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Activation of serotonin receptor-2B rescues small-for-size liver graft failure in mice


Tian, Y; Graf, R; El-Badry, A M; Lesurtel, M; Furrer, K; Moritz, W; Clavien, P A (2011). Activation of serotonin receptor-2B rescues small-for-size liver graft failure in mice. Hepatology, 53(1):253-62.

Abstract

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. CONCLUSION: 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.

Abstract

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. CONCLUSION: 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Division of Surgical Research
04 Faculty of Medicine > University Hospital Zurich > Clinic for Visceral and Transplantation Surgery
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2011
Deposited On:18 Feb 2011 08:13
Last Modified:07 Dec 2017 07:22
Publisher:Wiley-Blackwell
ISSN:0270-9139
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1002/hep.23960
PubMed ID:21254175

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