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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Blocking H1/H2 histamine receptors inhibits damage/fibrosis in Mdr2 –/– –/– mice and human cholangiocarcinoma tumorigenesis
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Blocking H1/H2 histamine receptors inhibits damage/fibrosis in Mdr2 –/– –/– mice and human cholangiocarcinoma tumorigenesis

机译：阻断H1 / H2组胺受体抑制MDR2 - / - / - 小鼠和人胆管癌肿瘤发生中的损伤/纤维化

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Primary sclerosing cholangitis (PSC) patients are at risk of developing cholangiocarcinoma (CCA). We have shown that (1) histamine increases biliary hyperplasia through H1/H2 histamine receptors (HRs) and (2) histamine levels increase and mast cells (MCs) infiltrate during PSC and CCA. We examined the effects of chronic treatment with H1/H2HR antagonists on PSC and CCA. Wild‐type and multidrug‐resistant knockout (Mdr2 –/– ) mice were treated by osmotic minipumps with saline, mepyramine, or ranitidine (10 mg/kg body weight/day) or a combination of mepyramine/ranitidine for 4 weeks. Liver damage was assessed by hematoxylin and eosin. We evaluated (1) H1/H2HR expression, (2) MC presence, (3) L‐histidine decarboxylase/histamine axis, (4) cholangiocyte proliferation/bile duct mass, and (5) fibrosis/hepatic stellate cell activation. Nu/nu mice were implanted with Mz‐ChA‐1 cells into the hind flanks and treated with saline, mepyramine, or ranitidine. Tumor growth was measured, and (1) H1/H2HR expression, (2) proliferation, (3) MC activation, (4) angiogenesis, and (5) epithelial–mesenchymal transition (EMT) were evaluated. In vitro, human hepatic stellate cells were evaluated for H1HR and H2HR expression. Cultured cholangiocytes and CCA lines were treated with saline, mepyramine, or ranitidine (25 μM) before evaluating proliferation, angiogenesis, EMT, and potential signaling mechanisms. H1/H2HR and MC presence increased in human PSC and CCA. In H1/H2HR antagonist (alone or in combination)–treated Mdr2 –/– mice, liver and biliary damage and fibrosis decreased compared to saline treatment. H1/H2HR antagonists decreased tumor growth, serum histamine, angiogenesis, and EMT. In vitro, H1/H2HR blockers reduced biliary proliferation, and CCA cells had decreased proliferation, angiogenesis, EMT, and migration. Conclusion : Inhibition of H1/H2HR reverses PSC‐associated damage and decreases CCA growth, angiogenesis, and EMT; because PSC patients are at risk of developing CCA, using HR blockers may be therapeutic for these diseases. (H epatology 2018).
机译：初级硬化性胆管炎（PSC）患者有发展胆管癌（CCA）的风险。我们已经表明，（1）组胺通过H1 / H 2组胺受体（HRS）和（2）组胺水平增加和肥大细胞（MCS）浸润在PSC和CCA期间的胆汁细胞增多增加。我们检查了在PSC和CCA上对H1 / H2HR拮抗剂的慢性治疗的影响。通过渗透微型泵（MDR2 - / - ）小鼠用盐水，甲嘧胺或雷尼氨基（10mg / kg体重/天）或梅勒胺/雷尼酸酯的组合处理野生型和多药抗敲除（MDR2 - / - ）小鼠4周。通过苏木精和曙红评估肝损伤。我们评估（1）H1 / H2HR表达，（2）MC存在，（3）L-组氨酸脱羧酶/组胺轴，（4）胆管细胞增殖/胆管肿块，（5）纤维化/肝星状细胞活化。将Nu / Nu小鼠用Mz-CHA-1细胞植入后侧面，并用盐水，甲嘧胺或雷硝酸盐处理。测量肿瘤生长，（1）H1 / H 2 HR表达，（2）增殖，（3）MC活化，（4）血管生成，和（5）上皮 - 间充质转换（EMT）。在体外，对H1HR和H2HR表达评估人肝星状细胞。在评估增殖，血管生成，EMT和潜在的信号传导机制之前，用盐水，甲嘧胺或雷尼氨酸（25μm）处理培养的胆管细胞和CCA系。 H1 / H2HR和MC存在在人PSC和CCA中增加。在H1 / H2HR拮抗剂（单独或组合）中 - 与盐水处理相比，治疗的MDR2 - / - 小鼠，肝脏和胆损伤和纤维化降低。 H1 / H2HR拮抗剂降低肿瘤生长，血清组胺，血管生成和EMT。体外，H1 / H2HR阻滞剂降低了胆道增殖，CCA细胞增殖降低，血管生成，EMT和迁移降低。结论：抑制H1 / H2HR逆转PSC相关损伤，降低CCA生长，血管生成和EMT;因为PSC患者面临CCA的风险，所以使用HR阻滞剂可能是这些疾病的治疗方法。 （2018年Hopatology）。

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