title: Sphingosine-1-phosphate is increased in patients with idiopathic pulmonary fibrosis and mediates epithelial to mesenchymal transition.
abstract: BACKGROUND
  Idiopathic pulmonary fibrosis (IPF) is characterised by the aberrant epithelial to mesenchymal transition (EMT) and myofibroblast accumulation. Sphingosine-1-phosphate (S1P) and sphingosine kinase 1 (SPHK1) have been implicated in lung myofibroblast transition, but their role in EMT and their expression in patients with IPF is unknown.
  
  
  RESULTS
  S1P levels were measured in serum (n=27) and bronchoalveolar lavage (BAL; n=15) from patients with IPF and controls (n=30 for serum and n=15 for BAL studies). SPHK1 expression was measured in lung tissue from patients with IPF (n=12) and controls (n=15). Alveolar type II transformation into mesenchymal cells was studied in response to S1P (10(-9)-10(-5) M). The median (IQR) of S1P serum levels was increased in patients with IPF (1.4 (0.4) μM) versus controls (1 (0.26) μM; p<0.0001). BAL S1P levels were increased in patients with IPF (1.12 (0.53) μM) versus controls (0.2 (0.5); p<0.0001) and correlated with diffusion capacity of the lung for carbon monoxide, forced expiratory volume in 1 s and forced vital capacity (Spearman's r=-0.87, -0.72 and -0.68, respectively) in patients with IPF. SPHK1 was upregulated in lung tissue from patients with IPF and correlated with α-smooth muscle actin, vimentin and collagen type I (Spearman's r=0.82, 0.85 and 0.72, respectively). S1P induced EMT in alveolar type II cells by interacting with S1P(2) and S1P(3), as well as by the activation of p-Smad3, RhoA-GTP, oxidative stress and transforming growth factor-β1 (TGF-β1) release. Furthermore, TGF-β1-induced EMT was partially conducted by the S1P/SPHK1 activation, suggesting crosstalk between TGF-β1 and the S1P/SPHK1 axis.
  
  
  CONCLUSIONS
  S1P is elevated in patients with IPF, correlates with the lung function and mediates EMT.
authors: Research foundation, University General Hospital Consortium, Valencia, Spain. xmilara@hotmail.com
authors: Javier
authors: J
authors: Milara
authors: Rafael
authors: R
authors: Navarro
authors: Gustavo
authors: G
authors: Juan
authors: Teresa
authors: T
authors: Peiró
authors: Adela
authors: A
authors: Serrano
authors: Mercedes
authors: M
authors: Ramón
authors: Esteban
authors: E
authors: Morcillo
authors: Julio
authors: J
authors: Cortijo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016022:Case-Control Studies; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology*; D008168:Lung / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000473:pathology / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D051900:Smad3 Protein / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000502:physiology; D000099157:Sphingosine Kinase
chemical_list: D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D017382:Reactive Oxygen Species; D051900:Smad3 Protein; D013110:Sphingosine; D053773:Transforming Growth Factor beta1; D020742:rhoA GTP-Binding Protein; D000099157:Sphingosine Kinase; C497790:SMAD3 protein, human; C060506:sphingosine 1-phosphate