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Activation of EP4 receptors prevents endotoxin-induced neutrophil infiltration into the airways and enhances microvascular barrier function.

Abstract：

BACKGROUND AND PURPOSE:Pulmonary vascular dysfunction is a key event in acute lung injury. We recently demonstrated that PGE2 , via activation of E-prostanoid (EP)4 receptors, strongly enhances microvascular barrier function in vitro. The aim of this study was to investigate the beneficial effects of concomitant EP4 receptor activation in murine models of acute pulmonary inflammation. EXPERIMENTAL APPROACH:Pulmonary inflammation in male BALB/c mice was induced by LPS (20 μg per mouse intranasally) or oleic acid (0.15 μL·g-1 , i.v. ). In-vitro, endothelial barrier function was determined by measuring electrical impedance. KEY RESULTS:PGE2 activation of EP4 receptors reduced neutrophil infiltration, pulmonary vascular leakage and TNF-α concentration in bronchoalveolar lavage fluid from LPS-induced pulmonary inflammation. Similarly, pulmonary vascular hyperpermeability induced by oleic acid was counteracted by EP4 receptor activation. In lung function assays, the EP4 agonist ONO AE1-329 restored the increased resistance and reduced compliance upon methacholine challenge in mice treated with LPS or oleic acid. In agreement with these findings, EP4 receptor activation increased the in vitro vascular barrier function of human and mouse pulmonary microvascular endothelial cells and diminished the barrier disruption induced by LPS. The EP2 agonist ONO AE1-259 likewise reversed LPS-induced lung dysfunction without enhancing vascular barrier function. CONCLUSION AND IMPLICATIONS:Our results show that activation of the EP4 receptor strengthens the microvascular barrier function and thereby ameliorates the pathology of acute lung inflammation, including neutrophil infiltration, vascular oedema formation and airway dysfunction. This suggests a potential benefit for EP4 agonists in acute pulmonary inflammation.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Konya V,Maric J,Jandl K,Luschnig P,Aringer I,Lanz I,Platzer W,Theiler A,Bärnthaler T,Frei R,Marsche G,Marsh LM,Olschewski A,Lippe IT,Heinemann A,Schuligoi R

doi

10.1111/bph.13229

subject

Has Abstract

pub_date

2015-09-01 00:00:00

pages

4454-4468

issue

eissn

0007-1188

issn

1476-5381

journal_volume

172

pub_type

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Activation of EP4 receptors prevents endotoxin-induced neutrophil infiltration into the airways and enhances microvascular barrier function.