Cholangiocyte endothelin 1 and transforming growth factor β1 production in rat experimental hepatopulmonary syndrome

Bao Luo, Liping Tang, Zhishan Wang, Junlan Zhang, Yiqun Ling, Wenguang Feng, Ju Zhong Sun, Cecil R. Stockard, Andra R. Frost, Yiu Fai Chen, William E. Grizzle, Michael B. Fallon

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

Background & Aims: Hepatic production and release of endothelin 1 plays a central role in experimental hepatopulmonary syndrome after common bile duct ligation by stimulating pulmonary endothelial nitric oxide production. In thioacetamide-induced nonbiliary cirrhosis, hepatic endothelin 1 production and release do not occur, and hepatopulmonary syndrome does not develop. However, the source and regulation of hepatic endothelin 1 after common bile duct ligation are not fully characterized. We evaluated the sources of hepatic endothelin 1 production after common bile duct ligation in relation to thioacetamide cirrhosis and assessed whether transforming growth factor β1 regulates endothelin 1 production. Methods: Hepatopulmonary syndrome and hepatic and plasma endothelin 1 levels were evaluated after common bile duct ligation or thioacetamide administration. Cellular sources of endothelin 1 were assessed by immunohistochemistry and laser capture microdissection of cholangiocytes. Transforming growth factor β1 expression and signaling were assessed by using immunohistochemistry and Western blotting and by evaluating normal rat cholangiocytes. Results: Hepatic and plasma endothelin 1 levels increased and hepatopulmonary syndrome developed only after common bile duct ligation. Hepatic endothelin 1 and transforming growth factor β1 levels increased over a similar time frame, and cholangiocytes were a major source of each peptide. Transforming growth factor β1 signaling in cholangiocytes in vivo was evident by increased phosphorylation and nuclear localization of Smad2, and hepatic endothelin 1 levels correlated directly with liver transforming growth factor β1 and phosphorylated Smad2 levels. Transforming growth factor β1 also stimulated endothelin 1 promoter activity, expression, and production in normal rat cholangiocytes. Conclusions: Cholangiocytes are a major source of hepatic endothelin 1 production during the development of hepatopulmonary syndrome after common bile duct ligation, but not in thioacetamide-induced cirrhosis. Transforming growth factor β1 stimulates cholangiocyte endothelin 1 expression and production. Cholangiocyte-derived endothelin 1 may be an important endocrine mediator of experimental hepatopulmonary syndrome.

Original languageEnglish (US)
Pages (from-to)682-695
Number of pages14
JournalGastroenterology
Volume129
Issue number2
DOIs
StatePublished - Aug 2005
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Luo, B., Tang, L., Wang, Z., Zhang, J., Ling, Y., Feng, W., Sun, J. Z., Stockard, C. R., Frost, A. R., Chen, Y. F., Grizzle, W. E., & Fallon, M. B. (2005). Cholangiocyte endothelin 1 and transforming growth factor β1 production in rat experimental hepatopulmonary syndrome. Gastroenterology, 129(2), 682-695. https://doi.org/10.1016/j.gastro.2005.05.050