Physiological incompatibilities of porcine hepatocytes for clinical liver support

✍ Scribed by Harald Schrem; Moritz Kleine; Jürgen Borlak; Jürgen Klempnauer

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 294 KB
• Volume: 12
• Category: Article
• ISSN: 1527-6465
• DOI: 10.1002/lt.20918

✦ Synopsis

In fulminant hepatic failure, the use of bioartificial liver support (BAL) with porcine hepatocytes is the subject of a current and controversial debate. 1 Specifically, the issue of cross-species physiological incompatibilities has not been addressed so far. We therefore investigated the effects of species-specific cytokines in single and cocultures on hepatocyte function. Hepatocyte cultures were isolated from human resection specimens and from Landrace pigs. Single and cocultures were exposed to porcine and human interleukin (IL)-6 or tumor necrosis factor (TNF)-␣. Changes in expression of C-reactive protein (CRP), albumin, CCAAT enhancer binding protein (C/EBP)-␣ and C/EBP-␤ and metabolic competence of cultured cells was studied by measuring testosterone metabolite production. After human or porcine IL-6 dosing, CRP was induced up to 100-fold in human hepatocyte cultures, while porcine hepatocytes responded marginally (2-to 5-fold). Treatment with human or porcine IL-6 or TNF-␣ resulted in reduced albumin production, albeit at different levels when human and porcine hepatocytes were compared (P ϭ 0.001). Unlike human, porcine hepatocytes produced less of 6␣-hydroxytestosterone (6␣-HT) (P Ͻ 0.001) and 7␣-HT (P Ͻ 0.001) after human or porcine IL-6 dosing and treatment with species-specific TNF-␣ induced (human hepatocytes) or decreased (porcine hepatocytes) 6␤-HT production (P ϭ 0.021). In coculture with free exchange of metabolites, porcine hepatocytes produced less 6␣-HT (P ϭ 0.048) and 16␣-HT (P ϭ 0.033), whereas after treatment with human IL-6 reduced CRP gene and protein expression was observed with human hepatocytes (P ϭ 0.013). In conclusion, species-specific responses of hepatocytes to cytokines and interactions with xenobiotic metabolites may limit the clinical effectiveness of porcine hepatocytes in BAL.