Sphingosine-1-phosphate receptor-3 is a novel biomarker in acute lung injury

Xiaoguang Sun, Patrick A. Singleton, Eleftheria Letsiou, Jing Zhao, Patrick Belvitch, Saad Sammani, Eddie T. Chiang, Liliana Moreno-Vinasco, Michael S. Wade, Tong Zhou, Bin Liu, Ioannis Parastatidis, Leonor Thomson, Harry Ischiropoulos, Viswanathan Natarajan, Jeffrey R. Jacobson, Roberto F. MacHado, Steven M. Dudek, Joe G.N. Garcia

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

The inflamed lung exhibits oxidative and nitrative modifications of multiple target proteins, potentially reflecting disease severity and progression. We identified sphingosine-1-phosphate receptor-3 (S1PR3), a critical signaling molecule mediating cell proliferation and vascular permeability, as a nitrated plasma protein in mice with acute lung injury (ALI). We explored S1PR3 as a potential biomarker in murine and human ALI. In vivo nitrated and total S1PR3 concentrations were determined by immunoprecipitation and microarray studies in mice, and by ELISA in human plasma. In vitro nitrated S1PR3 concentrations were evaluated in human lung vascular endothelial cells (ECs) or within microparticles shed from ECs after exposure to barrier-disrupting agonists (LPS, low-molecular-weight hyaluronan, and thrombin). The effects of S1PR3-containingmicroparticles on EC barrier function were assessed by transendothelial electrical resistance (TER). Nitrated S1PR3 was identified in the plasma of murine ALI and in humans with severe sepsis-induced ALI. Elevated total S1PR3 plasma concentrations (> 251 pg/ml) were linked to sepsis and ALI mortality. In vitro EC exposure to barrierdisrupting agents induced S1PR3 nitration and the shedding of S1PR3-containing microparticles, which significantly reduced TER, consistent with increased permeability. These changes were attenuated by reduced S1PR3 expression (small interfering RNAs). These results suggest that microparticles containing nitrated S1PR3 shed into the circulation during inflammatory lung states, and represent a novel ALI biomarker linked to disease severity and outcome.

Original languageEnglish (US)
Pages (from-to)628-636
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume47
Issue number5
DOIs
StatePublished - Nov 1 2012

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Keywords

  • Acute lung injury
  • Biomarker
  • Microparticles
  • Nitration
  • Sphingosine-1-phosphate receptor-3

ASJC Scopus subject areas

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

Cite this

Sun, X., Singleton, P. A., Letsiou, E., Zhao, J., Belvitch, P., Sammani, S., Chiang, E. T., Moreno-Vinasco, L., Wade, M. S., Zhou, T., Liu, B., Parastatidis, I., Thomson, L., Ischiropoulos, H., Natarajan, V., Jacobson, J. R., MacHado, R. F., Dudek, S. M., & Garcia, J. G. N. (2012). Sphingosine-1-phosphate receptor-3 is a novel biomarker in acute lung injury. American journal of respiratory cell and molecular biology, 47(5), 628-636. https://doi.org/10.1165/rcmb.2012-0048OC