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Activation of EP 4 receptors prevents endotoxin‐induced neutrophil infiltration into the airways and enhances microvascular barrier function
Author(s) -
Konya V,
Maric J,
Jandl K,
Luschnig P,
Aringer I,
Lanz I,
Platzer W,
Theiler A,
Bärnthaler T,
Frei R,
Marsche G,
Marsh L M,
Olschewski A,
Lippe I T,
Heinemann A,
Schuligoi R
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13229
Subject(s) - bronchoalveolar lavage , inflammation , receptor , lung , vascular permeability , barrier function , methacholine , agonist , infiltration (hvac) , immunology , chemistry , medicine , pharmacology , biology , respiratory disease , microbiology and biotechnology , physics , thermodynamics
Background and Purpose Pulmonary vascular dysfunction is a key event in acute lung injury. We recently demonstrated that PGE 2 , 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 EP 4 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 PGE 2 activation of EP 4 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 EP 4 receptor activation. In lung function assays, the EP 4 agonist ONO AE 1‐329 restored the increased resistance and reduced compliance upon methacholine challenge in mice treated with LPS or oleic acid. In agreement with these findings, EP 4 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 EP 2 agonist ONO AE 1‐259 likewise reversed LPS ‐induced lung dysfunction without enhancing vascular barrier function. Conclusion and Implications Our results show that activation of the EP 4 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 EP 4 agonists in acute pulmonary inflammation.