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.