Schrem Harald, Kleine Moritz, Borlak Jürgen, Klempnauer Jürgen
Visceral and Transplantation Surgery, Medizinische Hochschule, Hannover, Germany.
Liver Transpl. 2006 Dec;12(12):1832-40. doi: 10.1002/lt.20918.
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)-alpha. Changes in expression of C-reactive protein (CRP), albumin, CCAAT enhancer binding protein (C/EBP)-alpha and C/EBP-beta 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-alpha resulted in reduced albumin production, albeit at different levels when human and porcine hepatocytes were compared (P = 0.001). Unlike human, porcine hepatocytes produced less of 6alpha-hydroxytestosterone (6alpha-HT) (P < 0.001) and 7alpha-HT (P < 0.001) after human or porcine IL-6 dosing and treatment with species-specific TNF-alpha induced (human hepatocytes) or decreased (porcine hepatocytes) 6beta-HT production (P = 0.021). In coculture with free exchange of metabolites, porcine hepatocytes produced less 6alpha-HT (P = 0.048) and 16alpha-HT (P = 0.033), whereas after treatment with human IL-6 reduced CRP gene and protein expression was observed with human hepatocytes (P = 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.
在暴发性肝衰竭中，使用含猪肝细胞的生物人工肝支持（BAL）是当前一个存在争议的话题。具体而言，跨物种生理不相容性问题迄今尚未得到解决。因此，我们研究了物种特异性细胞因子在单培养和共培养中对肝细胞功能的影响。肝细胞培养物取自人类切除标本和长白猪。单培养和共培养物分别暴露于猪和人类白细胞介素（IL）-6或肿瘤坏死因子（TNF）-α。通过测量睾酮代谢产物的产生，研究培养细胞中C反应蛋白（CRP）、白蛋白、CCAAT增强子结合蛋白（C/EBP）-α和C/EBP-β的表达变化以及代谢能力。给予人类或猪IL-6后，人类肝细胞培养物中CRP诱导增加高达100倍，而猪肝细胞仅有轻微反应（2至5倍）。用人类或猪IL-6或TNF-α处理导致白蛋白产生减少，不过在比较人类和猪肝细胞时减少程度不同（P = 0.001）。与人类不同，给予人类或猪IL-6后，猪肝细胞产生的6α-羟基睾酮（6α-HT）（P < 0.001）和7α-HT（P < 0.001）较少，并且用物种特异性TNF-α处理会诱导（人类肝细胞）或降低（猪肝细胞）6β-HT的产生（P = 0.021）。在代谢产物可自由交换的共培养中，猪肝细胞产生的6α-HT（P = 0.048）和16α-HT（P = 0.033）较少，而用人类IL-6处理后，人类肝细胞中观察到CRP基因和蛋白表达降低（P = 0.013）。总之，肝细胞对细胞因子的物种特异性反应以及与外源性代谢产物的相互作用可能会限制猪肝细胞在BAL中的临床效果。
