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


RESULTS
It 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.


CONCLUSIONS
This 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.
Faculty of Medicine, Department of Respiratory Pharmacology, National Heart and Lung Institute, Imperial College London, London, UK MRC-Asthma UK Centre in Allergic Mechanisms of Asthma.
Mark A
MA
Birrell
Faculty of Medicine, Department of Respiratory Pharmacology, National Heart and Lung Institute, Imperial College London, London, UK.
Sarah A
SA
Maher
Faculty of Medicine, Department of Respiratory Pharmacology, National Heart and Lung Institute, Imperial College London, London, UK.
Bilel
B
Dekkak
Faculty of Medicine, Department of Respiratory Pharmacology, National Heart and Lung Institute, Imperial College London, London, UK.
Victoria
V
Jones
Faculty of Medicine, Department of Respiratory Pharmacology, National Heart and Lung Institute, Imperial College London, London, UK.
Sissie
S
Wong
Faculty of Medicine, Department of Respiratory Pharmacology, National Heart and Lung Institute, Imperial College London, London, UK.
Peter
P
Brook
Faculty of Medicine, Department of Respiratory Pharmacology, National Heart and Lung Institute, Imperial College London, London, UK MRC-Asthma UK Centre in Allergic Mechanisms of Asthma.
Maria G
MG
Belvisi
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018078:Receptors, Prostaglandin E / Q000627:therapeutic use*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism*
C545651:Ptger4 protein, mouse; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype
Asthma Mechanisms; Asthma Pharmacology; COPD Pharmacology