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The prostaglandin D2 receptor 2 pathway in asthma: a key player in airway inflammation.

ABSTRACT: Asthma is characterised by chronic airway inflammation, airway obstruction and hyper-responsiveness. The inflammatory cascade in asthma comprises a complex interplay of genetic factors, the airway epithelium, and dysregulation of the immune response.Prostaglandin D2 (PGD2) is a lipid mediator, predominantly released from mast cells, but also by other immune cells such as TH2 cells and dendritic cells, which plays a significant role in the pathophysiology of asthma. PGD2 mainly exerts its biological functions via two G-protein-coupled receptors, the PGD2 receptor 1 (DP1) and 2 (DP2). The DP2 receptor is mainly expressed by the key cells involved in type 2 immune responses, including TH2 cells, type 2 innate lymphoid cells and eosinophils. The DP2 receptor pathway is a novel and important therapeutic target for asthma, because increased PGD2 production induces significant inflammatory cell chemotaxis and degranulation via its interaction with the DP2 receptor. This interaction has serious consequences in the pulmonary milieu, including the release of pro-inflammatory cytokines and harmful cationic proteases, leading to tissue remodelling, mucus production, structural damage, and compromised lung function. This review will discuss the importance of the DP2 receptor pathway and the current understanding of its role in asthma.

SUBMITTER: Domingo C

PROVIDER: S-EPMC6162887 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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The prostaglandin D2 receptor 2 pathway in asthma: a key player in airway inflammation.

Domingo Christian C Palomares Oscar O Sandham David A DA Erpenbeck Veit J VJ Altman Pablo P

Respiratory research 20180929 1

Asthma is characterised by chronic airway inflammation, airway obstruction and hyper-responsiveness. The inflammatory cascade in asthma comprises a complex interplay of genetic factors, the airway epithelium, and dysregulation of the immune response.Prostaglandin D2 (PGD2) is a lipid mediator, predominantly released from mast cells, but also by other immune cells such as TH2 cells and dendritic cells, which plays a significant role in the pathophysiology of asthm ...[more]

PMID: 30268119

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Project description:BackgroundBronchoalveolar lavage (BAL) fluid prostaglandin D?(PGD?) levels are increased in patients with severe, poorly controlled asthma in association with epithelial mast cells (MCs). PGD?, 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 PGD? receptor 1 (DP1). However, much remains to be understood regarding the presence and activation of these pathway elements in asthmatic patients.ObjectiveWe sought to compare the expression and activation of PGD? 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.MethodsEpithelial cells and BAL fluid were evaluated for HPGDS (quantitative real-time PCR/immunohistochemistry [IHC]) and PGD? (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? pathway markers were then compared with asthma severity, level of control, and markers of TH2 inflammation (blood eosinophils and fraction of exhaled nitric oxide).ResultsConfirming previous results, BAL fluid PGD? 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 PGD?, HPGDS, and CRTH2 levels.ConclusionThe current study identifies coordinated upregulation of the PGD? pathway in patients with severe, poorly controlled, TH2-high asthma despite corticosteroid use.

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The prostaglandin D2 receptor 2 pathway in asthma: a key player in airway inflammation.

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The prostaglandin D<sub>2</sub> receptor 2 pathway in asthma: a key player in airway inflammation.

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