Particulate matter disrupts human lung endothelial cell barrier integrity via Rho-dependent pathways
Kelly, Gabriel T.
Garcia, Joe G.N.
AffiliationUniv Arizona, Dept Pharmacol & Toxicol
MetadataShow full item record
PublisherSAGE PUBLICATIONS INC
CitationParticulate matter disrupts human lung endothelial cell barrier integrity via Rho-dependent pathways 2017, 7 (3):617 Pulmonary Circulation
Rights© The Author(s) 2017. Creative Commons Non Commercial CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License.
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AbstractIncreased exposure to ambient particulate matter (PM) is associated with elevated morbidity and mortality in patients with cardiopulmonary diseases and cancer. We and others have shown that PM induces lung microvascular barrier dysfunction which potentially enhances the systemic toxicity of PM. However, the mechanisms by which PM disrupts vascular endothelial integrity remain incompletely explored. We hypothesize that PM induces endothelial cell (EC) cytoskeleton rearrangement via Rho GTPase-dependent pathways to facilitate vascular hyperpermeability. Fine PM induced time-dependent activation of cytoskeletal machinery with increases in myosin light chain (MLC) phosphorylation and EC barrier disruption measured by transendothelial electrical resistance (TER), events attenuated by the Rho-dependent kinase (ROCK) inhibitor Y-27632 or the reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC). Both Y-27632 and NAC prevented PM-induced stress fiber formation and phospho-MLC accumulation in human lung ECs. PM promotes rapid accumulation of Rho-GTP. This event is attenuated by NAC or knockdown of RhoA (siRNA). Consistent with ROCK activation, PM induced phosphorylation of myosin light chain phosphatase (MYPT) at Thr850, a post-translational modification known to inhibit phosphatase activity. Furthermore, PM activates the guanine nucleotide exchange factor (GEF) for Rho, p115, with p115 translocation to the cell periphery, in a ROS-dependent manner. Together these results demonstrate that fine PM induces EC cytoskeleton rearrangement via Rho-dependent pathways that are dependent upon the generation of oxidative stress. As the disruption of vascular integrity further contributes to cardiopulmonary physiologic derangements, these findings provide pharmacologic targets for prevention of PM-induced cardiopulmonary toxicity.
Note12 month embargo; published: 1 Sept 2017.
VersionFinal published version
SponsorsParker B Francis Foundation, National Institutes of Health grants [R01HL091899, P01HL126609, P30ES006694, T32HL007249]; National Natural Science Foundation of China ; Anhui Provincial Natural Science Research Project of University [KJ2013A188]; International Science and Technology Cooperation Project - Key Research and Development Program of Anhui Province [1604b0602026]
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