肝脏微血管表型和功能以及存活时间变化的数据。收集肝组织和血浆并通过免疫印迹，定量聚合酶链反应，免疫（荧光）组织化学和免疫测定进行分析。
结果

LPS的施用通过增加肝内微血管功能障碍的严重性，加剧肝脏炎症，增加氧化应激和募集肝星状细胞和中性粒细胞来加重肝硬化大鼠的门静脉高压症。给予LPS的肝硬化大鼠的存活时间明显短于肝硬化大鼠，辛伐他汀似乎可增加肝窦功能，降低门脉高压和炎症及氧化指标。该药物是转氨酶，总胆红素和氨水平降低，以及LPS介导的肝硬化大鼠肝组织中肝星状细胞的活化。
结论

在对肝硬化大鼠的研究中，我们发现给予LPS以促进ACLF的发展，加重慢性肝病的并发症并减少存活时间。辛伐他汀可减轻LPS诱导的ACLF大鼠的炎症和肝损伤，支持其用于治疗晚期慢性肝病患者。

StephenW

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