Role of sphingolipids in murine radiation-induced lung injury: Protection by sphingosine 1-phosphate analogs

Biji Mathew, Jeffrey R. Jacobson, Evgeny Berdyshev, Yong Huang, Xiaoguang Sun, Yutong Zhao, Lynnette M. Gerhold, Jessica Siegler, Carrie Evenoski, Ting Wang, Tong Zhou, Rafe Zaidi, Liliana Moreno-Vinasco, Robert Bittman, Chin Tu Chen, Patrick J. LaRiviere, Saad Sammani, Yves A. Lussier, Steven M. Dudek, Viswanathan NatarajanRalph R. Weichselbaum, Joe G.N. Garcia

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Clinically significant radiation-induced lung injury (RILI) is a common toxicity in patients administered thoracic radiotherapy. Although the molecular etiology is poorly understood, we previously characterized a murine model of RILI in which alterations in lung barrier integrity surfaced as a potentially important pathobiological event and genome-wide lung gene mRNA levels identified dysregulation of sphingolipid metabolic pathway genes. We hypothesized that sphingolipid signaling components serve as modulators and novel therapeutic targets of RILI. Sphingolipid involvement in murine RILI was confirmed by radiation-induced increases in lung expression of sphingosine kinase (SphK) isoforms 1 and 2 and increases in the ratio of ceramide to sphingosine 1-phosphate (S1P) and dihydro-S1P (DHS1P) levels in plasma, bronchoalveolar lavage fluid, and lung tissue. Mice with a targeted deletion of SphK1 (SphK1 -/-) or with reduced expression of S1P receptors (S1PR1 +/-, S1PR2 -/-, and S1PR3 -/-) exhibited marked RILI susceptibility. Finally, studies of 3 potent vascular barrier-protective S1P analogs, FTY720, (S)-FTY720-phosphonate (fTyS), and SEW-2871, identified significant RILI attenuation and radiation-induced gene dysregulation by the phosphonate analog, fTyS (0.1 and 1 mg/kg i.p., 2x/wk) and to a lesser degree by SEW-2871 (1 mg/kg i.p., 2x/wk), compared with those in controls. These results support the targeting of S1P signaling as a novel therapeutic strategy in RILI.

Original languageEnglish (US)
Pages (from-to)3388-3400
Number of pages13
JournalFASEB Journal
Volume25
Issue number10
DOIs
StatePublished - Oct 2011

Keywords

  • FTY720
  • Gene dysregulation
  • S1P receptors
  • fTysiponate

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Mathew, B., Jacobson, J. R., Berdyshev, E., Huang, Y., Sun, X., Zhao, Y., Gerhold, L. M., Siegler, J., Evenoski, C., Wang, T., Zhou, T., Zaidi, R., Moreno-Vinasco, L., Bittman, R., Chen, C. T., LaRiviere, P. J., Sammani, S., Lussier, Y. A., Dudek, S. M., ... Garcia, J. G. N. (2011). Role of sphingolipids in murine radiation-induced lung injury: Protection by sphingosine 1-phosphate analogs. FASEB Journal, 25(10), 3388-3400. https://doi.org/10.1096/fj.11-183970