The EP1/EP3 receptor agonist 17-pt-PGE2acts as an EP4 receptor agonist on endothelial barrier function and in a model of LPS-induced pulmonary inflammation.
Endothelial dysfunction is a hallmark of inflammatory conditions. We recently demonstrated that prostaglandin (PG)E2enhances the resistance of pulmonary endothelium in vitro and counteracts lipopolysaccharide (LPS)-induced pulmonary inflammation in vivo via EP4 receptors. The aim of this study was to investigate the role of the EP1/EP3 receptor agonist 17-phenyl-trinor-(pt)-PGE2on acute lung inflammation in a mouse model. In LPS-induced pulmonary inflammation in mice, 17-pt-PGE2reduced neutrophil infiltration and inhibited vascular leakage. These effects were unaltered by an EP1 antagonist, but reversed by EP4 receptor antagonists. 17-pt-PGE2increased the resistance of pulmonary microvascular endothelial cells and prevented thrombin-induced disruption of endothelial junctions. Again, these effects were not mediated via EP1 or EP3 but through activation of the EP4 receptor, as demonstrated by the lack of effect of more selective EP1 and EP3 receptor agonists, prevention of these effects by EP4 antagonists and EP4 receptor knock-down by siRNA. In contrast, the aggregation enhancing effect of 17-pt-PGE2in human platelets was mediated via EP3 receptors. Our results demonstrate that 17-pt-PGE2enhances the endothelial barrier in vitro on pulmonary microvascular endothelial cells, and accordingly ameliorates the recruitment of neutrophils, via EP4 receptors in vivo. This suggests a beneficial effect of 17-pt-PGE2on pulmonary inflammatory diseases.
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, 8010 Graz, Austria. Electronic address: anna.theiler@medunigraz.at.
Anna
A
Theiler
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, 8010 Graz, Austria. Electronic address: viktoria.konya@medunigraz.at.
Viktoria
V
Konya
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, 8010 Graz, Austria. Electronic address: lisa.pasterk@medunigraz.at.
Lisa
L
Pasterk
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, 8010 Graz, Austria. Electronic address: jovana.maric@medunigraz.at.
Jovana
J
Maric
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, 8010 Graz, Austria. Electronic address: thomas.baernthaler@medunigraz.at.
Thomas
T
Bärnthaler
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, 8010 Graz, Austria. Electronic address: ilse.lanz@medunigraz.at.
Ilse
I
Lanz
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, 8010 Graz, Austria. Electronic address: wolfgang.platzer@medunigraz.at.
Wolfgang
W
Platzer
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, 8010 Graz, Austria. Electronic address: rufina.schuligoi@medunigraz.at.
Rufina
R
Schuligoi
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, 8010 Graz, Austria. Electronic address: akos.heinemann@medunigraz.at.
Akos
A
Heinemann
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000187:drug effects; D011014:Pneumonia / Q000188:drug therapy* / Q000473:pathology; D034741:RNA, Small Interfering / Q000008:administration & dosage; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000819:agonists; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000819:agonists; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists* / Q000235:genetics
C092396:17-phenyltrinorprostaglandin E2; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone
17-Phenyl-trinor-prostaglandin E(2); EP receptors; Endothelial barrier function; Platelet aggregation; Pulmonary inflammation; Vascular hyperpermeability
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