Importance of Connexin-43 based gap junction in cirrhosis and acute-on-chronic liver failure
| Autor: | David L. Becker, Anne E. Warner, Nathan Davies, V. Balasubramaniyan, Beverley Bright, Rajiv Jalan, Azin Farzan Amiri, Rajeshwar P. Mookerjee, Wai-Yin Vivien Li, Dipok Kumar Dhar |
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| Rok vydání: | 2013 |
| Předmět: |
Lipopolysaccharides
Liver Cirrhosis Male medicine.medical_specialty Cirrhosis medicine.medical_treatment Connexin Alcoholic hepatitis Inflammation Cell Communication Connexins Rats Sprague-Dawley Mice Internal medicine Animals Medicine Hepatology Tumor Necrosis Factor-alpha business.industry NF-kappa B Gap junction Antibodies Monoclonal Gap Junctions Alanine Transaminase medicine.disease Infliximab Rats Connexin 26 Cytokine Endocrinology Connexin 43 Immunology Tumor necrosis factor alpha medicine.symptom business Ligation Liver Failure |
| Zdroj: | Journal of Hepatology. 58:1194-1200 |
| ISSN: | 0168-8278 |
| DOI: | 10.1016/j.jhep.2013.01.023 |
| Popis: | Background & Aims In cirrhosis, superimposed inflammation often culminates in acute-on-chronic liver failure (ACLF) but the mechanism underlying this increased sensitivity is not clear. Cx43 is a ubiquitous gap junction protein that allows transmission of signals between cells at a much higher rate than the constitutively expressed gap junctions. The aims of the study were to test the hypothesis that inflammation drives the increased expression of hepatic Cx43 and to determine its role by Cx43 inhibition. Methods Four weeks after bile-duct ligation (BDL) or sham operation, rats were treated with an anti-TNF antibody, or saline; with or without LPS (1mg/kg); given 3h prior to termination. Biochemistry and cytokines were measured in the plasma and hepatic protein expression (NFkB, TNFα, iNOS, 4HNE, Cx26, 32, and 43) and confocal microscopy (Cx26, 32, and 43) were performed. The effect of a Cx43-specific inhibitory peptide was studied in a mouse BDL model. Results BDL animals administered LPS developed typical features of ACLF but animals administered infliximab were relatively protected. Cx26/32 expression was significantly decreased in BDL animals while Cx43 was significantly increased and increased further following LPS. Infliximab treatment prevented this increase. However, inhibiting Cx43 in BDL mice produced detrimental effects with markedly greater hepatocellular necrosis. Conclusions The results of this study show for the first time an increased expression of hepatic Cx43 in cirrhosis and ACLF, which was related to the severity of inflammation. This increased Cx43 expression is likely to be an adaptive protective response of the liver to allow better cell-to-cell communication. |
| Databáze: | OpenAIRE |
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