Experimental Cell Research. 365(1):97–105, APR 2018
DOI: 10.1016/j.yexcr.2018.02.026
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PMID: 29481792
Issn Print: 0014-4827
Publication Date: 2018/04/01
Fasudil inhibits neutrophil-endothelial cell interactions by regulating the expressions of GRP78 and BMPR2
Jingjing Wang;Jian Xu;Xinyun Zhao;Weiping Xie;Hong Wang;Hui Kong;
+ Author Information
aDepartment of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, ChinabDepartment of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
Abstract
Regulation of leukocyte-endothelial cell interactions and of vascular permeability plays a critical role in the maintenance of functional pulmonary microvascular barriers. Little is yet known about the effect of the Rho-associated protein kinase (ROCK) inhibitor fasudil on leukocyte-endothelial cell interactions or the underlying mechanism. In the present study, as evaluated using co-culture systems of neutrophils and human pulmonary microvascular endothelial cells (HPMECs), fasudil dose-dependently suppressed neutrophil chemotaxis by decreasing the production of chemotactic factors in lipopolysaccharide (LPS)-treated HPMECs. The inhibitory role of fasudil in neutrophil chemotaxis was mediated by down-regulation of the chaperone glucose-regulated protein 78 (GRP78), since the inhibition was abolished by 4-phenyl butyric acid (a chemical chaperone mimicking GRP78). In addition, fasudil inhibited LPS-induced neutrophil-endothelial adhesion by reducing the expression of intercellular adhesion molecule (ICAM)-1. By use of lentiviral transfection in HPMECs, bone morphogenic protein receptor 2 (BMPR2) overexpression suppressed the LPS-induced increase of both ICAM-1 expression and neutrophil-endothelial adhesion, whereas knocking down BMPR2 abolished the inhibitory role of fasudil in both ICAM-1 expression and neutrophil-endothelial adhesion. Moreover, fasudil alleviated LPS-induced hyperpermeability of HPMEC monolayers by leading to the recovery of intercellular junctions, thereafter reduced neutrophil transendothelial cell migration. Therefore, fasudil inhibited leukocyte-endothelial cell interactions and vascular hyperpermeability through modulation of GRP78 and BMPR2 expression, suggesting a potential role for ROCK as a switch for inhibiting leukocyte-endothelial cell interactions.Fasudil suppressed neutrophil-endothelial chemotaxis in a dose-dependent manner.Fasudil inhibited neutrophil-endothelial chemotaxis via GRP78 down-regulation.Fasudil attenuated neutrophil-endothelial adhesion by modulating BMPR2 expression.Fasudil reduced neutrophil transendothelial cell migration.
