Prostacyclin post-treatment improves LPS-induced acute lung injury and endothelial barrier recovery via Rap1
dc.contributor.author | Birukova, Anna A. | |
dc.contributor.author | Meng, Fanyong | |
dc.contributor.author | Tian, Yufeng | |
dc.contributor.author | Meliton, Angelo | |
dc.contributor.author | Sarich, Nicolene | |
dc.contributor.author | Quilliam, Lawrence A. | |
dc.contributor.author | Birukov, Konstantin G. | |
dc.contributor.department | Department of Biochemistry & Molecular Biology, IU School of Medicine | en_US |
dc.date.accessioned | 2017-07-10T18:58:05Z | |
dc.date.available | 2017-07-10T18:58:05Z | |
dc.date.issued | 2015-05 | |
dc.description.abstract | Protective effects of prostacyclin (PC) or its stable analog beraprost against agonist-induced lung vascular inflammation have been associated with elevation of intracellular cAMP and Rac GTPase signaling which inhibited the RhoA GTPase-dependent pathway of endothelial barrier dysfunction. This study investigated a distinct mechanism of PC-stimulated lung vascular endothelial (EC) barrier recovery and resolution of LPS-induced inflammation mediated by small GTPase Rap1. Efficient barrier recovery was observed in LPS-challenged pulmonary EC after prostacyclin administration even after 15 h of initial inflammatory insult and was accompanied by the significant attenuation of p38 MAP kinase and NFκB signaling and decreased production of IL-8 and soluble ICAM1. These effects were reproduced in cells post-treated with 8CPT, a small molecule activator of Rap1-specific nucleotide exchange factor Epac. By contrast, pharmacologic Epac inhibitor, Rap1 knockdown, or knockdown of cell junction-associated Rap1 effector afadin attenuated EC recovery caused by PC or 8CPT post-treatment. The key role of Rap1 in lung barrier restoration was further confirmed in the murine model of LPS-induced acute lung injury. Lung injury was monitored by measurements of bronchoalveolar lavage protein content, cell count, and Evans blue extravasation and live imaging of vascular leak over 6 days using a fluorescent tracer. The data showed significant acceleration of lung recovery by PC and 8CPT post-treatment, which was abrogated in Rap1a(-/-) mice. These results suggest that post-treatment with PC triggers the Epac/Rap1/afadin-dependent mechanism of endothelial barrier restoration and downregulation of p38MAPK and NFκB inflammatory cascades, altogether leading to accelerated lung recovery. | en_US |
dc.eprint.version | Author's manuscript | en_US |
dc.identifier.citation | Birukova, A. A., Meng, F., Tian, Y., Meliton, A., Sarich, N., Quilliam, L. A., & Birukov, K. G. (2015). Prostacyclin post-treatment improves LPS-induced acute lung injury and endothelial barrier recovery via Rap1. Biochimica et Biophysica Acta, 1852(5), 778–791. http://doi.org/10.1016/j.bbadis.2014.12.016 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/13372 | |
dc.language.iso | en_US | en_US |
dc.publisher | Elsevier | en_US |
dc.relation.isversionof | 10.1016/j.bbadis.2014.12.016 | en_US |
dc.relation.journal | Biochimica et Biophysica Sinica | en_US |
dc.rights | Publisher Policy | en_US |
dc.source | PMC | en_US |
dc.subject | Cytoskeleton | en_US |
dc.subject | Endothelium | en_US |
dc.subject | Permeability | en_US |
dc.subject | Lung | en_US |
dc.subject | Inflammation | en_US |
dc.title | Prostacyclin post-treatment improves LPS-induced acute lung injury and endothelial barrier recovery via Rap1 | en_US |
dc.type | Article | en_US |