並列タイトル等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
タイトル（掲載誌）World journal of gastroenterology
一般注記type:Thesis
BACKGROUND
Hepatic overload of gut-derived lipopolysaccharide dictates the progression of
alcoholic liver disease (ALD) by inducing oxidative stress and activating Kupffer
cells and hepatic stellate cells through toll-like receptor 4 signaling. Therefore,
targeting the maintenance of intestinal barrier integrity has attracted attention for
the treatment of ALD. Zinc acetate and rifaximin, which is a nonabsorbable
antibiotic, had been clinically used for patients with cirrhosis, particularly those
with hepatic encephalopathy, and had been known to improve intestinal barrier
dysfunction. However, only few studies focused on their efficacies in preventing
the ALD-related fibrosis development.
AIM
To investigate the effects of a combined zinc acetate with rifaximin on liver
fibrosis in a mouse ALD model.
METHODS
To 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 carbon
tetrachloride (CCl4) injection twice weekly (1 mL/kg) for 8 wk. Zinc acetate (100
mg/L) and/or rifaximin (100 mg/L) were orally administered during experimental
period. Hepatic steatosis, inflammation and fibrosis as well as intestinal
barrier function were evaluated by histological and molecular analyses. Moreover,
the direct effects of both agents on Caco-2 barrier function were assessed by in
vitro assays.RESULTSIn the ethanol plus CCl4-treated mice, combination of zinc acetate and rifaximin
attenuated oxidative lipid peroxidation with downregulation of Nox2 and Nox4.
This combination significantly inhibited the Kupffer cells expansion and the
proinflammatory response with blunted hepatic exposure of lipopolysaccharide
and the toll-like receptor 4/nuclear factor kB pathway. Consequently, liver
fibrosis and hepatic stellate cells activation were efficiently suppressed with
downregulation of Mmp-2, -9, -13, and Timp1. Both agents improved the atrophic
changes and permeability in the ileum, with restoration of tight junction proteins
(TJPs) by decreasing the expressions of tumor necrosis factor α and myosin light
chain kinase. In the in vitro assay, both agents directly reinforced ethanol or
lipopolysaccharide-stimulated paracellular permeability and upregulated TJPs in
Caco-2 cells.
CONCLUSION
Dual therapy with zinc acetate and rifaximin may serve as a strategy to prevent
ALD-related fibrosis by maintaining intestinal barrier integrity.
博士（医学）・甲第862号・令和5年3月15日
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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
連携機関・データベース国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）
提供元機関・データベース奈良県立医科大学 : 奈良県立医科大学機関リポジトリ GINMU