PMID- 19851125
OWN - NLM
STAT- MEDLINE
DCOM- 20100719
LR  - 20161125
IS  - 1540-0514 (Electronic)
IS  - 1073-2322 (Linking)
VI  - 33
IP  - 4
DP  - 2010 Apr
TI  - Sphingosine kinase inhibition alleviates endothelial permeability induced by 
      thrombin and activated neutrophils.
PG  - 381-6
LID - 10.1097/SHK.0b013e3181c6bb75 [doi]
AB  - Inflammation and microvascular thrombosis are interrelated causes of acute lung 
      injury in the systemic inflammatory response syndrome. Neutrophils 
      (polymorphonuclear neutrophil [PMN]) and endothelial cells (EC) activated by 
      systemic inflammatory response syndrome interact to increase pulmonary vascular 
      permeability, but the interactions between PMN and EC are difficult to study. 
      Recently, we reported that sphingosine 1-phosphate is a second messenger 
      eliciting store-operated calcium entry (SOCE) in response to inflammatory 
      agonists in both PMN and EC. Store-operated calcium entry is therefore a target 
      mechanism for the therapeutic modulation of inflammatory PMN-EC interactions. 
      Here, we isolated, modeled, and studied the effects of pharmacologic SOCE 
      inhibition using real-time systems to monitor EC permeability after exposure to 
      activated PMN. We created systems to continuously assess permeability of human 
      pulmonary artery endothelial cells and human microvascular endothelial cells from 
      lung. Endothelial cells show increased permeability after challenge by activated 
      PMN. Such permeability increases can be attenuated by exposure of the cocultures 
      to sphingosine kinase (SK) inhibitors (SKI-2, N,N-dimethylsphingosine [DMS]) or 
      Ca2+ entry inhibitors (Gd3+, MRS-1845). Human microvascular endothelial cells 
      from lung pretreated with SKI-2 or DMS showed decreased permeability when later 
      exposed to activated PMN. Likewise, when PMNs were activated with thapsigargin 
      (TG) in the presence of SKI-2, DMS, Gd, or MRS-1845, their ability to cause EC 
      permeability subsequently was reduced. SKI-2 also inhibited the activation of 
      human pulmonary artery ECs by thrombin. These studies will provide a firm 
      mechanistic foundation for understanding how systemic SOCE inhibition may be used 
      to prevent acute lung injury in vivo.
FAU - Itagaki, Kiyoshi
AU  - Itagaki K
AD  - Department of Surgery, Beth Israel Deaconess Medical Center, Boston, 
      Massachusetts 02215, USA. kitagaki@bidmc.harvard.edu
FAU - Zhang, Qin
AU  - Zhang Q
FAU - Hauser, Carl J
AU  - Hauser CJ
LA  - eng
GR  - R01GM059179/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Shock
JT  - Shock (Augusta, Ga.)
JID - 9421564
RN  - 0 (4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol)
RN  - 0 (Aminophenols)
RN  - 0 (MRS 1845)
RN  - 0 (Thiazoles)
RN  - 67526-95-8 (Thapsigargin)
RN  - 9B627AW319 (Nitrendipine)
RN  - AU0V1LM3JT (Gadolinium)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.- (sphingosine kinase)
RN  - EC 3.4.21.5 (Thrombin)
RN  - L9QRA71834 (N,N-dimethylsphingosine)
RN  - NGZ37HRE42 (Sphingosine)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Aminophenols/pharmacology
MH  - Calcium/metabolism
MH  - Capillary Permeability/*drug effects
MH  - Cells, Cultured
MH  - Computer Systems
MH  - Endothelial Cells/metabolism
MH  - Gadolinium/pharmacology
MH  - Humans
MH  - Neutrophils/metabolism/*physiology
MH  - Nitrendipine/analogs & derivatives/pharmacology
MH  - Phosphotransferases (Alcohol Group Acceptor)/*antagonists & inhibitors
MH  - Sphingosine/analogs & derivatives/pharmacology
MH  - Thapsigargin/pharmacology
MH  - Thiazoles/pharmacology
MH  - Thrombin/*pharmacology
EDAT- 2009/10/24 06:00
MHDA- 2010/07/20 06:00
CRDT- 2009/10/24 06:00
PHST- 2009/10/24 06:00 [entrez]
PHST- 2009/10/24 06:00 [pubmed]
PHST- 2010/07/20 06:00 [medline]
AID - 10.1097/SHK.0b013e3181c6bb75 [doi]
PST - ppublish
SO  - Shock. 2010 Apr;33(4):381-6. doi: 10.1097/SHK.0b013e3181c6bb75.