Combination of CCl4 with alcoholic and metabolic injuries mimics human liver fibrosis

被引：50

作者：

Brol, Maximilian Joseph ^{[1
]}

Roesch, Felicitas ^{[1
]}

Schierwagen, Robert ^{[1
]}

Magdaleno, Fernando ^{[1
]}

Uschner, Frank Erhard ^{[1
,2
]}

Manekeller, Steffen ^{[3
]}

Queck, Alexander ^{[2
]}

Schwarzkopf, Katharina ^{[2
]}

Odenthal, Margarete ^{[4
]}

Drebber, Uta ^{[4
]}

Thiele, Maja ^{[5
]}

Lingohr, Philipp ^{[3
]}

Plamper, Andreas ^{[6
]}

Kristiansen, Glen ^{[7
]}

Lotersztajn, Sophie ^{[8
,9
,10
]}

Krag, Aleksander ^{[5
]}

Klein, Sabine ^{[1
,2
]}

Rheinwalt, Karl P. ^{[6
]}

Trebicka, Jonel ^{[1
,2
,5
,11
,12
]}

机构：

[1] Univ Bonn, Dept Internal Med 1, Bonn, Germany

[2] Johann Wolfgang Goethe Univ Hosp, Dept Internal Med 1, Div Gastroenterol, Frankfurt, Germany

[3] Univ Hosp Bonn, Dept Surg, Bonn, Germany

[4] Univ Cologne, Inst Pathol, Cologne, Germany

[5] Odense Univ Hosp, Dept Med Gastroenterol & Hepatol, Odense, Denmark

[6] St Franziskus Hosp Cologne, Dept Bariatr Metab & Plast Surg, Cologne, Germany

[7] Univ Bonn, Inst Pathol, Bonn, Germany

[8] INSERM, Ctr Rech Inflammat, UMR 1149, Paris, France

[9] Univ Paris Diderot, Sorbonne Paris Cite, Lab Excellence Inflamex, Fac Med, Site Xavier Bichat, Paris, France

[10] Hop Beaujon, AP HP, Dept Hosp Univ UNITY, Serv Hepatol, Clichy, France

[11] European Fdn Study Chron Liver Failure EF Clif, Barcelona, Spain

[12] Inst Bioengn Catalonia, Barcelona, Spain

来源：

AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY | 2019年 / 317卷 / 02期

基金：

欧盟地平线“2020”;

关键词：

ASH; liver fibrosis; NAFLD; NASH; MODEL; MICE; STEATOSIS;

D O I：

10.1152/ajpgi.00361.2018

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Metabolic and alcoholic liver injuries result in nonalcoholic (NAFLD) or alcoholic (ALD) fatty liver disease, respectively. In particular, presence of fibrosis in (NAFLD) and (ALD) requires treatment, but development of drugs is hampered by the lack of suitable models with significant fibrosis. The carbon tetrachloride (CCl4) liver fibrosis model does not reflect human NAFLD or ALD, but CCl4 may serve as a fibrosis accelerator in addition to another injury. Ethanol in drinking water (16%) or Western diet (WD) were administered for 7 wk in mice either alone or in combination with CCl4 intoxications. Extent of fibrosis. steatosis, and inflammation was assessed by histology, transcription, and biochemistry. Furthermore, transcription of fibrosis, proliferation, and inflammation-related genes was studied on human liver samples with fibrosis resulting from hepatitis C virus infection (n = 7), NAFLD (n = 8), or ALD (n = 7). WD or ethanol alone induced only mild steatosis and inflammation. Combination of CCl4 and WD induced the most severe steatosis together with significant liver fibrosis and moderate inflammation. Combination of CCl4 and ethanol induced the strongest inflammation, with significant liver fibrosis and moderate steatosis. The relationship pattern between fibrosis, proliferation, and inflammation of human ALD was mostly similar in mice treated with CCl4 and ethanol. The combination of CCl4 intoxication with WD validates previous data suggesting it as an appropriate model for human nonalcoholic steato-hepatitis. Especially, CCl4 plus ethanol for 7 wk induces ALD in mice, providing a model suitable for further basic research and drug testing. NEW & NOTEWORTHY Alcoholic fatty liver disease with significant fibrosis is generated within 7 wk using carbon tetrachloride as a fibrosis accelerator and administering gradually ethanol (up to 16%) in mice. The similarity in the pattern of steatosis, inflammation, and fibrosis involved in alcoholic fatty liver disease to those of the human condition renders this mouse model suitable as a preclinical model for drug development.

引用

页码：G182 / G194

页数：13

共 25 条

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