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新型缺乏 l-组氨酸脱羧酶/组氨酸信号的小鼠模型可改善胆汁损伤和肝纤维化。

Biliary damage and liver fibrosis are ameliorated in a novel mouse model lacking l-histidine decarboxylase/histamine signaling.

机构信息

Richard L. Roudebush VA Medical Center, and Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.

Central Texas Veterans Health Care System, Temple, TX, USA.

出版信息

Lab Invest. 2020 Jun;100(6):837-848. doi: 10.1038/s41374-020-0405-8. Epub 2020 Feb 13.

DOI:10.1038/s41374-020-0405-8
PMID:32054995
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7286781/
Abstract

Primary sclerosing cholangitis (PSC) is characterized by biliary damage and fibrosis. Multidrug resistance-2 gene knockout (Mdr2) mice and PSC patients have increased histamine (HA) levels (synthesized by l-histidine decarboxylase, HDC) and HA receptor (HR) expression. Cholestatic HDC mice display ameliorated biliary damage and hepatic fibrosis. The current study evaluated the effects of knockout of HDC in Mdr2 mice (DKO) on biliary damage and hepatic fibrosis. WT, Mdr2 mice, and homozygous DKO mice were used. Selected DKO mice were treated with HA. We evaluated liver damage along with HDC expression and HA serum levels. Changes in ductular reaction were evaluated along with liver fibrosis, inflammation and bile acid signaling pathways. The expression of H1HR/PKC-α/TGF-β1 and H2HR/pERK/VEGF-C was determined. In vitro, cholangiocyte lines were treated with HA with/without H1/H2 inhibitors before measuring: H1/H2HR, TGF-β1, and VEGF-C expression. Knockout of HDC ameliorates hepatic damage, ductular reaction, fibrosis, inflammation, bile acid signaling and H1HR/PKC-α/TGF-β1 and H2HR/pERK/VEGF-C signaling. Reactivation of the HDC/HA axis increased these parameters. In vitro, stimulation with HA increased HR expression and PKC-α, TGF-β1, and VEGF-C expression, which was reduced with HR inhibitors. Our data demonstrate the key role for the HDC/HA axis in the management of PSC progression.

摘要

原发性硬化性胆管炎 (PSC) 的特征是胆道损伤和纤维化。多药耐药基因 2 敲除 (Mdr2) 小鼠和 PSC 患者的组织胺 (HA) 水平升高（由 l-组氨酸脱羧酶 HDC 合成），且 HA 受体 (HR) 表达增加。胆淤积性 HDC 小鼠的胆道损伤和肝纤维化程度减轻。本研究评估了 Mdr2 小鼠（DKO）中 HDC 敲除对胆道损伤和肝纤维化的影响。使用 WT、Mdr2 小鼠和纯合 DKO 小鼠。选择 DKO 小鼠进行 HA 处理。我们评估了肝损伤以及 HDC 表达和 HA 血清水平。评估了胆管反应的变化以及肝纤维化、炎症和胆汁酸信号通路。测定了 H1HR/PKC-α/TGF-β1 和 H2HR/pERK/VEGF-C 的表达。在体外，用 HA 处理胆管细胞系，然后用 H1/H2 抑制剂处理，然后测量 H1/H2HR、TGF-β1 和 VEGF-C 的表达。HDC 敲除可改善肝损伤、胆管反应、纤维化、炎症、胆汁酸信号和 H1HR/PKC-α/TGF-β1 和 H2HR/pERK/VEGF-C 信号。HDC/HA 轴的再激活增加了这些参数。在体外，HA 刺激增加了 HR 表达和 PKC-α、TGF-β1 和 VEGF-C 的表达，HR 抑制剂可降低这些表达。我们的数据表明，HDC/HA 轴在 PSC 进展的管理中起着关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace1/7286781/3fbb5639efef/nihms-1550400-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace1/7286781/65a89dd50c17/nihms-1550400-f0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace1/7286781/633fc90c8ad2/nihms-1550400-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace1/7286781/3fbb5639efef/nihms-1550400-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace1/7286781/65a89dd50c17/nihms-1550400-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace1/7286781/5fcab19239b1/nihms-1550400-f0002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace1/7286781/633fc90c8ad2/nihms-1550400-f0006.jpg
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