Document Detail

Sphingosine-1-phosphate, FTY720, and sphingosine-1-phosphate receptors in the pathobiology of acute lung injury.
MedLine Citation:
PMID:  23449739     Owner:  NLM     Status:  MEDLINE    
Acute lung injury (ALI) attributable to sepsis or mechanical ventilation and subacute lung injury because of ionizing radiation (RILI) share profound increases in vascular permeability as a key element and a common pathway driving increased morbidity and mortality. Unfortunately, despite advances in the understanding of lung pathophysiology, specific therapies do not yet exist for the treatment of ALI or RILI, or for the alleviation of unremitting pulmonary leakage, which serves as a defining feature of the illness. A critical need exists for new mechanistic insights that can lead to novel strategies, biomarkers, and therapies to reduce lung injury. Sphingosine 1-phosphate (S1P) is a naturally occurring bioactive sphingolipid that acts extracellularly via its G protein-coupled S1P1-5 as well as intracellularly on various targets. S1P-mediated cellular responses are regulated by the synthesis of S1P, catalyzed by sphingosine kinases 1 and 2, and by the degradation of S1P mediated by lipid phosphate phosphatases, S1P phosphatases, and S1P lyase. We and others have demonstrated that S1P is a potent angiogenic factor that enhances lung endothelial cell integrity and an inhibitor of vascular permeability and alveolar flooding in preclinical animal models of ALI. In addition to S1P, S1P analogues such as 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720), FTY720 phosphate, and FTY720 phosphonates offer therapeutic potential in murine models of lung injury. This translational review summarizes the roles of S1P, S1P analogues, S1P-metabolizing enzymes, and S1P receptors in the pathophysiology of lung injury, with particular emphasis on the development of potential novel biomarkers and S1P-based therapies for ALI and RILI.
Viswanathan Natarajan; Steven M Dudek; Jeffrey R Jacobson; Liliana Moreno-Vinasco; Long Shuang Huang; Taimur Abassi; Biji Mathew; Yutong Zhao; Lichun Wang; Robert Bittman; Ralph Weichselbaum; Evgeny Berdyshev; Joe G N Garcia
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Review    
Journal Detail:
Title:  American journal of respiratory cell and molecular biology     Volume:  49     ISSN:  1535-4989     ISO Abbreviation:  Am. J. Respir. Cell Mol. Biol.     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-07-02     Completed Date:  2013-09-04     Revised Date:  2014-07-01    
Medline Journal Info:
Nlm Unique ID:  8917225     Medline TA:  Am J Respir Cell Mol Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6-17     Citation Subset:  IM    
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MeSH Terms
Acute Lung Injury / drug therapy,  physiopathology*
Anti-Inflammatory Agents / therapeutic use
Biological Markers / metabolism
Capillary Permeability
Lung / blood supply,  physiopathology
Lysophospholipids / metabolism*
Membrane Proteins / genetics,  metabolism
Nerve Tissue Proteins / genetics,  metabolism
Phosphotransferases (Alcohol Group Acceptor) / genetics,  metabolism
Pneumonia / metabolism,  pathology
Propylene Glycols / therapeutic use*
Receptors, Lysosphingolipid / metabolism*
Sepsis / metabolism,  pathology
Sphingosine / analogs & derivatives*,  metabolism,  therapeutic use
Transferases (Other Substituted Phosphate Groups) / genetics,  metabolism
Translational Medical Research
Grant Support
Reg. No./Substance:
0/Anti-Inflammatory Agents; 0/Biological Markers; 0/Lysophospholipids; 0/Membrane Proteins; 0/Nerve Tissue Proteins; 0/Propylene Glycols; 0/Receptors, Lysosphingolipid; 26993-30-6/sphingosine 1-phosphate; 3QN8BYN5QF/fingolimod; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC 2.7.1.-/sphingosine kinase; EC 2.7.8.-/SGMS1 protein, human; EC 2.7.8.-/Transferases (Other Substituted Phosphate Groups); NGZ37HRE42/Sphingosine

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