Prostaglandin D2 pathway upregulation: Relation to asthma severity, control, and TH2 inflammation

Background: Bronchoalveolar lavage (BAL) fluid prostaglandin D-2 (PGD(2)) levels are increased in patients with severe, poorly controlled asthma in association with epithelial mast cells (MCs). PGD(2), which is generated by hematopoietic prostaglandin D synthase (HPGDS), acts on 3 G protein-coupled receptors, including chemoattractant receptor-homologous molecule expressed on T(H)2 lymphocytes (CRTH2) and PGD(2) 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 PGD(2) 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 T(H)2 pathway elements. Methods: Epithelial cells and BAL fluid were evaluated for HPGDS (quantitative real-time PCR/immunohistochemistry [IHC]) and PGD(2) (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 PGD(2) pathway markers were then compared with asthma severity, level of control, and markers of T(H)2 inflammation (blood eosinophils and fraction of exhaled nitric oxide). Results: Confirming previous results, BAL fluid PGD(2) 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 T(H)2 inflammatory markers were associated with higher PGD(2), HPGDS, and CRTH2 levels. Conclusion: The current study identifies coordinated upregulation of the PGD(2) pathway in patients with severe, poorly controlled, T(H)2-high asthma despite corticosteroid use.