Bile duct ligation-induced biliary hyperplasia, hepatic injury, and fibrosis are reduced in mast cell-deficient Kit W-sh mice.

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  • Additional Information
    • Source:
      Publisher: Wolters Kluwer Health, Inc Country of Publication: United States NLM ID: 8302946 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1527-3350 (Electronic) Linking ISSN: 02709139 NLM ISO Abbreviation: Hepatology Subsets: MEDLINE
    • Publication Information:
      Publication: 2023- : [Philadelphia] : Wolters Kluwer Health, Inc.
      Original Publication: Baltimore, MD : Williams & Wilkins, [c1981]-
    • Subject Terms:
      Biliary Tract Diseases/*pathology ; Liver/*injuries ; Liver Cirrhosis/*pathology ; Mast Cells/*transplantation ; Vascular Endothelial Growth Factor A/*metabolism; Animals ; Apoptosis ; Bile Ducts, Intrahepatic/surgery ; Biliary Tract Diseases/physiopathology ; Biopsy, Needle ; Cell Proliferation ; Cells, Cultured ; Disease Models, Animal ; Hepatic Stellate Cells/metabolism ; Hepatic Stellate Cells/pathology ; Hyperplasia/pathology ; Immunohistochemistry ; Ligation/methods ; Liver/pathology ; Male ; Mast Cells/cytology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Random Allocation ; Reference Values
    • Abstract:
      Activated mast cells (MCs) release histamine (HA) and MCs infiltrate the liver following bile duct ligation (BDL), increasing intrahepatic bile duct mass (IBDM) and fibrosis. We evaluated the effects of BDL in MC-deficient (Kit W-sh ) mice. Wild-type (WT) and Kit W-sh mice were subjected to sham or BDL for up to 7 days and Kit W-sh mice were injected with cultured mast cells or 1× phosphate-buffered saline (PBS) before collecting serum, liver, and cholangiocytes. Liver damage was assessed by hematoxylin and eosin and alanine aminotransferase levels. IBDM was detected by cytokeratin-19 expression and proliferation by Ki-67 immunohistochemistry (IHC). Fibrosis was detected by IHC, hydroxyproline content, and by qPCR for fibrotic markers. Hepatic stellate cell (HSC) activation and transforming growth factor-beta 1 (TGF-β1) expression/secretion were evaluated. Histidine decarboxylase (HDC) and histamine receptor (HR) expression were detected by qPCR and HA secretion by enzymatic immunoassay. To evaluate vascular cells, von Willebrand factor (vWF) and vascular endothelial growth factor (VEGF)-C expression were measured. In vitro, cultured HSCs were stimulated with cholangiocyte supernatants and alpha-smooth muscle actin levels were measured. BDL-induced liver damage was reduced in BDL Kit W-sh mice, whereas injection of MCs did not mimic BDL-induced damage. In BDL Kit W-sh mice, IBDM, proliferation, HSC activation/fibrosis, and TGF-β1 expression/secretion were decreased. The HDC/HA/HR axis was ablated in sham and BDL Kit W-sh mice. vWF and VEGF-C expression decreased in BDL Kit W-sh mice. In Kit W-sh mice injected with MCs, IBDM, proliferation, fibrosis, and vascular cell activation increased. Stimulation with cholangiocyte supernatants from BDL WT or Kit W-sh mice injected with MCs increased HSC activation, which decreased with supernatants from BDL Kit W-sh mice.
      Conclusion: MCs promote hyperplasia, fibrosis, and vascular cell activation. Knockout of MCs decreases BDL-induced damage. Modulation of MCs may be important in developing therapeutics for cholangiopathies. (Hepatology 2017;65:1991-2004).
      (© 2017 by the American Association for the Study of Liver Diseases. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)
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    • Grant Information:
      R01 DK108959 United States DK NIDDK NIH HHS; R01 DK082435 United States DK NIDDK NIH HHS; I01 BX001724 United States BX BLRD VA; I01 BX003031 United States BX BLRD VA; I01 BX002638 United States BX BLRD VA
    • Accession Number:
      0 (Vascular Endothelial Growth Factor A)
    • Publication Date:
      Date Created: 20170126 Date Completed: 20170901 Latest Revision: 20181113
    • Publication Date:
      20231215
    • Accession Number:
      PMC5444972
    • Accession Number:
      10.1002/hep.29079
    • Accession Number:
      28120369