title: Sphingosine-1-phosphate induces pro-remodelling response in airway smooth muscle cells.
abstract: BACKGROUND
  Increased proliferation of airway smooth muscle (ASM) cells leading to hyperplasia and increased ASM mass is one of the most characteristic features of airway remodelling in asthma. A bioactive lipid, sphingosine-1-phosphate (S1P), has been suggested to affect airway remodelling by stimulation of human ASM cell proliferation.
  
  
  OBJECTIVE
  To investigate the effect of S1P on signalling and regulation of gene expression in ASM cells from healthy and asthmatic individuals.
  
  
  METHODS
  Airway smooth muscle cells grown from bronchial biopsies of healthy and asthmatic individuals were exposed to S1P. Gene expression was analysed using microarray, real-time PCR and Western blotting. Receptor signalling and function were determined by mRNA knockdown and intracellular calcium mobilization experiments.
  
  
  RESULTS
  S1P potently regulated the expression of more than 80 genes in human ASM cells, including several genes known to be involved in the regulation of cell proliferation and airway remodelling (HBEGF, TGFB3, TXNIP, PLAUR, SERPINE1, RGS4). S1P acting through S1P2 and S1P3 receptors activated intracellular calcium mobilization and extracellular signal-regulated and Rho-associated kinases to regulate gene expression. S1P-induced responses were not inhibited by corticosteroids and did not differ significantly between ASM cells from healthy and asthmatic individuals.
  
  
  CONCLUSIONS
  S1P induces a steroid-resistant, pro-remodelling pathway in ASM cells. Targeting S1P or its receptors could be a novel treatment strategy for inhibiting airway remodelling in asthma.
authors.affiliation: Division of Asthma, Allergy and Lung Biology, King's College London, London, UK; MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK.
authors.forename: E
authors.initials: E
authors.lastname: Fuerst
authors.forename: H R
authors.initials: HR
authors.lastname: Foster
authors.forename: J P T
authors.initials: JP
authors.lastname: Ward
authors.forename: C J
authors.initials: CJ
authors.lastname: Corrigan
authors.forename: D J
authors.initials: DJ
authors.lastname: Cousins
authors.forename: G
authors.initials: G
authors.lastname: Woszczek
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D056151:Airway Remodeling / Q000187:drug effects* / Q000235:genetics; D001249:Asthma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D016000:Cluster Analysis; D004351:Drug Resistance; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D000305:Adrenal Cortex Hormones; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C477522:S1PR2 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; C060506:sphingosine 1-phosphate; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D013110:Sphingosine; D002118:Calcium
keywords: airway smooth muscle; asthma; remodelling; sphingosine-1-phosphate