The family of serotonin receptors is subdivided into seven subgroups. These receptors

have been grouped according to their genetic and structural similarities and also according to the intracellular signaling pathways associated with each receptor. Serotonin regulates hepatic function and response to injury, blood flow, and proliferation of hepatocyte.14 In further studies, we could not detect any negative impact of serotonin in a model of ischemia/reperfusion injury. In contrast, we identified a new role for serotonin in tissue repair following ischemic injury.15 We therefore hypothesize that serotonin rescues liver regeneration after implantation of a small graft without enhancing the inherent ischemic damage, and thereby prevents SFS syndrome. 5-HT, 5-hydroxytryptamine; Navitoclax 5-HT2B, serotonin receptor-2B; AST, aspartate aminotransferase; DOI, α-methyl-5-HT; IL-6, interleukin-6; OLT, orthotopic liver transplantation; PCNA, proliferating cell nuclear antigen; PTX, pentoxifylline; SEC, sinusoidal endothelial cell; SFS, small-for-size; TNF-α, tumor necrosis factor α. Male inbred C57BL/6 mice were purchased from Harlan, Netherlands, IL-6−/−

mice with C57BL/6 background were obtained from selleck chemicals Jackson Laboratory and used as syngeneic transplant donors and recipients. Animals were kept in accordance with the guidelines of the University of Zurich Animal Care Committee. The protocol of the study was approved by the Cantonal Veterinary office of Zurich. All mice were kept in a temperature-controlled environment

with a 12-hour light/dark cycle and with free access to food and tap water. We performed 30% partial OLTs in mice using techniques described previously.10 Some mice received a 25% OLT graft consisting of the right liver lobe. The recipient mice were divided into two groups: (1) α-methyl-5-HT (DOI, an agonist of the serotonin receptor and (2) a control group. DOI (1 mg/kg dissolved in saline) was given intravenously immediately following reperfusion of the partial enough liver graft. Subsequently, recipients were injected subcutaneously twice a day for 2 days postoperatively. In control recipients, the same amount of vehicle solution was administered. Recipients were sacrificed at 1 hour, 3 hours, 2 days, or 7 days postoperatively. Hepatic regeneration, aspartate aminotransferase (AST) levels in serum, transcript levels of 5-HT2 receptors, IL-6, TNF-α in liver grafts, histology, scanning electron microscopy, and intravital microscopy were evaluated. In separate series of experiments, the recipient survival rates of 7 days after transplantation were tested. Some animals were treated with an antagonist of the 5-HT2B receptor: SB206553 (3 mg/kg) was injected subcutaneously into the donor and recipient before surgery and twice a day for 2 days after transplantation. Tissues were immersion-fixed in 4% buffered formalin and embedded in paraffin wax, then sectioned, and stained with hematoxylin-eosin.