PMID- 29444470 OWN - NLM STAT- MEDLINE DCOM- 20180906 LR - 20180906 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 824 DP - 2018 Apr 5 TI - Effect of sirolimus on liver cirrhosis and hepatic encephalopathy of common bile duct-ligated rats. PG - 133-139 LID - S0014-2999(18)30094-3 [pii] LID - 10.1016/j.ejphar.2018.02.016 [doi] AB - Cirrhosis is often associated with portal hypertension and portal-systemic collateral vessels formation attributed to angiogenesis, which leads to severe complications as hepatic encephalopathy. Sirolimus has anti-fibrosis and anti-angiogenesis effects, but whether it influences the severity of portal-systemic collaterals and hepatic encephalopathy is unknown. This study was thus designed to address this issue in rats with common bile duct ligation-induced liver cirrhosis. Sham-operated rats were surgical controls. Rats were intraperitoneally administered with 0.5 and 2 mg/kg/day sirolimus or vehicle for 2 weeks. Four weeks post operations, motor activities, body weight, biochemistry and hemodynamic data were measured. The liver was dissected for histopathology, immunohistochemical stains and protein analysis. On the parallel cirrhotic groups, the portal-systemic shunting was determined. The results showed that the body weight gain was significantly lower in sirolimus-treated rats. Sirolimus reduced portal pressure and plasma levels of alanine aminotransferase, aspartate aminotransferase and ammonia, and attenuated hepatic inflammation and fibrosis in cirrhotic rats. In addition, the hepatic phosphorylated mammalian target of rapamycin (mTOR) and P70S6K protein expressions were significantly downregulated and endothelial nitric oxide synthase (eNOS) expression upregulated by sirolimus. Sirolimus did not influence portal-systemic shunting and motor activities of cirrhotic rats. In conclusion, sirolimus significantly improved hepatic inflammation and fibrosis accompanied by portal pressure reduction in cirrhotic rats, in which down-regulated mTOR/P70S6K and up-regulated eNOS expressions might play a role. However, sirolimus did not significantly change the severity of portal-systemic collaterals and motor activities, suggesting that the multifactorial pathogenesis of hepatic encephalopathy could not be fully overcome by sirolimus. CI - Copyright (c) 2018 Elsevier B.V. All rights reserved. FAU - Wu, Kuo-Cheng AU - Wu KC AD - Divisions of General Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC. FAU - Huang, Hui-Chun AU - Huang HC AD - Divisions of General Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Divisions of Gastroenterology and Hepatology, Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC. FAU - Chang, Ting AU - Chang T AD - Divisions of General Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC. FAU - Lee, Wen-Shin AU - Lee WS AD - Divisions of General Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC. FAU - Chuang, Chiao-Lin AU - Chuang CL AD - Divisions of General Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC. FAU - Hsin, I-Fang AU - Hsin IF AD - Divisions of Gastroenterology and Hepatology, Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Divisions of Endoscopy Center for Diagnosis and Treatment, Taipei Veterans, General Hospital, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Institute of Pharmacology, National, Yang-Ming University School of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC. FAU - Hsu, Shao-Jung AU - Hsu SJ AD - Divisions of Gastroenterology and Hepatology, Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC. FAU - Lee, Fa-Yauh AU - Lee FY AD - Divisions of Gastroenterology and Hepatology, Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC. FAU - Chang, Ching-Chih AU - Chang CC AD - Divisions of General Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Divisions of Gastroenterology and Hepatology, Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC. Electronic address: ccchang7@vghtpe.gov.tw. FAU - Lee, Shou-Dong AU - Lee SD AD - Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Cheng-Hsin General Hospital, Taipei, Taiwan, ROC. LA - eng PT - Journal Article DEP - 20180211 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Body Weight/drug effects MH - Common Bile Duct/*surgery MH - Fibrosis MH - Hemodynamics/drug effects MH - Hepatic Encephalopathy/*drug therapy/*etiology/metabolism/physiopathology MH - Ligation/adverse effects MH - Liver Cirrhosis/*drug therapy/*etiology/metabolism/physiopathology MH - Male MH - Motor Activity/drug effects MH - Rats MH - Rats, Sprague-Dawley MH - Sirolimus/*pharmacology/therapeutic use OTO - NOTNLM OT - Hepatic encephalopathy OT - Liver cirrhosis OT - Portal-systemic shunts OT - Sirolimus EDAT- 2018/02/15 06:00 MHDA- 2018/09/07 06:00 CRDT- 2018/02/15 06:00 PHST- 2017/09/11 00:00 [received] PHST- 2018/02/09 00:00 [revised] PHST- 2018/02/09 00:00 [accepted] PHST- 2018/02/15 06:00 [pubmed] PHST- 2018/09/07 06:00 [medline] PHST- 2018/02/15 06:00 [entrez] AID - S0014-2999(18)30094-3 [pii] AID - 10.1016/j.ejphar.2018.02.016 [doi] PST - ppublish SO - Eur J Pharmacol. 2018 Apr 5;824:133-139. doi: 10.1016/j.ejphar.2018.02.016. Epub 2018 Feb 11.