Impact of rapamycin on liver regeneration.

The remarkable capacity of the liver to regenerate after injury and the prospects of organ self-renewal have attracted much interest in the understanding and modulation of the underlying molecular events. We investigated the effect of mammalian target of rapamycin (mTOR) inhibitor rapamycin (RAPA) on liver by correlating intravital microscopy, immunohistochemistry, and reverse transcriptase polymerase chain reaction in a rat model of 2/3 hepatectomy. RAPA significantly retarded proliferation of hepatocytes, endothelial cells, and hepatic stellate cells (HSCs) mostly between days 2 and 4 after hepatectomy and downregulated major cytokines and growth factors (tumor necrosis factor alpha, hepatocyte growth factor, platelet-derived growth factor, platelet-derived growth factor receptor, insulin-like growth factor-1, transforming growth factor beta 1) important for liver regeneration. These effects were almost absent at later time points. RAPA also had a transient, but broad effect on angiogenesis, and impaired sinusoidal density as well as mRNA levels of vascular endothelial growth factor, vascular endothelial growth factor receptor 1, vascular endothelial growth factor receptor 2, and angiopoietin-1. Activation of HSC was also transiently suppressed as observed by smooth muscle protein 1 alpha protein expression and intercellular adhesion molecule-1 mRNA levels. The rate of apoptosis in liver was significantly increased by RAPA between day 3 and day 7. The effect of RAPA on liver repair, angiogenesis, and HSC activation is confined to the phase of active cell proliferation. This transient effect might allow further exploration of mTOR inhibitors in clinical situations that involve liver regeneration, and seems to have implications beyond immunosuppression.

Endothelin-A receptor antagonist reduces microcirculatory disturbances and transplant dysfunction after partial liver transplantation.

Endothelin-1 can induce microcirculatory disorders by mediating sinusoidal vasoconstriction, lowering the perfusion rate and promoting leukocyte adhesion, all of which may play a role in the pathogenesis of the damage sustained by partial liver transplants. In this pilot study, we investigated a selective endothelin-A receptor antagonist (Darusentan; Knoll GmbH, Ludwigshafen, Germany) for its potential influence on the microcirculation in the setting of partial liver transplantation. One hundred and forty isogeneic Lewis rats were divided into four groups: 1. partial liver transplantation (30% of the initial liver volume); 2. partial liver transplantation treated with Darusentan (1 mg/kg bodyweight intravenously) immediately before reperfusion; 3. full-size liver transplantation; and 4. sham operation. Subsequently, the liver microcirculation was evaluated by intravital microscopy, and survival, liver function, and morphology were followed up to the fourteenth day. Compared with full-size transplanted animals, rats subjected to partial liver transplantation without Darusentan (group I) displayed severe microcirculatory lesions characterized by a significantly decreased perfusion rate, increased leukocyte velocity, and increased leukocyte adhesion. Disintegration of endothelium and increased recruitment of Kupffer cells were frequent morphologic findings. The Darusentan-treated group II showed improved parameters of microcirculatory function and morphology as well as improved liver function. Microcirculatory disturbances play a key role in the pathogenesis of partial liver transplant dysfunction. Treatment with selective endothelin-A receptor antagonists represent a new therapeutic approach to improve the function of partial liver transplants by reducing microcirculatory lesions and their sequelae affecting sinusoidal endothelium and hepatocytes.