Cholangiocyte senescence has been linked to primary sclerosing cholangitis (PSC). Persistent secretion of growth factors by senescent cholangiocytes leads to the activation of stromal fibroblasts (ASFs), which are drivers of fibrosis. The activated phenotype of ASFs is characterized by an increased sensitivity to apoptotic stimuli. Here, we examined the mechanisms of apoptotic priming in ASFs and explored a combined targeting strategy to deplete senescent cholangiocytes and ASFs from fibrotic tissue to ameliorate liver fibrosis. Using a coculture system, we determined that senescent cholangiocytes promoted quiescent mesenchymal cell activation in a platelet‐derived growth factor (PDGF)‐dependent manner. We also identified B‐cell lymphoma‐extra large (Bcl‐xL) as a key survival factor in PDGF‐activated human and mouse fibroblasts. Bcl‐xL was also up‐regulated in senescent cholangiocytes. In vitro, inhibition of Bcl‐xL by the small molecule Bcl‐2 homology domain 3 mimetic, A‐1331852, or Bcl‐xL‐specific small interfering RNA induced apoptosis in PDGF‐activated fibroblasts, but not in quiescent fibroblasts. Likewise, inhibition of Bcl‐xL reduced the survival and increased apoptosis of senescent cholangiocytes, compared to nonsenescent cells. Treatment of multidrug resistance 2 gene knockout (Mdr2^−/−) mice with A‐1331852 resulted in an 80% decrease in senescent cholangiocytes, a reduction of fibrosis‐inducing growth factors and cytokines, decrease of α‐smooth muscle actin–positive ASFs, and finally in a significant reduction of liver fibrosis. Conclusion: Bcl‐xL is a key survival factor in ASFs as well as in senescent cholangiocytes. Treatment with the Bcl‐xL‐specific inhibitor, A‐1331852, reduces liver fibrosis, possibly by a dual effect on activated fibroblasts and senescent cholangiocytes. This mechanism represents an attractive therapeutic strategy in biliary fibrosis. (Hepatology 2018;67:247‐259).

中文翻译：

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使用B细胞淋巴瘤超大型抑制剂靶向衰老的胆管细胞和活化的成纤维细胞可改善多药耐药性2基因敲除（Mdr2-/-）小鼠的纤维化

胆管细胞衰老与原发性硬化性胆管炎（PSC）相关。衰老的胆管细胞持续分泌生长因子会导致基质成纤维细胞（ASF）活化，后者是纤维化的驱动力。ASF的活化表型的特征在于对凋亡刺激的敏感性增加。在这里，我们检查了ASFs中的细胞凋亡引发机制，并探索了一种联合靶向策略，以从纤维化组织中消耗衰老的胆管细胞和ASFs，以改善肝脏纤维化。使用共培养系统，我们确定衰老的胆管细胞以血小板衍生的生长因子（PDGF）依赖性方式促进了静止的间充质细胞活化。我们还发现B细胞淋巴瘤超大（Bcl-xL）是PDGF激活的人和小鼠成纤维细胞中的关键生存因素。在体外，小分子Bcl-2同源结构域3模拟物，A-1331852或Bcl-xL特异性小干扰RNA抑制Bcl-xL诱导了PDGF活化的成纤维细胞的凋亡，但没有诱导静止的成纤维细胞凋亡。同样，与非衰老细胞相比，抑制Bcl-xL降低了衰老胆管细胞的存活率并增加了其凋亡。用A‐1331852治疗多药抗性2基因敲除（Mdr2 ^-/-）小鼠导致衰老的胆管细胞减少80％，纤维化诱导生长因子和细胞因子减少，α平滑肌肌动蛋白阳性ASF减少，并最终明显减少了肝纤维化。结论：Bcl-xL是ASF和衰老的胆管细胞中的关键生存因素。使用Bcl-xL特异性抑制剂A-1331852治疗可减轻肝纤维化，可能是通过对活化的成纤维细胞和衰老的胆管细胞产生双重影响。该机制代表了胆汁纤维化的一种有吸引力的治疗策略。（H epatology 2018; 67：247‐259）。