Prostacyclin post-treatment improves LPS-induced acute lung injury and endothelial barrier recovery via Rap1

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1852

Article

Birukova, Anna A.¹  Meng, Fanyong¹  Tian, Yufeng¹  Meliton, Angelo¹  Sarich, Nicolene¹  Quilliam, Lawrence A.²  Birukov, Konstantin G.¹ 

[1] Univ Chicago, Dept Med, Lung Injury Ctr, Sect Pulm & Crit Med, Chicago, IL 60637 USA

[2] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA

关键词: Cytoskeleton;    Endothelium;    Permeability;    Lung;    Inflammation;   

DOI  :  10.1016/j.bbadis.2014.12.016

来源: Elsevier

【 摘 要 】

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 NF kappa B 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 NF kappa B inflammatory cascades, altogether leading to accelerated lung recovery. (C) 2014 Elsevier B.V. All rights reserved.

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