title: Importance of Connexin-43 based gap junction in cirrhosis and acute-on-chronic liver failure.
abstract: OBJECTIVE
  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.
authors: Liver Failure Group, UCL Institute for Liver and Digestive Health, Royal Free Hospital, Pond Street, London NW3 2PF, UK.
authors: Vairappan
authors: V
authors: Balasubramaniyan
authors: Dipok Kumar
authors: DK
authors: Dhar
authors: Anne E
authors: AE
authors: Warner
authors: Wai-Yin
authors: WY
authors: Vivien Li
authors: Azin Farzan
authors: AF
authors: Amiri
authors: Beverley
authors: B
authors: Bright
authors: Rajeshwar P
authors: RP
authors: Mookerjee
authors: Nathan A
authors: NA
authors: Davies
authors: David L
authors: DL
authors: Becker
authors: Rajiv
authors: R
authors: Jalan
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002450:Cell Communication; D000072259:Connexin 26; D018031:Connexin 43 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D017630:Connexins / Q000032:analysis; D017629:Gap Junctions / Q000502:physiology*; D000069285:Infliximab; D008070:Lipopolysaccharides / Q000494:pharmacology; D008103:Liver Cirrhosis / Q000150:complications*; D017093:Liver Failure / Q000209:etiology*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D018031:Connexin 43; D017630:Connexins; C000607044:Gjb2 protein, rat; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D000072259:Connexin 26; D000069285:Infliximab; D000410:Alanine Transaminase