Endothelin Receptor-A Inhibition Decreases Ductular Reaction, Liver Fibrosis, and Angiogenesis in a Model of Cholangitis.
Endothelin Receptor-A Inhibition Decreases Ductular Reaction, Liver Fibrosis, and Angiogenesis in a Model of Cholangitis.
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DOI：
10.1016/j.jcmgh.2023.06.005
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发表时间：
2023
影响因子：
7.2
通讯作者：
Kennedy, Lindsey
中科院分区：
文献类型：
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作者：
Owen, Travis;Carpino, Guido;Chen, Lixian;Kundu, Debjyoti;Wills, Payton;Ekser, Burcin;Onori, Paolo;Gaudio, Eugenio;Alpini, Gianfranco;Francis, Heather;Kennedy, Lindsey
原发性硬化性胆管炎（PSC）可导致胆管反应和纤维化，并伴有血管功能障碍。胆汁淤积模型中胆管细胞和内皮细胞的相互作用调节它们的增殖。内皮素（ET）-1和ET-2与其受体ET-A结合，胆管细胞是胆管结扎后ET-1的主要来源。我们的目的是评估ET-A抑制在PSC中的治疗潜力以及该途径介导的胆汁-内皮串扰。通过每天腹膜内注射，用媒介物或安立生坦（ET-A拮抗剂）处理12周龄的野生型和多药耐药性2敲除（Mdr 2-/-）小鼠1周。使用人对照和PSC样品。在4、8和12周时的mdr 2-/-小鼠显示在12周时达到峰值的血管生成。Mdr 2-/-小鼠在12周时具有增强的胆汁ET-1/ET-2/ET-A表达和分泌，而人PSC具有增强的ET-1/ET-A表达和分泌。安立生坦可减少Mdr 2-/-小鼠的胆管损伤、免疫细胞浸润和纤维化。Mdr 2-/-小鼠有鳞状胆管细胞，微绒毛钝化，小动脉扩张，缺乏纤毛;然而，安立生坦逆转了这些变化。安立生坦通过调节cFOS降低促血管生成因子（特别是中期因子）的胆管细胞表达。在体外，ET-1/ET-A引起胆管细胞衰老、内皮细胞血管生成和巨噬细胞炎症。在体外，人PSC胆管细胞上清液增加内皮细胞迁移，这被安立生坦处理阻断。ET-A抑制减少了Mdr 2-/-小鼠的胆道和肝脏损伤。ET-A促进胆管血管分泌信号传导，其可反过来增强血管生成。靶向ET-A可以证明对PSC，特别是显示血管功能障碍的患者有治疗作用。
Primary sclerosing cholangitis (PSC) leads to ductular reaction and fibrosis and is complicated by vascular dysfunction. Cholangiocyte and endothelial cell crosstalk modulates their proliferation in cholestatic models. Endothelin (ET)-1 and ET-2 bind to their receptor, ET-A, and cholangiocytes are a key source of ET-1 after bile duct ligation. We aimed to evaluate the therapeutic potential of ET-A inhibition in PSC and biliary-endothelial crosstalk mediated by this pathway. Wild-type and multidrug resistance 2 knockout (Mdr2-/-) mice at 12 weeks of age were treated with vehicle or Ambrisentan (ET-A antagonist) for 1 week by daily intraperitoneal injections. Human control and PSC samples were used. Mdr2-/- mice at 4, 8, and 12 weeks displayed angiogenesis that peaked at 12 weeks. Mdr2-/- mice at 12 weeks had enhanced biliary ET-1/ET-2/ET-A expression and secretion, whereas human PSC had enhanced ET-1/ET-A expression and secretion. Ambrisentan reduced biliary damage, immune cell infiltration, and fibrosis in Mdr2-/- mice. Mdr2-/- mice had squamous cholangiocytes with blunted microvilli and dilated arterioles lacking cilia; however, Ambrisentan reversed these alterations. Ambrisentan decreased cholangiocyte expression of pro-angiogenic factors, specifically midkine, through the regulation of cFOS. In vitro, ET-1/ET-A caused cholangiocyte senescence, endothelial cell angiogenesis, and macrophage inflammation. In vitro, human PSC cholangiocyte supernatants increased endothelial cell migration, which was blocked with Ambrisentan treatment. ET-A inhibition reduced biliary and liver damage in Mdr2-/- mice. ET-A promotes biliary angiocrine signaling that may, in turn, enhance angiogenesis. Targeting ET-A may prove therapeutic for PSC, specifically patients displaying vascular dysfunction.
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影响因子：
21.1
作者：
Davenport AP;Hyndman KA;Dhaun N;Southan C;Kohan DE;Pollock JS;Pollock DM;Webb DJ;Maguire JJ
通讯作者：
Maguire JJ
影响因子：
13.5
作者：
Bahde, Ralf;Kapoor, Sorabh;Viswanathan, Preeti;Spiegel, Hans-Ullrich;Gupta, Sanjeev
通讯作者：
Gupta, Sanjeev
DOI：
10.1186/1476-5926-5-5
发表时间：
2006-10-24
期刊：
Comparative hepatology
影响因子：
--
作者：
Koda M;Bauer M;Krebs A;Hahn EG;Schuppan D;Murawaki Y
通讯作者：
Murawaki Y
影响因子：
9.5
作者：
Browatzki, M;Schmidt, J;Kranzhöfer, R
通讯作者：
Kranzhöfer, R
DOI：
10.1186/1476-5926-5-9
发表时间：
2006-12-05
期刊：
Comparative hepatology
影响因子：
--
作者：
De Gottardi, Andrea;Biecker, Erwin;Reichen, Jurg
通讯作者：
Reichen, Jurg