Metformin attenuates oxidative stress and liver damage after bile duct ligation in rats

The CXC chemokine receptor 2 (CXCR2) is critical for neutrophil recruitment and hepatocellular viability but has not been studied in the context of cholestatic liver injury following bile duct ligation (BDL). The present study sought to elucidate the cell-specific roles of CXCR2 on acute liver injury after BDL. Wild-type and CXCR2−/− mice were subjected BDL. CXCR2 chimeric mice were created to assess the cell-specific role of CXCR2 on liver injury after BDL. SB225002, a selective CXCR2 antagonist, was administrated intraperitoneally after BDL to investigate the potential of pharmacological inhibition. CXCR2−/− mice had significantly less liver injury than wild-type mice at 3 and 14 days after BDL. There was no difference in biliary fibrosis among groups. The chemokines CXCL1 and CXCL2 were induced around areas of necrosis and biliary structures, respectively, both areas where neutrophils accumulated after BDL. CXCR2−/− mice showed significantly less neutrophil accumulation in those injured areas. CXCR2Liver+/Myeloid+ and CXCR2Liver−/Myeloid− mice recapitulated the wild-type and CXCR2-knockout phenotypes, respectively. CXCR2Liver+/Myeloid+ mice suffered higher liver injury than CXCR2Liver+/Myeloid− and CXCR2Liver−/Myeloid+; however, only those chimeras with knockout of myeloid CXCR2 (CXCR2Liver+/Myeloid− and CXCR2Liver−/Myeloid−) showed reduction of neutrophil accumulation around areas of necrosis. Daily administration of SB225002 starting after 3 days of BDL reduced established liver injury at 6 days. In conclusion, neutrophil CXCR2 guides the cell to the site of injury, while CXCR2 on liver cells affects liver damage independent of neutrophil accumulation. CXCR2 appears to be a viable therapeutic target for cholestatic liver injury. NEW & NOTEWORTHY This study is the first to reveal cell-specific roles of the chemokine receptor CXCR2 in cholestatic liver injury caused by bile duct ligation. CXCR2 on neutrophils facilitates neutrophil recruitment to the liver, while CXCR2 on liver cells contributes to liver damage independent of neutrophils. CXCR2 may represent a viable therapeutic target for cholestatic liver injury.

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CIRRHOSIS INDUCES APOPTOSIS IN RENAL TISSUE THROUGH INTRACELLULAR OXIDATIVE STRESS

Arquivos de Gastroenterologia ◽

10.1590/s0004-28032015000100014 ◽

2015 ◽

Vol 52 (1) ◽

pp. 65-71 ◽

Cited By ~ 5

Author(s):

Keli Cristina Simões da SILVEIRA ◽

Cassiana Macagnan VIAU ◽

Josiane Raskopf COLARES ◽

Jenifer SAFFI ◽

Norma Possa MARRONI ◽

...

Keyword(s):

Oxidative Stress ◽

Antioxidant Enzymes ◽

Membrane Potential ◽

Bile Duct ◽

Mitochondrial Membrane Potential ◽

Mitochondrial Membrane ◽

Bile Duct Ligation ◽

Decompensated Cirrhosis ◽

Biliary Cirrhosis ◽

Duct Ligation

Background Renal failure is a frequent and serious complication in patients with decompensated cirrhosis. Objectives We aimed to evaluate the renal oxidative stress, cell damage and impaired cell function in animal model of cirrhosis. Methods Secondary biliary cirrhosis was induced in rats by ligation of the common bile duct. We measured TBARS, ROS and mitochondrial membrane potential in kidney as markers of oxidative stress, and activities of the antioxidant enzymes. Relative cell viability was determined by trypan blue dye-exclusion assay. Annexin V-PE was used with a vital dye, 7-AAD, to distinguish apoptotic from necrotic cells and comet assay was used for determined DNA integrity in single cells. Results In bile duct ligation animals there was significant increase in the kidney lipoperoxidation and an increase of the level of intracellular ROS. There was too an increase in the activity of all antioxidant enzymes evaluated in the kidney. The percentage viability was above 90% in the control group and in bile duct ligation was 64.66% and the dominant cell death type was apoptosis. DNA damage was observed in the bile duct ligation. There was a decreased in the mitochondrial membrane potential from 71.40% ± 6.35% to 34.48% ± 11.40% in bile duct ligation. Conclusions These results indicate that intracellular increase of ROS cause damage in the DNA and apoptosis getting worse the renal function in cirrhosis.

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Bile duct ligation and oxidative stress in the rat: effects in liver and kidney

Comparative Biochemistry and Physiology Part C Pharmacology Toxicology and Endocrinology ◽

10.1016/s0742-8413(00)00102-x ◽

2000 ◽

Vol 126 (2) ◽

pp. 105-111 ◽

Cited By ~ 20

Author(s):

Myriam Orellana ◽

Ramón Rodrigo ◽

Lilian Thielemann ◽

Viviana Guajardo

Keyword(s):

Oxidative Stress ◽

Bile Duct ◽

Bile Duct Ligation ◽

Duct Ligation ◽

Liver And Kidney ◽

And Oxidative Stress

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Renal dysfunction as a consequence of acute liver damage by bile duct ligation in cirrhotic rats

Experimental and Toxicologic Pathology ◽

10.1016/j.etp.2006.05.001 ◽

2006 ◽

Vol 58 (2-3) ◽

pp. 185-195 ◽

Cited By ~ 24

Author(s):

Sandra Rivera-Huizar ◽

Ana Rosa Rincón-Sánchez ◽

Amador Covarrubias-Pinedo ◽

María Cristina Islas-Carbajal ◽

Genaro Gabriel-Ortíz ◽

...

Keyword(s):

Bile Duct ◽

Renal Dysfunction ◽

Liver Damage ◽

Bile Duct Ligation ◽

Acute Liver Damage ◽

Duct Ligation

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Effects of methylene blue in reducing cholestatic oxidative stress and hepatic damage after bile-duct ligation in rats

Acta Histochemica ◽

10.1016/j.acthis.2008.12.002 ◽

2010 ◽

Vol 112 (3) ◽

pp. 259-269 ◽

Cited By ~ 17

Author(s):

Burhan Aksu ◽

Hasan Umit ◽

Mehmet Kanter ◽

Ahmet Guzel ◽

Cevat Aktas ◽

...

Keyword(s):

Oxidative Stress ◽

Methylene Blue ◽

Bile Duct ◽

Bile Duct Ligation ◽

Hepatic Damage ◽

Duct Ligation

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Comparing distress of mouse models for liver damage

Scientific Reports ◽

10.1038/s41598-020-76391-w ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Guanglin Tang ◽

Nico Seume ◽

Christine Häger ◽

Simone Kumstel ◽

Kerstin Abshagen ◽

...

Keyword(s):

Multivariate Analysis ◽

Carbon Tetrachloride ◽

Bile Duct ◽

Animal Models ◽

Mouse Models ◽

Liver Damage ◽

Bile Duct Ligation ◽

Characteristic Curve ◽

Support Vector ◽

Duct Ligation

AbstractIn order to foster animal welfare as well as high quality of research, many countries regulate by law that the severity of animal experiments must be evaluated and considered when performing biomedical research. It is well accepted that multiple parameters rather than a single readout parameter should be applied to describe animal distress or suffering. However, since the performance of readout parameters for animal distress is rarely defined and methods for multivariate analysis have only in rare cases been used, it is not known which methodology is most appropriate to define animal distress. This study used receiver operating characteristic curve analysis to quantify the performance of burrowing activity, body weight change and a distress score of mice after induction of liver damage by bile duct ligation or carbon tetrachloride. In addition, Support Vector Machine classification was used to compare the distress of these mouse models. This approach demonstrated that bile duct ligation causes much more distress than carbon tetrachloride-induced liver damage. This study, therefore, provides a prototype how to compare two animal models by considering several readout parameters. In the future these or similar methods for multivariate analysis will be necessary, when assessing and comparing the severity of animal models.

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