Sphingosine-1-phosphate, FTY720, and sphingosine-1-phosphate receptors in the pathobiology of acute lung injury

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

Research output: Contribution to journalReview article

78 Scopus citations

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 othershave demonstratedthatS1P 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.

Original languageEnglish (US)
Pages (from-to)6-17
Number of pages12
JournalAmerican journal of respiratory cell and molecular biology
Volume49
Issue number1
DOIs
StatePublished - Jul 2013

Keywords

  • S1P lyase
  • S1P receptors
  • Sepsis
  • Sphingolipids
  • Sphingosine kinase

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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  • Cite this

    Natarajan, V., Dudek, S. M., Jacobson, J. R., Moreno-Vinasco, L., Huang, L. S., Abassi, T., Mathew, B., Zhao, Y., Wang, L., Bittman, R., Weichselbaum, R., Berdyshev, E., & Garcia, J. G. N. (2013). Sphingosine-1-phosphate, FTY720, and sphingosine-1-phosphate receptors in the pathobiology of acute lung injury. American journal of respiratory cell and molecular biology, 49(1), 6-17. https://doi.org/10.1165/rcmb.2012-0411TR