Anti-inflammatory effects of PGE₂ in the lung: role of the EP₄ receptor subtype

Abstract

BackgroundAsthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the airway. Current treatment options (long acting β-adrenoceptor agonists and glucocorticosteroids) are not optimal as they are only effective in certain patient groups and safety concerns exist regarding both compound classes. Therefore, novel bronchodilator and anti-inflammatory strategies are being pursued. Prostaglandin E2 (PGE2) is an arachidonic acid-derived eicosanoid produced by the lung which acts on four different G-protein coupled receptors (EP1–4) to cause an array of beneficial and deleterious effects. The aim of this study was to identify the EP receptor mediating the anti-inflammatory actions of PGE2 in the lung using a range of cell-based assays and in vivo models.Methods and resultsIt was demonstrated in three distinct model systems (innate stimulus, lipopolysaccharide (LPS); allergic response, ovalbumin (OVA); inhaled pollutant, cigarette smoke) that mice missing functional EP4 (Ptger4−/−) receptors had higher levels of airway inflammation, suggesting that endogenous PGE2 was suppressing inflammation via EP4 receptor activation. Cell-based assay systems (murine and human monocytes/alveolar macrophages) demonstrated that PGE2 inhibited cytokine release from LPS-stimulated cells and that this was mimicked by an EP4 (but not EP1–3) receptor agonist and inhibited by an EP4 receptor antagonist. The anti-inflammatory effect occurred at the transcriptional level and was via the adenylyl cyclase/cAMP/ cAMP-dependent protein kinase (PKA) axis.ConclusionThis study demonstrates that EP4 receptor activation is responsible for the anti-inflammatory activity of PGE2 in a range of disease relevant models and, as such, could represent a novel therapeutic target for chronic airway inflammatory conditions.

Mass spectrometry profiling of oxylipins, endocannabinoids, and N-acylethanolamines in human lung lavage fluids reveals responsiveness of prostaglandin E2 and associated lipid metabolites to biodiesel exhaust exposure

“…However, endogenous PGE 2 is present at higher concentrations in the lung than in plasma and has anti-inflammatory and bronchodilator properties despite being associated with airway irritation and coughing [54]. In a recent study using a mouse model, Birrell et al concluded that the anti-inflammatory properties of PGE 2 are mediated via activation of the EP4 prostanoid receptor, resulting in suppression of airway irritation, supporting a protective effect PGE 2 in the lung [55]. Bronchial epithelial cell-derived PGE 2 has also been shown to dampen the reactivity of dendritic cells [56].…”

Human lung and monocyte-derived macrophages differ with regard to the effects of β2-adrenoceptor agonists on cytokine release

“…Since the adenylyl cyclase/cAMP/cAMP-dependent protein kinase A axis stimulated by PGE 2 reduces the LPS-induced cytokine production [42], the β 2 -adrenoceptor agonists’ lack of effect in LMs is probably due to the low expression of β 2 -adrenoceptors in these cells and thus insufficient stimulation of the pathway. The use of ten-fold lower concentrations of LPS (to markedly reduce the strength of the stimulus) unmasked a modest inhibitory effect of salbutamol on the release of TNF-α by LMs [45] - suggesting that the β 2 -adrenoceptor-dependent rise in cAMP content might be only sufficient to counteract a relatively weak inflammatory stimulus.…”

Exhaled and non-exhaled non-invasive markers for assessment of respiratory inflammation in patients with stable COPD and healthy smokers

“…As PGE 2 can have both pro-inflammatory [1,2] and anti-inflammatory effects [3,4] in the respiratory system, the biological meaning of this correlation is unknown because it could reflect either increased respiratory inflammation which parallels elevated 15-F 2t -isoprostane or a protective mechanism to counteract oxidative stress.…”