title: Prostaglandin D₂ pathway upregulation: relation to asthma severity, control, and TH2 inflammation.
abstract: BACKGROUND
  Bronchoalveolar lavage (BAL) fluid prostaglandin D₂(PGD₂) levels are increased in patients with severe, poorly controlled asthma in association with epithelial mast cells (MCs). PGD₂, which is generated by hematopoietic prostaglandin D synthase (HPGDS), acts on 3 G protein-coupled receptors, including chemoattractant receptor-homologous molecule expressed on TH2 lymphocytes (CRTH2) and PGD₂ receptor 1 (DP1). However, much remains to be understood regarding the presence and activation of these pathway elements in asthmatic patients.
  
  
  OBJECTIVE
  We sought to compare the expression and activation of PGD₂ pathway elements in bronchoscopically obtained samples from healthy control subjects and asthmatic patients across a range of disease severity and control, as well as in relation to TH2 pathway elements.
  
  
  METHODS
  Epithelial cells and BAL fluid were evaluated for HPGDS (quantitative real-time PCR/immunohistochemistry [IHC]) and PGD₂ (ELISA/liquid chromatography mass spectrometry) in relation to levels of MC proteases. Expression of the 2 inflammatory cell receptors DP1 and CRTH2 was evaluated on luminal cells. These PGD₂ pathway markers were then compared with asthma severity, level of control, and markers of TH2 inflammation (blood eosinophils and fraction of exhaled nitric oxide).
  
  
  RESULTS
  Confirming previous results, BAL fluid PGD₂ levels were highest in patients with severe asthma (overall P = .0001). Epithelial cell compartment HPGDS mRNA and IHC values differed among groups (P = .008 and P < .0001, respectively) and correlated with MC protease mRNA. CRTH2 mRNA and IHC values were highest in patients with severe asthma (P = .001 and P = .0001, respectively). Asthma exacerbations, poor asthma control, and TH2 inflammatory markers were associated with higher PGD₂, HPGDS, and CRTH2 levels.
  
  
  CONCLUSIONS
  The current study identifies coordinated upregulation of the PGD₂ pathway in patients with severe, poorly controlled, TH2-high asthma despite corticosteroid use.
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh Asthma Institute at UPMC/University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. fajtml@upmc.edu
authors.forename: Merritt L
authors.initials: ML
authors.lastname: Fajt
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Gelhaus
authors.forename: Bruce
authors.initials: B
authors.lastname: Freeman
authors.forename: Crystal E
authors.initials: CE
authors.lastname: Uvalle
authors.forename: John B
authors.initials: JB
authors.lastname: Trudeau
authors.forename: Fernando
authors.initials: F
authors.lastname: Holguin
authors.forename: Sally E
authors.initials: SE
authors.lastname: Wenzel
mesh_terms: D000328:Adult; D001249:Asthma / Q000276:immunology* / Q000378:metabolism* / Q000517:prevention & control; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015230:Prostaglandin D2 / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D054834:Lipocalins; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor