Inhibition of mast cell-secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2(-/-) mice.
Inhibition of mast cell-secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2(-/-) mice.
复制标题
DOI：
10.1002/hep.28704
复制
发表时间：
2016-10
期刊：
影响因子：
13.5
通讯作者：
Francis, Heather
中科院分区：
文献类型：
--
作者：
Jones, Hannah;Hargrove, Laura;Kennedy, Lindsey;Meng, Fanyin;Graf-Eaton, Allyson;Owens, Jennifer;Alpini, Gianfranco;Johnson, Christopher;Bernuzzi, Francesca;Demieville, Jennifer;DeMorrow, Sharon;Invernizzi, Pietro;Francis, Heather
肝纤维化以肝星状细胞（HSC）的活化为标志。胆汁淤积性损伤先于肝纤维化，胆管细胞与HSC相互作用促进纤维化。肥大细胞（MC）浸润后，肝损伤和释放组胺增加胆汁增殖。我们评估了MC衍生的组胺的抑制是否降低了胆汁增殖和纤维化。WT和Mdr 2 −/−小鼠（9-11周）用克罗埃因钠处理1周，以阻断MC衍生的组胺。通过CK-19和Ki-67的免疫组织化学评价胆管质量和增殖。在所有小鼠中测量胆汁流量、碳酸氢盐排泄和总胆汁酸。通过天狼星红/Fast绿色染色和α-SMA、纤连蛋白、1a型胶原和TGF-β1的qPCR评价纤维化。通过在总肝脏中的qPCR和在组织中的突触体蛋白9的免疫荧光染色来评价HSC活化。EIA法测定血清组胺分泌量。通过qPCR和免疫组织化学评价来自对照或PSC患者的小鼠肝脏和人肝脏样品的MC标志物。在体外，培养的MC用HDC shRNA转染以减少组胺分泌，随后与胆管细胞或HSC共培养，然后测量纤维化标志物、增殖和TGF-β1分泌。克罗埃因钠治疗可降低Mdr 2 −/−小鼠的胆汁增殖、纤维化、组胺分泌和胆汁流量。PSC小鼠和患者具有增加的MC。MC-HDC的敲低降低了胆管细胞和HSC的增殖/活化。MC被募集以增殖胆管细胞并促进纤维化。抑制MC衍生的组胺可减少纤维化，调节MC介质可能是PSC的治疗方法。
Hepatic fibrosis is marked by activation of hepatic stellate cells (HSCs). Cholestatic injury precedes liver fibrosis and cholangiocytes interact with HSCs promoting fibrosis. Mast cells (MCs) infiltrate following liver injury and release histamine increasing biliary proliferation. We evaluated if inhibition of MC-derived histamine decreases biliary proliferation and fibrosis. WT and Mdr2−/− mice (9-11 weeks) were treated with cromolyn sodium for 1 week to block MC-derived histamine. Biliary mass and proliferation were evaluated by immunohistochemistry for CK-19 and Ki-67. Bile flow, bicarbonate excretion and total bile acids were measured in all mice. Fibrosis was evaluated by Sirius Red/Fast Green staining and by qPCR for α-SMA, fibronectin, collagen type 1a and TGF-β1. HSC activation was evaluated by qPCR in total liver and immunofluorescent staining in tissues for synaptophysin 9. Histamine serum secretion was measured by EIA. Mouse liver and human liver samples from control or PSC patients were evaluated for MC markers by qPCR and immunohistochemistry. In vitro, cultured MCs were transfected with HDC shRNA to decrease histamine secretion and subsequently co-cultured with cholangiocytes or HSCs prior to measuring fibrosis markers, proliferation and TGF-β1 secretion. Treatment with cromolyn sodium decreased biliary proliferation, fibrosis, histamine secretion, and bile flow in Mdr2−/− mice. PSC mice and patients have increased MCs. Knockdown of MC HDC decreased cholangiocyte and HSC proliferation/activation. MCs are recruited to proliferating cholangiocytes and promote fibrosis. Inhibition of MC-derived histamine decreases fibrosis and regulation of MC mediators may be a therapeutic for PSC.
登录
查看更多内容
姜黄素通过抑制胆管细胞炎症反应和门户肌纤维细胞增殖来改善MDR2 - / - 小鼠中的硬化性胆管炎。
影响因子：
24.5
作者：
Baghdasaryan A;Claudel T;Kosters A;Gumhold J;Silbert D;Thüringer A;Leski K;Fickert P;Karpen SJ;Trauner M
通讯作者：
Trauner M
影响因子：
24.5
作者：
GITTLEN, SD;SCHULMAN, ES;MADDREY, WC
通讯作者：
MADDREY, WC
影响因子：
9.6
作者：
Bartelds, Beatrijs;van Loon, Rosa Laura E.;Berger, Rolf M. F.
通讯作者：
Berger, Rolf M. F.
影响因子：
5
作者：
Kennedy, Lindsey L.;Hargrove, Laura A.;Francis, Heather L.
通讯作者：
Francis, Heather L.
影响因子：
5
作者：
Koda, W;Harada, K;Nakanuma, Y
通讯作者：
Nakanuma, Y