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SHR Neuro Cancer Cardio Lipid Metab Microb
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.
Activation of EP4 receptors prevents endotoxin-induced neutrophil infiltration into the airways and enhances microvascular barrier function.
Br J Pharmacol. 2015; 172(18):4454-4468
Doi: 10.1111/bph.13229
[OPEN ACCESS]
Web of Science
PubMed
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- Leading authors Med Uni Graz
- Heinemann Akos
- Konya Viktoria
- Co-authors Med Uni Graz
- Aringer Ida
- Bärnthaler Thomas
- Frei-Winterleitner Robert
- Jandl Katharina
- Lanz Ilse
- Lippe Irmgard Theresia
- Luschnig Petra
- Maric Jovana
- Marsche Gunther
- Marsh Leigh
- Olschewski Andrea
- Platzer Wolfgang
- Schuligoi Rufina
- Theiler Anna
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- Abstract:
- 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. 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. 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. 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. © 2015 The British Pharmacological Society.