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.
Palmes
Daniel
D
Surgical Research, Department of General Surgery, Muenster University Hospital, Waldeyerstr. 1, 48149 Muenster, Germany.
Zibert
Andree
A
Budny
Tymotheus
T
Bahde
Ralf
R
Minin
Evgeny
E
Kebschull
Linus
L
Hölzen
Jens
J
Schmidt
Hartmut
H
Spiegel
Hans-Ullrich
HU
D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects* / Q000502:physiology; D008297:Male; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
D000199:Actins; D007166:Immunosuppressive Agents; D020123:Sirolimus; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; C498862:Acta2 protein, rat