Clinic for Gastroenterology and Hepatology, Center for Internal Medicine, University Hospital Essen, Essen, Germany.
J Pharmacol Exp Ther. 2012 Sep;342(3):730-41. doi: 10.1124/jpet.112.194167. Epub 2012 Jun 6.
Various models are used for investigating human liver diseases and testing new drugs. However, data generated in such models have only limited relevance for in vivo conditions in humans. We present here an ex vivo perfusion system using human liver samples that enables the characterization of parameters in a functionally intact tissue context. Resected samples of noncirrhotic liver (NC; n = 10) and cirrhotic liver (CL; n = 12) were perfused for 6-h periods. General and liver-specific parameters (glucose, lactate, oxygen, albumin, urea, and bile acids), liver enzymes (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, glutamate dehydrogenase, and γ-glutamyl transferase), overall (M65) and apoptotic (M30) cell-death markers, and indicators of phase-I/phase-II biotransformations were analyzed. The measurement readings closely resembled (patho)physiological characteristics in patients with NC and CL. Mean courses of glucose levels reflected the CLs' reduced glycogen storage capability. Furthermore, CL samples exhibited significantly stronger increases in lactate, bile acids, and the M30/M65 ratio than NC specimens. Likewise, NC samples exhibited more rapid phase-I transformations of phenacetin, midazolam, and diclofenac and phase-I to phase-II turnover rates of the respective intermediates than CL tissue. Collectively, these findings reveal the better hepatic functionality in NC. Perfusion of human liver tissue with this system emulates in vivo conditions and clearly discriminates between noncirrhotic and cirrhotic tissue. This highly reliable device for investigating basic hepatic functionality and testing safety/toxicity, pharmacokinetics/pharmacodynamics and efficacies of novel therapeutic modalities promises to generate superior data compared with those obtained via existing economic perfusion systems.
各种模型被用于研究人类肝脏疾病和测试新药。然而，这些模型中产生的数据对于人类体内的实际情况只有有限的相关性。我们在此介绍一种使用人类肝组织样本的离体灌注系统，该系统能够在功能完整的组织环境中对参数进行特征描述。对非肝硬化（NC；n = 10）和肝硬化（CL；n = 12）的肝切除样本进行了 6 小时的灌注。分析了一般和肝脏特异性参数（葡萄糖、乳酸、氧、白蛋白、尿素和胆汁酸）、肝酶（天冬氨酸氨基转移酶、丙氨酸氨基转移酶、乳酸脱氢酶、谷氨酸脱氢酶和γ-谷氨酰转移酶）、整体（M65）和凋亡（M30）细胞死亡标志物以及 I 相/II 相生物转化的指标。测量读数与 NC 和 CL 患者的（病）生理特征非常相似。葡萄糖水平的平均值反映了 CL 糖原储存能力的降低。此外，CL 样本中乳酸、胆汁酸和 M30/M65 比值的升高明显强于 NC 标本。同样，NC 样本中苯乙酰氨基酚、咪达唑仑和双氯芬酸的 I 相转化以及各自中间产物的 I 相到 II 相的转化率均快于 CL 组织。总的来说，这些发现揭示了 NC 中更好的肝脏功能。用该系统灌注人类肝组织模拟了体内条件，并清楚地区分了非肝硬化和肝硬化组织。这种用于研究基本肝脏功能、测试安全性/毒性、药代动力学/药效学以及新型治疗方法疗效的高度可靠设备，有望产生优于现有经济灌注系统的更好数据。
