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Ketanserin, a serotonin 2A receptor antagonist, alleviates ischemia‐related biliary fibrosis following donation after cardiac death liver transplantation in rats
Author(s) -
Chen Liping,
Chen Geng,
Guo Yibin,
Liu Lei,
Xiao Li,
Fan Wenmei,
Shi Bingyi,
Qian Yeyong
Publication year - 2014
Publication title -
liver transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.814
H-Index - 150
eISSN - 1527-6473
pISSN - 1527-6465
DOI - 10.1002/lt.23947
Subject(s) - ketanserin , medicine , endocrinology , liver transplantation , transplantation , fibrosis , serotonin , receptor , 5 ht receptor
Biliary fibrosis is a major complication after donation after cardiac death (DCD) liver transplantation. In this process, the roles of serotonin [5‐hydroxytryptamine (5‐HT)] and the 5‐HT2A receptor subtype are still unknown. In this study, we analyzed markers of portal fibroblast (PF)/myofibroblast (MF) transdifferentiation such as transforming growth factor β1 (TGF‐β1), phosphorylated smad2/3, α‐smooth muscle actin (α‐SMA), collagen I, and collagen III in a primary culture system of PFs after the administration of 5‐HT or 5‐HT plus ketanserin (a selective 5‐HT2A receptor antagonist). A rat DCD transplant model was established with 30 minutes of warm ischemia and 4 hours of cold ischemia during organ procurement. Recipients were intraperitoneally injected with ketanserin (1 mg·kg −1 ·day −1 ) or normal saline. Grafts without in situ warm ischemia instead of minimal cold storage (30 minutes) served as controls. The serum biochemistry, the liver contents of 5‐HT and hydroxyproline (HYP), and the expression of fibrosis‐related genes (including TGF‐β1, matrix metalloproteinase 2, procollagen α1, and α‐SMA messenger RNA) were determined. The extent of biliary fibrosis was also assessed histopathologically. The results indicated that ketanserin inhibited 5‐HT–activated TGF‐β1–smad2/3 signaling in vitro and thereby depressed the MF conversion of PFs. Rats receiving DCD livers showed increased liver contents of 5‐HT and HYP, impaired biliary function, up‐regulation of fibrosis‐related genes, and aggravated biliary fibrosis. However, these phenomena were alleviated by treatment with ketanserin. We concluded that the profibrotic activity of 5‐HT occurred through the activation of TGF‐β1 signaling and the 5‐HT2A receptor. Thus, these data suggest that the 5‐HT2A receptor may be a potential therapeutic target for ischemia‐related biliary fibrosis after DCD liver transplantation. Liver Transpl 20:1317‐1326, 2014 . © 2014 AASLD.