| Sphingosine kinase inhibition alleviates endothelial permeability induced by thrombin and activated neutrophils. | |
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MedLine Citation:
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PMID: 19851125 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Kiyoshi Itagaki; Qin Zhang; Carl J Hauser |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Shock (Augusta, Ga.) Volume: 33 ISSN: 1540-0514 ISO Abbreviation: Shock Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-22 Completed Date: 2010-07-19 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9421564 Medline TA: Shock Country: United States |
Other Details:
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Languages: eng Pagination: 381-6 Citation Subset: IM |
Affiliation:
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Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. kitagaki@bidmc.harvard.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Aminophenols
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pharmacology Calcium / metabolism Capillary Permeability / drug effects* Cells, Cultured Computer Systems Endothelial Cells / metabolism Gadolinium / pharmacology Humans Neutrophils / metabolism, physiology* Nitrendipine / analogs & derivatives, pharmacology Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors* Sphingosine / analogs & derivatives, pharmacology Thapsigargin / pharmacology Thiazoles / pharmacology Thrombin / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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R01GM059179/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/4-(4-(4-chlorophenyl)thiazol-2-ylamino)phenol; 0/Aminophenols; 0/MRS 1845; 0/Thiazoles; 122314-67-4/N,N-dimethylsphingosine; 123-78-4/Sphingosine; 39562-70-4/Nitrendipine; 67526-95-8/Thapsigargin; 7440-54-2/Gadolinium; 7440-70-2/Calcium; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC 2.7.1.-/sphingosine kinase; EC 3.4.21.5/Thrombin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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