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Regulation of lung endothelial permeability and inflammatory responses by prostaglandin A2: role of EP4 receptor
The role of prostaglandin A2 (PGA2) in modulation of vascular endothelial function is unknown. We investigated effects of PGA2 on pulmonary endothelial cell (EC) permeability and inflammatory activation and identified a receptor mediating these effects. PGA2 enhanced the EC barrier and protected aga...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469606/ https://www.ncbi.nlm.nih.gov/pubmed/28428256 http://dx.doi.org/10.1091/mbc.E16-09-0639 |
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author | Ohmura, Tomomi Tian, Yufeng Sarich, Nicolene Ke, Yunbo Meliton, Angelo Shah, Alok S. Andreasson, Katrin Birukov, Konstantin G. Birukova, Anna A. |
author_facet | Ohmura, Tomomi Tian, Yufeng Sarich, Nicolene Ke, Yunbo Meliton, Angelo Shah, Alok S. Andreasson, Katrin Birukov, Konstantin G. Birukova, Anna A. |
author_sort | Ohmura, Tomomi |
collection | PubMed |
description | The role of prostaglandin A2 (PGA2) in modulation of vascular endothelial function is unknown. We investigated effects of PGA2 on pulmonary endothelial cell (EC) permeability and inflammatory activation and identified a receptor mediating these effects. PGA2 enhanced the EC barrier and protected against barrier dysfunction caused by vasoactive peptide thrombin and proinflammatory bacterial wall lipopolysaccharide (LPS). Receptor screening using pharmacological and molecular inhibitory approaches identified EP4 as a novel PGA2 receptor. EP4 mediated barrier-protective effects of PGA2 by activating Rap1/Rac1 GTPase and protein kinase A targets at cell adhesions and cytoskeleton: VE-cadherin, p120-catenin, ZO-1, cortactin, and VASP. PGA2 also suppressed LPS-induced inflammatory signaling by inhibiting the NFκB pathway and expression of EC adhesion molecules ICAM1 and VCAM1. These effects were abolished by pharmacological or molecular inhibition of EP4. In vivo, PGA2 was protective in two distinct models of acute lung injury (ALI): LPS-induced inflammatory injury and two-hit ALI caused by suboptimal mechanical ventilation and injection of thrombin receptor–activating peptide. These protective effects were abolished in mice with endothelial-specific EP4 knockout. The results suggest a novel role for the PGA2–EP4 axis in vascular EC protection that is critical for improvement of pathological states associated with increased vascular leakage and inflammation. |
format | Online Article Text |
id | pubmed-5469606 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-54696062017-08-30 Regulation of lung endothelial permeability and inflammatory responses by prostaglandin A2: role of EP4 receptor Ohmura, Tomomi Tian, Yufeng Sarich, Nicolene Ke, Yunbo Meliton, Angelo Shah, Alok S. Andreasson, Katrin Birukov, Konstantin G. Birukova, Anna A. Mol Biol Cell Articles The role of prostaglandin A2 (PGA2) in modulation of vascular endothelial function is unknown. We investigated effects of PGA2 on pulmonary endothelial cell (EC) permeability and inflammatory activation and identified a receptor mediating these effects. PGA2 enhanced the EC barrier and protected against barrier dysfunction caused by vasoactive peptide thrombin and proinflammatory bacterial wall lipopolysaccharide (LPS). Receptor screening using pharmacological and molecular inhibitory approaches identified EP4 as a novel PGA2 receptor. EP4 mediated barrier-protective effects of PGA2 by activating Rap1/Rac1 GTPase and protein kinase A targets at cell adhesions and cytoskeleton: VE-cadherin, p120-catenin, ZO-1, cortactin, and VASP. PGA2 also suppressed LPS-induced inflammatory signaling by inhibiting the NFκB pathway and expression of EC adhesion molecules ICAM1 and VCAM1. These effects were abolished by pharmacological or molecular inhibition of EP4. In vivo, PGA2 was protective in two distinct models of acute lung injury (ALI): LPS-induced inflammatory injury and two-hit ALI caused by suboptimal mechanical ventilation and injection of thrombin receptor–activating peptide. These protective effects were abolished in mice with endothelial-specific EP4 knockout. The results suggest a novel role for the PGA2–EP4 axis in vascular EC protection that is critical for improvement of pathological states associated with increased vascular leakage and inflammation. The American Society for Cell Biology 2017-06-15 /pmc/articles/PMC5469606/ /pubmed/28428256 http://dx.doi.org/10.1091/mbc.E16-09-0639 Text en © 2017 Ohmura et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. |
spellingShingle | Articles Ohmura, Tomomi Tian, Yufeng Sarich, Nicolene Ke, Yunbo Meliton, Angelo Shah, Alok S. Andreasson, Katrin Birukov, Konstantin G. Birukova, Anna A. Regulation of lung endothelial permeability and inflammatory responses by prostaglandin A2: role of EP4 receptor |
title | Regulation of lung endothelial permeability and inflammatory responses by prostaglandin A2: role of EP4 receptor |
title_full | Regulation of lung endothelial permeability and inflammatory responses by prostaglandin A2: role of EP4 receptor |
title_fullStr | Regulation of lung endothelial permeability and inflammatory responses by prostaglandin A2: role of EP4 receptor |
title_full_unstemmed | Regulation of lung endothelial permeability and inflammatory responses by prostaglandin A2: role of EP4 receptor |
title_short | Regulation of lung endothelial permeability and inflammatory responses by prostaglandin A2: role of EP4 receptor |
title_sort | regulation of lung endothelial permeability and inflammatory responses by prostaglandin a2: role of ep4 receptor |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469606/ https://www.ncbi.nlm.nih.gov/pubmed/28428256 http://dx.doi.org/10.1091/mbc.E16-09-0639 |
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