PMID- 18398622
OWN - NLM
STAT- MEDLINE
DCOM- 20080731
LR  - 20211020
IS  - 0945-6317 (Print)
IS  - 0945-6317 (Linking)
VI  - 452
IP  - 5
DP  - 2008 May
TI  - Impact of rapamycin on liver regeneration.
PG  - 545-57
LID - 10.1007/s00428-008-0604-y [doi]
AB  - 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.
FAU - Palmes, Daniel
AU  - Palmes D
AD  - Surgical Research, Department of General Surgery, Muenster University Hospital, 
      Waldeyerstr. 1, 48149 Muenster, Germany.
FAU - Zibert, Andree
AU  - Zibert A
FAU - Budny, Tymotheus
AU  - Budny T
FAU - Bahde, Ralf
AU  - Bahde R
FAU - Minin, Evgeny
AU  - Minin E
FAU - Kebschull, Linus
AU  - Kebschull L
FAU - Holzen, Jens
AU  - Holzen J
FAU - Schmidt, Hartmut
AU  - Schmidt H
FAU - Spiegel, Hans-Ullrich
AU  - Spiegel HU
LA  - eng
PT  - Journal Article
PL  - Germany
TA  - Virchows Arch
JT  - Virchows Archiv : an international journal of pathology
JID - 9423843
RN  - 0 (Actins)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (smooth muscle actin, rat)
RN  - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-1)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Actins/metabolism
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Cell Proliferation/*drug effects
MH  - Hepatectomy
MH  - Hepatocytes/cytology/drug effects/metabolism
MH  - Immunosuppressive Agents/*pharmacology
MH  - Liver/cytology/drug effects/metabolism
MH  - Liver Regeneration/*drug effects/physiology
MH  - Male
MH  - Models, Animal
MH  - Neovascularization, Physiologic/drug effects
MH  - Rats
MH  - Rats, Inbred Lew
MH  - Sirolimus/*pharmacology
MH  - Vascular Endothelial Growth Factor A/metabolism
MH  - Vascular Endothelial Growth Factor Receptor-1/metabolism
EDAT- 2008/04/10 09:00
MHDA- 2008/08/01 09:00
CRDT- 2008/04/10 09:00
PHST- 2007/11/05 00:00 [received]
PHST- 2008/02/29 00:00 [accepted]
PHST- 2008/02/12 00:00 [revised]
PHST- 2008/04/10 09:00 [pubmed]
PHST- 2008/08/01 09:00 [medline]
PHST- 2008/04/10 09:00 [entrez]
AID - 10.1007/s00428-008-0604-y [doi]
PST - ppublish
SO  - Virchows Arch. 2008 May;452(5):545-57. doi: 10.1007/s00428-008-0604-y.