PMID- 24700614
OWN - NLM
STAT- MEDLINE
DCOM- 20150511
LR  - 20140925
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 60
IP  - 4
DP  - 2014 Oct
TI  - Systemic protection through remote ischemic preconditioning is spread by 
      platelet-dependent signaling in mice.
PG  - 1409-17
LID - 10.1002/hep.27089 [doi]
AB  - Remote ischemic preconditioning (RIPC), the repetitive transient mechanical 
      obstruction of vessels at a limb remote to the operative site, is a novel 
      strategy to mitigate distant organ injury associated with surgery. In the clinic, 
      RIPC has demonstrated efficacy in protecting various organs against ischemia 
      reperfusion (IR), but a common mechanism underlying the systemic protection has 
      not been identified. Here, we reasoned that protection may rely on adaptive 
      physiological responses toward local stress, as is incurred through RIPC. 
      Standardized mouse models of partial hepatic IR and of RIPC to the femoral 
      vascular bundle were applied. The roles of platelets, peripheral serotonin, and 
      circulating vascular endothelial growth factor (Vegf) were studied in 
      thrombocytopenic mice, Tph1(-) (/) (-) mice, and through neutralizing antibodies, 
      respectively. Models of interleukin-10 (Il10) and matrix metalloproteinase 8 
      (Mmp8) deficiency were used to assess downstream effectors of organ protection. 
      The protection against hepatic IR through RIPC was dependent on platelet-derived 
      serotonin. Downstream of serotonin, systemic protection was spread through 
      up-regulation of circulating Vegf. Both RIPC and serotonin-Vegf induced 
      differential gene expression in target organs, with Il10 and Mmp8 displaying 
      consistent up-regulation across all organs investigated. Concerted inhibition of 
      both molecules abolished the protective effects of RIPC. RIPC was able to 
      mitigate pancreatitis, indicating that it can protect beyond ischemic insults. 
      CONCLUSIONS: We have identified a platelet-serotonin-Vegf-Il10/Mmp8 axis that 
      mediates the protective effects of RIPC. The systemic action, the conservation of 
      RIPC effects among mice and humans, and the protection beyond ischemic insults 
      suggest that the platelet-dependent axis has evolved as a preemptive response to 
      local stress, priming the body against impending harm.
CI  - (c) 2014 by the American Association for the Study of Liver Diseases.
FAU - Oberkofler, Christian E
AU  - Oberkofler CE
AD  - Laboratory of the Swiss Hepato-Pancreatico-Biliary (HPB) Center, Department of 
      Surgery, University Hospital Zurich, Zurich, Switzerland.
FAU - Limani, Perparim
AU  - Limani P
FAU - Jang, Jae-Hwi
AU  - Jang JH
FAU - Rickenbacher, Andreas
AU  - Rickenbacher A
FAU - Lehmann, Kuno
AU  - Lehmann K
FAU - Raptis, Dimitri A
AU  - Raptis DA
FAU - Ungethuem, Udo
AU  - Ungethuem U
FAU - Tian, Yinghua
AU  - Tian Y
FAU - Grabliauskaite, Kamile
AU  - Grabliauskaite K
FAU - Humar, Rok
AU  - Humar R
FAU - Graf, Rolf
AU  - Graf R
FAU - Humar, Bostjan
AU  - Humar B
FAU - Clavien, Pierre-Alain
AU  - Clavien PA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140813
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 130068-27-8 (Interleukin-10)
RN  - 333DO1RDJY (Serotonin)
RN  - EC 1.14.16.4 (Tph1 protein, mouse)
RN  - EC 1.14.16.4 (Tryptophan Hydroxylase)
RN  - EC 3.4.24.34 (MMP8 protein, mouse)
RN  - EC 3.4.24.34 (Matrix Metalloproteinase 8)
SB  - IM
CIN - Hepatology. 2014 Oct;60(4):1136-8. PMID: 24668800
MH  - Animals
MH  - Blood Platelets/*physiology
MH  - Disease Models, Animal
MH  - Interleukin-10/deficiency/genetics/metabolism
MH  - Ischemic Preconditioning/*methods
MH  - Liver/*blood supply
MH  - Matrix Metalloproteinase 8/deficiency/genetics/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Reperfusion Injury/*physiopathology/*prevention & control
MH  - Serotonin/deficiency/genetics/metabolism
MH  - Signal Transduction/*physiology
MH  - Thrombocytopenia/metabolism/pathology/physiopathology
MH  - Tryptophan Hydroxylase/deficiency/genetics/metabolism
MH  - Vascular Endothelial Growth Factor A/deficiency/genetics/metabolism
EDAT- 2014/04/05 06:00
MHDA- 2015/05/12 06:00
CRDT- 2014/04/05 06:00
PHST- 2013/09/04 00:00 [received]
PHST- 2014/02/19 00:00 [accepted]
PHST- 2014/04/05 06:00 [entrez]
PHST- 2014/04/05 06:00 [pubmed]
PHST- 2015/05/12 06:00 [medline]
AID - 10.1002/hep.27089 [doi]
PST - ppublish
SO  - Hepatology. 2014 Oct;60(4):1409-17. doi: 10.1002/hep.27089. Epub 2014 Aug 13.