title: Activation of EP4receptors prevents endotoxin-induced neutrophil infiltration into the airways and enhances microvascular barrier function.
abstract: OBJECTIVE
  Pulmonary vascular dysfunction is a key event in acute lung injury. We recently demonstrated that PGE2, via activation of E-prostanoid (EP)4receptors, strongly enhances microvascular barrier function in vitro. The aim of this study was to investigate the beneficial effects of concomitant EP4receptor activation in murine models of acute pulmonary inflammation.
  
  
  METHODS
  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.
  
  
  RESULTS
  PGE2activation of EP4receptors 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 EP4receptor activation. In lung function assays, the EP4agonist 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, EP4receptor 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 EP2agonist ONO AE1-259 likewise reversed LPS-induced lung dysfunction without enhancing vascular barrier function.
  
  
  CONCLUSIONS
  Our results show that activation of the EP4receptor 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 EP4agonists in acute pulmonary inflammation.
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: V
authors.initials: V
authors.lastname: Konya
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Maric
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Jandl
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Luschnig
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.|Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: I
authors.initials: I
authors.lastname: Aringer
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: I
authors.initials: I
authors.lastname: Lanz
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: W
authors.initials: W
authors.lastname: Platzer
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Theiler
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Bärnthaler
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Frei
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Marsche
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
authors.forename: L M
authors.initials: LM
authors.lastname: Marsh
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Olschewski
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: I T
authors.initials: IT
authors.lastname: Lippe
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Heinemann
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Schuligoi