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Prostaglandin D₂ pathway upregulation: relation to asthma severity, control, and TH2 inflammation
Merritt L Fajt1, Stacy L Gelhaus, Bruce Freeman
1Division 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
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.
Conclusion:
The current study identifies coordinated upregulation of the PGD₂ pathway in patients with severe, poorly controlled, TH2-high asthma despite corticosteroid use.
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