Research ArticleImportance of Connexin-43 based gap junction in cirrhosis and acute-on-chronic liver failure

Background & AimsIn 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.MethodsFour weeks after bile-duct ligation (BDL) or sham operation, rats were treated with an anti-TNF antibody, or saline; with or without LPS (1 mg/kg); given 3 h 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.ResultsBDL 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.ConclusionsThe 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.

Graphical abstractSchematic representation of the adaptive and protective inducible expression of cx43 in chronic and acute-on-chronic liver injuries. Upon hepatic insult, endogenous expression of Cx26 and Cx32 is reduced to alleviate the spread out of noxious injurious agents among the hepatocytes, whereas Cx43 expression is induced between hepatocytes and endothelial cells, to drain out the hepatic metabolites and endotoxin into the draining veins. It is assumed that in this way the inducible Cx43 expression during the hepatic injury exerts a protective effect and therefore, inhibition of Cx43 by a mimetic peptide accentuates the hepatic injury following bile duct ligation in mice.Download high-res image (151KB)Download full-size image