Abstract:
:Increased 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.
journal_name
Pulm Circjournal_title
Pulmonary circulationauthors
Wang T,Shimizu Y,Wu X,Kelly GT,Xu X,Wang L,Qian Z,Chen Y,Garcia JGNdoi
10.1086/689906subject
Has Abstractpub_date
2017-07-01 00:00:00pages
617-623issue
3eissn
2045-8932issn
2045-8940journal_volume
7pub_type
杂志文章abstract::Pregnancy is not advised for patients with Pulmonary hypertension (PH) because of high risk of PH crisis. However, some patients have undiagnosed idiopathic pulmonary arterial hypertension (IPAH) before pregnancy. Upfront combination therapy has high efficacy for patients with IPAH. However, some patients are unable t...
journal_title:Pulmonary circulation
pub_type:
doi:10.1177/2045894020910140
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journal_title:Pulmonary circulation
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journal_title:Pulmonary circulation
pub_type: 杂志文章
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doi:10.1177/2045894018793999
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pub_type: 杂志文章
doi:10.1177/2045894018798921
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journal_title:Pulmonary circulation
pub_type: 杂志文章
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pub_type: 杂志文章,评审
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journal_title:Pulmonary circulation
pub_type: 杂志文章
doi:10.1177/2045894020905510
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journal_title:Pulmonary circulation
pub_type: 杂志文章
doi:10.1177/2045893217710224
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journal_title:Pulmonary circulation
pub_type: 杂志文章
doi:10.1177/2045894018770654
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pub_type:
doi:10.1177/2045894019896682
更新日期:2019-12-27 00:00:00
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pub_type: 杂志文章
doi:10.4103/2045-8932.109921
更新日期:2013-01-01 00:00:00
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journal_title:Pulmonary circulation
pub_type: 杂志文章
doi:10.1177/2045894018800439
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pub_type: 杂志文章
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pub_type: 杂志文章,评审
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doi:10.1177/2045893217700156
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更新日期:2020-12-07 00:00:00
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journal_title:Pulmonary circulation
pub_type: 杂志文章
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journal_title:Pulmonary circulation
pub_type:
doi:10.1086/675643
更新日期:2014-03-01 00:00:00
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更新日期:2015-12-01 00:00:00
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