Inhibition of mast cell-secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2−/− mice

Hannah Jones, Laura Hargrove, Lindsey Kennedy, Fanyin Meng, Allyson Graf-Eaton, Jennifer Owens, Gianfranco Alpini, Christopher Johnson, Francesca Bernuzzi, Jennifer Demieville, Sharon DeMorrow, Pietro Invernizzi, Heather Francis

Research output: Contribution to journalArticle

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Abstract

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. Wild-type and multidrug resistance 2 knockout 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 cytokeratin 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 quantitative polymerase chain reaction for alpha-smooth muscle actin, fibronectin, collagen type 1a, and transforming growth factor-beta 1. HSC activation was evaluated by quantitative polymerase chain reaction in total liver and immunofluorescent staining in tissues for synaptophysin 9. Histamine serum secretion was measured by enzymatic immunoassay. Mouse liver and human liver samples from control or primary sclerosing cholangitis patients were evaluated for MC markers by quantitative polymerase chain reaction and immunohistochemistry. In vitro, cultured MCs were transfected with histidine decarboxylase short hairpin RNA to decrease histamine secretion and subsequently cocultured with cholangiocytes or HSCs prior to measuring fibrosis markers, proliferation, and transforming growth factor-beta 1 secretion. Treatment with cromolyn sodium decreased biliary proliferation, fibrosis, histamine secretion, and bile flow in multidrug resistance 2 knockout mice. Primary sclerosing cholangitis mice and patients have increased MCs. Knockdown of MC histidine decarboxylase decreased cholangiocyte and HSC proliferation/activation. Conclusion: MCs are recruited to proliferating cholangiocytes and promote fibrosis. Inhibition of MC-derived histamine decreases fibrosis, and regulation of MC mediators may be therapeutic for primary sclerosing cholangitis. (Hepatology 2016;64:1202-1216).

Original languageEnglish (US)
Pages (from-to)1202-1216
Number of pages15
JournalHepatology
Volume64
Issue number4
DOIs
StatePublished - Oct 1 2016
Externally publishedYes

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Sclerosing Cholangitis
Mast Cells
Histamine
Fibrosis
Hepatic Stellate Cells
Liver
Histidine Decarboxylase
Cromolyn Sodium
Multiple Drug Resistance
Knockout Mice
Bile
Transforming Growth Factor beta
Polymerase Chain Reaction
Immunohistochemistry
Staining and Labeling
Keratin-19
Synaptophysin
Histamine Release
Wounds and Injuries
Gastroenterology

ASJC Scopus subject areas

  • Hepatology

Cite this

Jones, H., Hargrove, L., Kennedy, L., Meng, F., Graf-Eaton, A., Owens, J., ... Francis, H. (2016). Inhibition of mast cell-secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2−/− mice. Hepatology, 64(4), 1202-1216. https://doi.org/10.1002/hep.28704

Inhibition of mast cell-secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2−/− mice. / 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.

In: Hepatology, Vol. 64, No. 4, 01.10.2016, p. 1202-1216.

Research output: Contribution to journalArticle

Jones, H, Hargrove, L, Kennedy, L, Meng, F, Graf-Eaton, A, Owens, J, Alpini, G, Johnson, C, Bernuzzi, F, Demieville, J, DeMorrow, S, Invernizzi, P & Francis, H 2016, 'Inhibition of mast cell-secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2−/− mice', Hepatology, vol. 64, no. 4, pp. 1202-1216. https://doi.org/10.1002/hep.28704
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. / Inhibition of mast cell-secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2−/− mice. In: Hepatology. 2016 ; Vol. 64, No. 4. pp. 1202-1216.
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abstract = "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. Wild-type and multidrug resistance 2 knockout 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 cytokeratin 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 quantitative polymerase chain reaction for alpha-smooth muscle actin, fibronectin, collagen type 1a, and transforming growth factor-beta 1. HSC activation was evaluated by quantitative polymerase chain reaction in total liver and immunofluorescent staining in tissues for synaptophysin 9. Histamine serum secretion was measured by enzymatic immunoassay. Mouse liver and human liver samples from control or primary sclerosing cholangitis patients were evaluated for MC markers by quantitative polymerase chain reaction and immunohistochemistry. In vitro, cultured MCs were transfected with histidine decarboxylase short hairpin RNA to decrease histamine secretion and subsequently cocultured with cholangiocytes or HSCs prior to measuring fibrosis markers, proliferation, and transforming growth factor-beta 1 secretion. Treatment with cromolyn sodium decreased biliary proliferation, fibrosis, histamine secretion, and bile flow in multidrug resistance 2 knockout mice. Primary sclerosing cholangitis mice and patients have increased MCs. Knockdown of MC histidine decarboxylase decreased cholangiocyte and HSC proliferation/activation. Conclusion: MCs are recruited to proliferating cholangiocytes and promote fibrosis. Inhibition of MC-derived histamine decreases fibrosis, and regulation of MC mediators may be therapeutic for primary sclerosing cholangitis. (Hepatology 2016;64:1202-1216).",
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AU - Graf-Eaton, Allyson

AU - Owens, Jennifer

AU - Alpini, Gianfranco

AU - Johnson, Christopher

AU - Bernuzzi, Francesca

AU - Demieville, Jennifer

AU - DeMorrow, Sharon

AU - Invernizzi, Pietro

AU - Francis, Heather

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AB - 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. Wild-type and multidrug resistance 2 knockout 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 cytokeratin 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 quantitative polymerase chain reaction for alpha-smooth muscle actin, fibronectin, collagen type 1a, and transforming growth factor-beta 1. HSC activation was evaluated by quantitative polymerase chain reaction in total liver and immunofluorescent staining in tissues for synaptophysin 9. Histamine serum secretion was measured by enzymatic immunoassay. Mouse liver and human liver samples from control or primary sclerosing cholangitis patients were evaluated for MC markers by quantitative polymerase chain reaction and immunohistochemistry. In vitro, cultured MCs were transfected with histidine decarboxylase short hairpin RNA to decrease histamine secretion and subsequently cocultured with cholangiocytes or HSCs prior to measuring fibrosis markers, proliferation, and transforming growth factor-beta 1 secretion. Treatment with cromolyn sodium decreased biliary proliferation, fibrosis, histamine secretion, and bile flow in multidrug resistance 2 knockout mice. Primary sclerosing cholangitis mice and patients have increased MCs. Knockdown of MC histidine decarboxylase decreased cholangiocyte and HSC proliferation/activation. Conclusion: MCs are recruited to proliferating cholangiocytes and promote fibrosis. Inhibition of MC-derived histamine decreases fibrosis, and regulation of MC mediators may be therapeutic for primary sclerosing cholangitis. (Hepatology 2016;64:1202-1216).

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