Alternative Title酢酸亜鉛とリファキシミンの併用療法による腸管バリアー機能維持によるエタノール誘発性肝線維化予防効果
Note (General)type:Thesis
BACKGROUNDHepatic overload of gut-derived lipopolysaccharide dictates the progression ofalcoholic liver disease (ALD) by inducing oxidative stress and activating Kupffercells and hepatic stellate cells through toll-like receptor 4 signaling. Therefore,targeting the maintenance of intestinal barrier integrity has attracted attention forthe treatment of ALD. Zinc acetate and rifaximin, which is a nonabsorbableantibiotic, had been clinically used for patients with cirrhosis, particularly thosewith hepatic encephalopathy, and had been known to improve intestinal barrierdysfunction. However, only few studies focused on their efficacies in preventingthe ALD-related fibrosis development.AIMTo investigate the effects of a combined zinc acetate with rifaximin on liverfibrosis in a mouse ALD model.METHODSTo induce ALD-related liver fibrosis, female C57BL/6J mice were fed a 2.5% (v/v)ethanol-containing Lieber-DeCarli liquid diet and received intraperitoneal carbontetrachloride (CCl4) injection twice weekly (1 mL/kg) for 8 wk. Zinc acetate (100mg/L) and/or rifaximin (100 mg/L) were orally administered during experimentalperiod. Hepatic steatosis, inflammation and fibrosis as well as intestinalbarrier function were evaluated by histological and molecular analyses. Moreover,the direct effects of both agents on Caco-2 barrier function were assessed by invitro assays.RESULTSIn the ethanol plus CCl4-treated mice, combination of zinc acetate and rifaximinattenuated oxidative lipid peroxidation with downregulation of Nox2 and Nox4.This combination significantly inhibited the Kupffer cells expansion and theproinflammatory response with blunted hepatic exposure of lipopolysaccharideand the toll-like receptor 4/nuclear factor kB pathway. Consequently, liverfibrosis and hepatic stellate cells activation were efficiently suppressed withdownregulation of Mmp-2, -9, -13, and Timp1. Both agents improved the atrophicchanges and permeability in the ileum, with restoration of tight junction proteins(TJPs) by decreasing the expressions of tumor necrosis factor α and myosin lightchain kinase. In the in vitro assay, both agents directly reinforced ethanol orlipopolysaccharide-stimulated paracellular permeability and upregulated TJPs inCaco-2 cells.CONCLUSIONDual therapy with zinc acetate and rifaximin may serve as a strategy to preventALD-related fibrosis by maintaining intestinal barrier integrity.
博士（医学）・甲第862号・令和5年3月15日
©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.
identifier:World journal of gastroenterology Vol.27 No.48 p.8323-8342 (2021 Dec)
identifier:10079327
identifier:http://ginmu.naramed-u.ac.jp/dspace/handle/10564/4093
identifier:World journal of gastroenterology, 27(48): 8323-8342
Collection (particular)国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文
Date Accepted (W3CDTF)2023-12-05T21:41:07+09:00
Data Provider (Database)国立国会図書館 : 国立国会図書館デジタルコレクション