Department of Internal Medicine IV, University Hospital of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
Department of Infectious Diseases, Medical Microbiology and Hygiene, University of Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
Biochim Biophys Acta Mol Basis Dis. 2018 Apr;1864(4 Pt B):1380-1389. doi: 10.1016/j.bbadis.2017.09.012. Epub 2017 Sep 22.
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown origin. Previous bile proteomic analyses in patients with PSC have revealed changes in disease activity specific to malignant transformation. In this study, we established a reference bile duct-derived bile proteome for PSC that can be used to evaluate biliary pathophysiology. Samples were collected from patients with PSC or with choledocholithiasis (control) (n=6 each). Furthermore, patients with PSC-associated cholangiocarcinoma (CC) and with CC without concomitant PSC were analyzed. None of the patients showed signs of inflammation or infection based on clinical and laboratory examinations. Proteins overexpressed in patients with PSC relative to control patients were detected by two-dimensional difference gel electrophoresis and identified by liquid chromatography-tandem mass spectrometry. Functional proteomic analysis was performed using STRING software. A total of 101 proteins were overexpressed in the bile fluid of patients with PSC but not in those of controls; the majority of these were predicted to be intracellular and related to the ribosomal and proteasomal pathways. On the other hand, 91 proteins were found only in the bile fluid of controls; most were derived from the extracellular space and were linked to cell adhesion, the complement system, and the coagulation cascade. In addition, proteins associated with inflammation and the innate immune response-e.g., cluster of differentiation 14, annexin-2, and components of the complement system-were upregulated in PSC. The most prominent pathways in PSC/CC-patients were inflammation associated cytokine and chemokine pathways, whereas in CC-patients the Wnt signaling pathway was upregulated. In PSC/CC-patients DIGE-analysis revealed biliary CD14 and Annexin-4 expression, among others, as the most prominent protein that discriminates between both cohorts. Thus, the bile-duct bile proteome of patients with PSC shows disease-specific changes associated with inflammation and the innate immune response even in the absence of obvious clinical signs of cholangitis, malignancy, or inflammation. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni and Peter Jansen.
原发性硬化性胆管炎 (PSC) 是一种病因不明的慢性胆汁淤积性肝病。先前在 PSC 患者中的胆汁蛋白质组学分析显示了与恶性转化相关的疾病活动特异性变化。在这项研究中，我们建立了一个 PSC 的参考胆管衍生的胆汁蛋白质组，可用于评估胆汁生理学。样本取自 PSC 患者或胆总管结石患者（对照）（每组各 6 例）。此外，还分析了伴有 PSC 相关胆管癌 (CC) 和无 PSC 合并 CC 的患者。根据临床和实验室检查，所有患者均无炎症或感染迹象。通过二维差异凝胶电泳检测 PSC 患者相对于对照患者表达上调的蛋白质，并通过液相色谱-串联质谱鉴定。使用 STRING 软件进行功能蛋白质组学分析。在 PSC 患者的胆汁中，有 101 种蛋白质表达上调，而在对照患者中没有表达；这些蛋白质大多数被预测为细胞内的，与核糖体和蛋白酶体途径有关。另一方面，只在对照患者的胆汁中发现了 91 种蛋白质；大多数来自细胞外空间，与细胞粘附、补体系统和凝血级联有关。此外，与炎症和先天免疫反应相关的蛋白质，如 CD14、膜联蛋白-2 和补体系统的成分，在 PSC 中上调。PSC/CC 患者最突出的途径是与炎症相关的细胞因子和趋化因子途径，而在 CC 患者中，Wnt 信号通路被上调。在 PSC/CC 患者的 DIGE 分析中，发现胆管 CD14 和膜联蛋白-4 表达等是区分两组的最显著的蛋白质。因此，PSC 患者的胆管胆汁蛋白质组显示出与炎症和先天免疫反应相关的疾病特异性变化，即使在没有明显的胆管炎、恶性肿瘤或炎症临床迹象的情况下也是如此。本文是由 Jesus Banales、Marco Marzioni 和 Peter Jansen 编辑的特刊“健康与疾病中的胆管细胞”的一部分。
