Prostaglandin D₂ pathway upregulation: Relation to asthma severity, control, and T_H2 inflammation

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• 作者：Merritt L. Fajt ; MD^a ; ^{fajtml@upmc.edu} ; Stacy L. Gelhaus ; PhD^b ; Bruce Freeman ; PhD^b ; Crystal E. Uvalle ; BS^a ; John B. Trudeau ; BA^a ; Fernando Holguin ; MD ; MPH^a ; Sally E. Wenzel ; MD^a
• 关键词：Asthma control ; chemoattractant receptor&ndash ; homologous molecule expressed on TH2 lymphocytes ; prostaglandin D2 ; severe asthma ; TH2 inflammation
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2013
• 出版时间：June, 2013
• 年：2013
• 卷：131
• 期：6
• 页码：1504-1512.e12
• 全文大小：1686 K

文摘

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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 T_H2 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 T_H2 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 T_H2 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 T_H2 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, T_H2-high asthma despite corticosteroid use.