Journal of Hepatology ( IF 26.8 ) Pub Date : 2022-08-18 , DOI: 10.1016/j.jhep.2022.07.034 Lindsey Kennedy 1 , Guido Carpino 2 , Travis Owen 3 , Ludovica Ceci 4 , Debjyoti Kundu 3 , Vik Meadows 3 , Konstantina Kyritsi 3 , Antonio Franchitto 5 , Paolo Onori 5 , Abdulkadir Isidan 6 , Wenjun Zhang 6 , Burcin Ekser 6 , Domenico Alvaro 5 , Eugenio Gaudio 5 , M Eric Gershwin 7 , Heather Francis 1 , Shannon Glaser 8 , Gianfranco Alpini 1
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Background & Aims
Primary biliary cholangitis (PBC) is characterised by ductopenia, ductular reaction, impairment of anion exchanger 2 (AE2) and the ‘bicarbonate umbrella’. Ductulo-canalicular junction (DCJ) derangement is hypothesised to promote PBC progression. The secretin (Sct)/secretin receptor (SR) axis regulates cystic fibrosis transmembrane receptor (CFTR) and AE2, thus promoting choleresis. We evaluated the role of Sct/SR signalling on biliary secretory processes and subsequent injury in a late-stage PBC mouse model and human samples.
Methods
At 32 weeks of age, female and male wild-type and dominant-negative transforming growth factor beta receptor II (late-stage PBC model) mice were treated with Sct for 1 or 8 weeks. Bulk RNA-sequencing was performed in isolated cholangiocytes from mouse models.
Results
Biliary Sct/SR/CFTR/AE2 expression and bile bicarbonate levels were reduced in late-stage PBC mouse models and human samples. Sct treatment decreased bile duct loss, ductular reaction, inflammation, and fibrosis in late-stage PBC models. Sct reduced hepatic bile acid levels, modified bile acid composition, and restored the DCJ and ‘bicarbonate umbrella’. RNA-sequencing identified that Sct promoted mature epithelial marker expression, specifically anterior grade protein 2 (Agr2). Late-stage PBC models and human samples exhibited reduced biliary mucin 1 levels, which were enhanced by Sct treatment.
Conclusion
Loss of Sct/SR signalling in late-stage PBC results in a faulty ‘bicarbonate umbrella’ and reduced Agr2-mediated mucin production. Sct restores cholangiocyte secretory processes and DCJ formation through enhanced mature cholangiocyte phenotypes and bile duct growth. Sct treatment may be beneficial for individuals with late-stage PBC.
Impact and implications
Secretin (Sct) regulates biliary proliferation and bicarbonate secretion in cholangiocytes via its receptor, SR, and in mouse models and human samples of late-stage primary biliary cholangitis (PBC), the Sct/SR axis is blunted along with loss of the protective ‘bicarbonate umbrella’. We found that both short- and long-term Sct treatment ameliorated ductular reaction, immune cell influx, and liver fibrosis in late-stage PBC mouse models. Importantly, Sct treatment promoted bicarbonate and mucin secretion and hepatic bile acid efflux, thus reducing cholestatic and toxic bile acid-associated injury in late-stage PBC mouse models. Our work perpetuates the hypothesis that PBC pathogenesis hinges on secretory defects, and restoration of secretory processes that promote the ‘bicarbonate umbrella’ may be important for amelioration of PBC-associated damage.
中文翻译：
分泌素通过恢复分泌过程减轻晚期原发性胆汁性胆管炎期间的胆道和肝脏损伤
背景与目标
原发性胆汁性胆管炎 (PBC) 的特征是导管减少、导管反应、阴离子交换剂 2 (AE2) 和“碳酸氢盐伞”受损。假设导管-小管交界处 (DCJ) 紊乱可促进 PBC 进展。分泌素 (Sct)/分泌素受体 (SR) 轴调节囊性纤维化跨膜受体 (CFTR) 和 AE2，从而促进胆汁分泌。我们在晚期 PBC 小鼠模型和人类样本中评估了 Sct/SR 信号对胆汁分泌过程和随后损伤的作用。
方法
在 32 周龄时，雌性和雄性野生型和显性失活转化生长因子β受体 II（晚期 PBC 模型）小鼠接受 Sct 治疗 1 或 8 周。在来自小鼠模型的分离的胆管细胞中进行大量 RNA 测序。
结果
在晚期 PBC 小鼠模型和人类样本中，胆道 Sct/SR/CFTR/AE2 表达和胆汁碳酸氢盐水平降低。Sct 治疗减少了晚期 PBC 模型中的胆管丢失、导管反应、炎症和纤维化。Sct 降低了肝胆汁酸水平，改变了胆汁酸组成，并恢复了 DCJ 和“碳酸氢盐伞”。RNA 测序确定 Sct 促进成熟上皮标记物的表达，特别是前级蛋白 2 (Agr2)。晚期 PBC 模型和人体样本表现出降低的胆汁粘蛋白 1 水平，而 Sct 治疗可增强这种水平。
结论
晚期 PBC 中 Sct/SR 信号的缺失会导致“碳酸氢盐伞”故障并减少 Agr2 介导的粘蛋白产生。Sct 通过增强成熟胆管细胞表型和胆管生长来恢复胆管细胞分泌过程和 DCJ 形成。Sct 治疗可能对晚期 PBC 患者有益。
影响和启示
分泌素 (Sct) 通过其受体 SR 调节胆管细胞的胆道增殖和碳酸氢盐分泌，在小鼠模型和晚期原发性胆汁性胆管炎 (PBC) 的人体样本中，Sct/SR 轴随着保护性 '碳酸氢盐伞'。我们发现，短期和长期 Sct 治疗均可改善晚期 PBC 小鼠模型中的导管反应、免疫细胞流入和肝纤维化。重要的是，Sct 治疗促进了碳酸氢盐和粘蛋白的分泌以及肝胆汁酸的流出，从而减少了晚期 PBC 小鼠模型中胆汁淤积和毒性胆汁酸相关的损伤。我们的工作延续了 PBC 发病机制取决于分泌缺陷的假设，恢复促进“碳酸氢盐伞”的分泌过程可能对改善 PBC 相关损伤很重要。
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