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Particulate matter air pollution disrupts endothelial cell barrier via calpain-mediated tight junction protein degradation
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نویسنده
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wang t. ,wang l. ,moreno-vinasco l. ,lang g.d. ,siegler j.h. ,mathew b. ,usatyuk p.v. ,samet j.m. ,geyh a.s. ,breysse p.n. ,natarajan v. ,garcia j.g.n.
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منبع
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particle and fibre toxicology - 2012 - دوره : 9 - شماره : 0
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چکیده
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Background: exposure to particulate matter (pm) is a significant risk factor for increased cardiopulmonary morbidity and mortality. the mechanism of pm-mediated pathophysiology remains unknown. however,pm is proinflammatory to the endothelium and increases vascular permeability in vitro and in vivo via ros generation.objectives: we explored the role of tight junction proteins as targets for pm-induced loss of lung endothelial cell (ec) barrier integrity and enhanced cardiopulmonary dysfunction.methods: changes in human lung ec monolayer permeability were assessed by transendothelial electrical resistance (ter) in response to pm challenge (collected from ft. mchenry tunnel,baltimore,md,particle size >0.1 μm). biochemical assessment of ros generation and ca2+ mobilization were also measured.results: pm exposure induced tight junction protein zona occludens-1 (zo-1) relocation from the cell periphery,which was accompanied by significant reductions in zo-1 protein levels but not in adherens junction proteins (ve-cadherin and β-catenin). n-acetyl-cysteine (nac,5 mm) reduced pm-induced ros generation in ecs,which further prevented ter decreases and atteneuated zo-1 degradation. pm also mediated intracellular calcium mobilization via the transient receptor potential cation channel m2 (trpm2),in a ros-dependent manner with subsequent activation of the ca2+-dependent protease calpain. pm-activated calpain is responsible for zo-1 degradation and ec barrier disruption. overexpression of zo-1 attenuated pm-induced endothelial barrier disruption and vascular hyperpermeability in vivo and in vitro.conclusions: these results demonstrate that pm induces marked increases in vascular permeability via ros-mediated calcium leakage via activated trpm2,and via zo-1 degradation by activated calpain. these findings support a novel mechanism for pm-induced lung damage and adverse cardiovascular outcomes. © 2012 wang et al.; licensee biomed central ltd.
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کلیدواژه
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Calpain; Endothelial permeability; Particulate matter; ROS; TRPM2
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آدرس
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institute for personalized respiratory medicine,section of pulmonary,critical care,sleep and allergy,department of medicine,university of illinois at chicago,chicago,il, United States, institute for personalized respiratory medicine,section of pulmonary,critical care,sleep and allergy,department of medicine,university of illinois at chicago,chicago,il, United States, institute for personalized respiratory medicine,section of pulmonary,critical care,sleep and allergy,department of medicine,university of illinois at chicago,chicago,il, United States, institute for personalized respiratory medicine,section of pulmonary,critical care,sleep and allergy,department of medicine,university of illinois at chicago,chicago,il, United States, institute for personalized respiratory medicine,section of pulmonary,critical care,sleep and allergy,department of medicine,university of illinois at chicago,chicago,il, United States, institute for personalized respiratory medicine,section of pulmonary,critical care,sleep and allergy,department of medicine,university of illinois at chicago,chicago,il, United States, institute for personalized respiratory medicine,section of pulmonary,critical care,sleep and allergy,department of medicine,university of illinois at chicago,chicago,il, United States, department of preventive medicine,keck school of medicine,university of southern california,los angeles,ca, United States, department of environmental health science,bloomberg school of public health,johns hopkins university,baltimore,md, United States, department of environmental health science,bloomberg school of public health,johns hopkins university,baltimore,md, United States, institute for personalized respiratory medicine,section of pulmonary,critical care,sleep and allergy,department of medicine,university of illinois at chicago,chicago,il, United States, institute for personalized respiratory medicine,section of pulmonary,critical care,sleep and allergy,department of medicine,university of illinois at chicago,chicago,il, United States
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