Liver regeneration is promoted by increasing serotonin content in rat liver with secondary biliary cirrhosis

Nagao, Yuhei; Akahoshi, Tomohiko; Kamori, Masahiro; Uehara, Hideo; Hashimoto, Noriyuki; Kinjo, Nao; Shirabe, Ken; Taketomi, Akinobu; Tomikawa, Morimasa; Hashizume, Makoto; Maehara, Yoshihiko

doi:10.1111/j.1872-034x.2011.00828.x

Cited by 22 publications

(22 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Accordingly, we observed significantly increased expression of major profibrogenic transcripts (eg, MMP2 , procollagen α1, TGF‐β1 , and α‐SMA ) that are strongly related to biliary fibrosis and nonanastomotic biliary stricture development . Moreover, ketanserin alleviated biliary fibrosis 4 weeks after the operation, as demonstrated by the reduction in collagen fibers and α‐SMA–positive MFs in the portal area as well as the down‐regulation of fibrosis‐related genes and HYP content in liver grafts.…”

Section: Discussionmentioning

confidence: 75%

“…The secretion of TGF‐β1 was measured in PF culture supernatants with a rat TGF‐β1 enzyme‐linked immunosorbent assay kit (BioSource‐Invitrogen, Carlsbad, CA) according to the manufacturer's instructions. Serotonin levels in liver homogenates were also determined 1 day, 3 days, 1 week, 2 weeks, and 4 weeks after liver transplantation with a rat 5‐HT enzyme‐linked immunosorbent assay kit (IBL International, Hamburg, Germany) . Protein concentrations were determined according to the Bradford method with a protein assay kit (Bio‐Rad Laboratories, Inc., Hercules, CA).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Ketanserin, a serotonin 2A receptor antagonist, alleviates ischemia-related biliary fibrosis following donation after cardiac death liver transplantation in rats

Chen

Guo

et al. 2014

Liver Transpl

View full text Add to dashboard Cite

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 b1 (TGF-b1), phosphorylated smad2/3, a-smooth muscle actin (a-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 mgÁkg 21 Áday 21 ) 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-b1, matrix metalloproteinase 2, procollagen a1, and a-SMA messenger RNA) were determined. The extent of biliary fibrosis was also assessed histopathologically. The results indicated that ketanserin inhibited 5-HT-activated TGF-b1-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-b1 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. V C 2014 AASLD.Received March 30, 2014; accepted July 2, 2014.The worldwide organ shortage has led to the increased use of donation after cardiac death (DCD) livers. Because of the additional warm ischemia before preservation, DCD liver grafts are at higher risk for failure and bile duct injury. Currently, DCD liver grafts are the most common cause of nonanastomotic biliary strictures, which are characterized as biliary strictures and dilatation at any location in the biliary system of the transplanted liver.1,2 They are associated with an increased incidence of biliary sludge, recurrent Abbreviations: 5-HT, 5-hydroxytryptamine; 5-HT1K, 5-hydroxytryptamine and ketanserin; a-SMA, a-smooth muscle actin; ALP, alkaline phosphatase; BECs, biliary epithelial cells; DCD, donation after cardiac death; GGT, gamma-glutamyl transpeptidase; HSC, hepatic stellate cell; HYP, hydroxyproline; MF, myofibroblast; MMP2, matrix metalloproteinase 2; mRNA, messenger RNA; PF, portal fibroblast; PI, proliferation index; p-smad, phosphorylated drosophila mothers against decapentaplegic protein; RTqPCR, quantitative real-time reverse-transcr...

show abstract

Section: Discussionmentioning

confidence: 75%

Section: Methodsmentioning

confidence: 99%

Ketanserin, a serotonin 2A receptor antagonist, alleviates ischemia-related biliary fibrosis following donation after cardiac death liver transplantation in rats

Chen

Guo

et al. 2014

Liver Transpl

View full text Add to dashboard Cite

show abstract

“…It has been reported that splenectomy improves liver regeneration after PH [15e18]. The splenectomy affects platelet activation, portal blood flow, and oxygen supply [15,28,29]. Indeed, Ren et al [15] reported that splenectomy improved liver regeneration in the rat.…”

Section: 2mentioning

confidence: 97%

Interleukin-17A plays a pivotal role after partial hepatectomy in mice

Furuya

Kono

Hara

et al. 2013

Journal of Surgical Research

View full text Add to dashboard Cite

“…While similar findings after splenectomy have been reported [5,21], only a few reports have described changes in liver function tests during long-term follow up after splenectomy in patients with HCC and advanced cirrhosis. The causes of these improvements in liver function following splenectomy may be due to the following: a reduction in bilirubin overload by the removal of a huge spleen with damaged red blood cells [5], the removal of spleenderived inhibitors of liver regeneration, such as transforming growth factor-β1 [22], and the enhanced production of promoters for liver regeneration, such as platelet-derived serotonin [23]. It is also possible that the beneficial effects observed in the liver because of splenectomy may be due to IFN therapy.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Outcome of Splenectomy in Advanced Cirrhotic Patients with Hepatocellular Carcinoma and Thrombocytopenia

et al. 2013

View full text Add to dashboard Cite

Summary: Splenectomy may be a treatment option in hepatocellular carcinoma (HCC) and cirrhosis when there is no potential donor for liver transplantation. We retrospectively investigated the long-term outcome of splenectomy on survival in advanced cirrhotic patients with HCC and thrombocytopenia. Between 1999 and 2009, 46 cirrhotic patients with thrombocytopenia (Child-Pugh class B or C) who underwent splenectomy for the simultaneous or secondary treatment of HCC at our institute were evaluated. The 1-, 3-, and 5-year survival rates were 93.5, 76.0, and 37.9%, respectively. Splenectomy resulted in a significant reduction in mean portal venous pressure from 21.2 to 16.8 mmHg and improvements in liver function tests such as total bilirubin, prothrombin time, platelet count, Child-Pugh score for 3 years, and albumin for 2 years. The mean frequency of treatment for HCC recurrence after surgery was 3.0 times (range 1-11). Seven patients out of 16 scheduled for Interferon (IFN) therapy after surgery achieved a sustained virological response (SVR). Multivariate analysis identified SVR after IFN therapy as an independent significant prognostic factor (Hazard ratio 0.18, 95%CI 0.03-0.65, P=0.006). Postoperative complications including liver failure (n=1), portal thrombosis (n=7), ascites (n=5), and bacterial infections (n=4) were observed in 14 patients (30%). Splenectomy can be a feasible supportive therapy for the continuation of anticancer therapy and completion of IFN therapy based on improvements in liver function and thrombocytopenia with minimum complications in patients with HCC and advanced cirrhosis with no potential donor.

show abstract

Liver regeneration is promoted by increasing serotonin content in rat liver with secondary biliary cirrhosis

Abstract: Our results showed that splenectomy promoted liver regeneration by increasing serotonin content in liver even under cirrhotic conditions.

Cited by 22 publications

References 41 publications

Ketanserin, a serotonin 2A receptor antagonist, alleviates ischemia-related biliary fibrosis following donation after cardiac death liver transplantation in rats

Ketanserin, a serotonin 2A receptor antagonist, alleviates ischemia-related biliary fibrosis following donation after cardiac death liver transplantation in rats

Interleukin-17A plays a pivotal role after partial hepatectomy in mice

Long-Term Outcome of Splenectomy in Advanced Cirrhotic Patients with Hepatocellular Carcinoma and Thrombocytopenia

Contact Info

Product

Resources

About