title: Sphingosine-1-phosphate receptor-3 is a novel biomarker in acute lung injury.
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-containing microparticles 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 barrier-disrupting 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.
authors: Institute for Personalized Respiratory Medicine, College of Medicine, University of Illinois at Chicago, 914 South Wood St., MC 719, Chicago, IL 60637, USA.
authors: Xiaoguang
authors: X
authors: Sun
authors: Patrick A
authors: PA
authors: Singleton
authors: Eleftheria
authors: E
authors: Letsiou
authors: Jing
authors: J
authors: Zhao
authors: Patrick
authors: P
authors: Belvitch
authors: Saad
authors: S
authors: Sammani
authors: Eddie T
authors: ET
authors: Chiang
authors: Liliana
authors: L
authors: Moreno-Vinasco
authors: Michael S
authors: MS
authors: Wade
authors: Tong
authors: T
authors: Zhou
authors: Bin
authors: B
authors: Liu
authors: Ioannis
authors: I
authors: Parastatidis
authors: Leonor
authors: L
authors: Thomson
authors: Harry
authors: H
authors: Ischiropoulos
authors: Viswanathan
authors: V
authors: Natarajan
authors: Jeffrey R
authors: JR
authors: Jacobson
authors: Roberto F
authors: RF
authors: Machado
authors: Steven M
authors: SM
authors: Dudek
authors: Joe G N
authors: JG
authors: Garcia
mesh_terms: D055371:Acute Lung Injury / Q000097:blood* / Q000276:immunology / Q000401:mortality; D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002199:Capillary Permeability; D016022:Case-Control Studies; D055252:Cell-Derived Microparticles / Q000378:metabolism; D002478:Cells, Cultured; D017097:Electric Impedance; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D011651:Pulmonary Artery / Q000473:pathology; D034622:RNA Interference; D049349:Receptors, Lysosphingolipid / Q000097:blood* / Q000235:genetics; D000081025:Sphingosine-1-Phosphate Receptors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood; D055397:Ventilator-Induced Lung Injury / Q000378:metabolism
chemical_list: D015415:Biomarkers; D008070:Lipopolysaccharides; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; C577483:sphingosine-1-phosphate receptor-3, human; C002744:3-nitrotyrosine; D014443:Tyrosine