title: Ketanserin, a serotonin 2A receptor antagonist, alleviates ischemia-related biliary fibrosis following donation after cardiac death liver transplantation in rats.
abstract: 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.
authors.affiliation: Institute of Organ Transplantation, the 309th Hospital of Chinese People's Liberation Army, Beijing, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Chen
authors.forename: Geng
authors.initials: G
authors.lastname: Chen
authors.forename: Yibin
authors.initials: Y
authors.lastname: Guo
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Xiao
authors.forename: Wenmei
authors.initials: W
authors.lastname: Fan
authors.forename: Bingyi
authors.initials: B
authors.lastname: Shi
authors.forename: Yeyong
authors.initials: Y
authors.lastname: Qian
mesh_terms: D000818:Animals; D001660:Biliary Tract Diseases / Q000209:etiology / Q000517:prevention & control*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D007511:Ischemia / Q000150:complications; D007650:Ketanserin / Q000494:pharmacology / Q000627:therapeutic use*; D008099:Liver / Q000098:blood supply / Q000166:cytology / Q000378:metabolism; D016031:Liver Transplantation; D008297:Male; D011183:Postoperative Complications / Q000209:etiology / Q000517:prevention & control*; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D058830:Serotonin 5-HT2 Receptor Antagonists; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D012701:Serotonin; D007650:Ketanserin