Activation of serotonin receptor-2B rescues small-for-size liver graft failure in mice.
The implantation of grafts below 30% of the normal liver volume is associated with a high risk of failure known as small-for-size (SFS) syndrome. Strategies to rescue small grafts may have a dramatic impact on organ shortage. Serotonin is a potent growth factor for the liver. The goal of this study was to determine whether enhanced serotonin signaling could prevent the deleterious effects of SFS syndrome. We performed 30% normal liver volume transplantations in wild-type C57/BL6 and interleukin-6 (IL-6)(-/-) mice. Some animals received α-methyl-5-HT (DOI), an agonist of serotonin receptor-2 (5-HT2B). Endpoints included long-term survival, serum and hepatic markers of liver injury and regeneration, assessment of hepatic microcirculation by intravital fluorescence microscopy and scanning electron microscopy, and transcript levels of a variety of serotonin receptors, tumor necrosis factor α, and IL-6. All recipients of small grafts (controls) died within 2-4 days of transplantation, whereas half of those receiving DOI survived permanently. Control animals disclosed major liver injury, including diffuse microvesicular steatosis in hepatocytes, impairment of microcirculation, and a failure of regeneration, whereas these parameters were dramatically improved in animals subjected to DOI. Blockage of 5-HT2B blunted the protective effects of DOI. Whereas IL-6 levels were higher in DOI-treated animals, IL-6(-/-) mice were still protected by DOI, suggesting a protective pathway independent of IL-6.


CONCLUSIONS
Serotonin through its action on receptor-2B protects SFS liver grafts from injury and prevents microcirculation and regeneration. The mechanism of hepato-protection is independent of IL-6.
Laboratory of Hepato-Biliary Surgery and Liver Transplantation, Swiss Hepato-Pancreato-Biliary Center, Department of Surgery, University Hospital Zurich, Zurich, Switzerland.
Yinghua
Y
Tian
Rolf
R
Graf
Ashraf Mohammad
AM
El-Badry
Mickaël
M
Lesurtel
Katarzyna
K
Furrer
Wolfgang
W
Moritz
Pierre-Alain
PA
Clavien
D000818:Animals; D006084:Graft Rejection / Q000188:drug therapy*; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000098:blood supply; D008115:Liver Regeneration / Q000187:drug effects*; D016031:Liver Transplantation / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism*; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015850:Interleukin-6; D044403:Receptor, Serotonin, 5-HT2B; D058826:Serotonin 5-HT2 Receptor Agonists; D014409:Tumor Necrosis Factor-alpha; C042390:alpha-methylserotonin; D012701:Serotonin