title: Sphingosine-1-phosphate, FTY720, and sphingosine-1-phosphate receptors in the pathobiology of acute lung injury.
abstract: 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.
authors: Department of Pharmacology, University of Illinois, Chicago, IL 60612, USA. visnatar@uic.edu
authors: Viswanathan
authors: V
authors: Natarajan
authors: Steven M
authors: SM
authors: Dudek
authors: Jeffrey R
authors: JR
authors: Jacobson
authors: Liliana
authors: L
authors: Moreno-Vinasco
authors: Long Shuang
authors: LS
authors: Huang
authors: Taimur
authors: T
authors: Abassi
authors: Biji
authors: B
authors: Mathew
authors: Yutong
authors: Y
authors: Zhao
authors: Lichun
authors: L
authors: Wang
authors: Robert
authors: R
authors: Bittman
authors: Ralph
authors: R
authors: Weichselbaum
authors: Evgeny
authors: E
authors: Berdyshev
authors: Joe G N
authors: JG
authors: Garcia
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy / Q000503:physiopathology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D002199:Capillary Permeability; D000068876:Fingolimod Hydrochloride; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000503:physiopathology; D008246:Lysophospholipids / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D011014:Pneumonia / Q000378:metabolism / Q000473:pathology; D011409:Propylene Glycols / Q000627:therapeutic use*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D018805:Sepsis / Q000378:metabolism / Q000473:pathology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism; D057170:Translational Research, Biomedical; D000099157:Sphingosine Kinase
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D000068876:Fingolimod Hydrochloride; D008246:Lysophospholipids; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D017855:Transferases (Other Substituted Phosphate Groups); D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C455440:SGMS1 protein, human