BACKGROUND & AIMS Senescent biliary epithelial cells (BECs) may be involved in the pathophysiology of primary biliary cholangitis (PBC) by secreting senescence-associated secretory phenotypes. We examined an association of the extent of cellular senescence in BECs with clinicopathological features including response to ursodeoxycholic acid (UDCA) and a possibility of senolytic therapy in PBC. METHODS The expression of senescent markers (p21WAF1/Cip1, p16INK4a) and B-cell lymphoma-extra large (Bcl-xL), a key regulator of senescent cell anti-apoptotic pathway, was immunohistochemically examined in livers from patients with PBC (n = 145) and 103 control livers. Senolytic effect of Bcl-xL inhibitors (A-1331852 and Navitoclax) was examined in senescent murine BECs. RESULTS Senescent BECs were increased in small bile ducts in PBC, compared with control livers (p < 0.01). Senescent BECs were increased in ductular reactions in PBC, stage 3-4, compared with PBC, stage 1-2 and control livers (p < 0.01). The extent of senescent BECs in bile ductules was significantly correlated with stage and hepatitis activity (p < 0.01) and the expression of p16INK4a in bile ductules was significantly correlated to inadequate response to UDCA in PBC (p < 0.01). Double immunofluorescence revealed an increased expression of Bcl-xL in p16INK4a-positive senescent BECs in PBC. Bcl-xL inhibitors selectively induced apoptosis in senescent murine BECs (p < 0.01). CONCLUSION The extent of senescent BECs in small bile ducts and bile ductules was closely related to stage and activity of PBC and the increased expression of p16 INK4a in bile ductules was correlated with inadequate response to UDCA.

中文翻译：

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在原发性胆管性胆管炎中，表达p16INK4a的衰老胆管细胞增加与对熊去氧胆酸的反应不足有关。

背景与目的衰老的胆管上皮细胞（BEC）可能通过分泌衰老相关的分泌表型参与原发性胆管性胆管炎（PBC）的病理生理。我们检查了BECs中细胞衰老程度与临床病理特征（包括对熊去氧胆酸（UDCA）的反应）和PBC进行疏溶治疗的可能性之间的相关性。方法用免疫组织化学方法检测了PBC患者肝脏中的衰老标志物（p21WAF1 / Cip1，p16INK4a）和B细胞淋巴瘤超大蛋白（Bcl-xL）的表达。Bcl-xL是衰老细胞抗凋亡途径的关键调节剂。 145）和103对照肝。Bcl-xL抑制剂（A-1331852和Navitoclax）的衰老作用在衰老的鼠BEC中进行了检查。结果PBC的小胆管中衰老的BEC增加，与对照肝脏相比（p <0.01）。与PBC，1-2期和对照肝脏相比，PBC 3-4期的衰老BECs在导管反应中增加（p <0.01）。胆管中衰老的BECs的程度与分期和肝炎活动显着相关（p <0.01），胆管中p16INK4a的表达与PBC对UDCA的反应不足相关（p <0.01）。双重免疫荧光显示在PBC中p16INK4a阳性衰老BEC中Bcl-xL的表达增加。Bcl-xL抑制剂选择性地诱导衰老小鼠BECs凋亡（p <0.01）。