title: Particulate matter disrupts human lung endothelial barrier integrity via ROS- and p38 MAPK-dependent pathways.
abstract: Epidemiologic studies have linked exposure to airborne pollutant particulate matter (PM) with increased cardiopulmonary mortality and morbidity. The mechanisms of PM-mediated lung pathophysiology, however, remain unknown. We tested the hypothesis that PM, via enhanced oxidative stress, disrupts lung endothelial cell (EC) barrier integrity, thereby enhancing organ dysfunction. Using PM collected from Ft. McHenry Tunnel (Baltimore, MD), we assessed PM-mediated changes in transendothelial electrical resistance (TER) (a highly sensitive measure of barrier function), reactive oxygen species (ROS) generation, and p38 mitogen-activated protein kinase (MAPK) activation in human pulmonary artery EC. PM induced significant dose (10-100 microg/ml)- and time (0-10 h)-dependent EC barrier disruption reflected by reduced TER values. Exposure of human lung EC to PM resulted in significant ROS generation, which was directly involved in PM-mediated EC barrier dysfunction, as N-acetyl-cysteine (NAC, 5 mM) pretreatment abolished both ROS production and barrier disruption induced by PM. Furthermore, PM induced p38 MAPK activation and HSP27 phosphorylation, events that were both attenuated by NAC. In addition, PM-induced EC barrier disruption was partially prevented by the p38 MAP kinase inhibitor SB203580 (10 microM) as well as by reduced expression of either p38 MAPK beta or HSP27 (siRNA). These results demonstrate that PM induces ROS generation in human lung endothelium, resulting in oxidative stress-mediated EC barrier disruption via p38 MAPK- and HSP27-dependent pathways. These findings support a novel mechanism for PM-induced lung dysfunction and adverse cardiopulmonary outcomes.
authors.affiliation: Department of Medicine, University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, W604, Chicago, IL 60637, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: Eddie T
authors.initials: ET
authors.lastname: Chiang
authors.forename: Liliana
authors.initials: L
authors.lastname: Moreno-Vinasco
authors.forename: Gabriel D
authors.initials: GD
authors.lastname: Lang
authors.forename: Srikanth
authors.initials: S
authors.lastname: Pendyala
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Samet
authors.forename: Alison S
authors.initials: AS
authors.lastname: Geyh
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Breysse
authors.forename: Steven N
authors.initials: SN
authors.lastname: Chillrud
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000393:Air Pollutants / Q000009:adverse effects* / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008168:Lung; D008171:Lung Diseases / Q000201:enzymology* / Q000209:etiology; D018832:Molecular Chaperones; D018384:Oxidative Stress / Q000187:drug effects; D052638:Particulate Matter / Q000009:adverse effects* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000393:Air Pollutants; D000975:Antioxidants; D004791:Enzyme Inhibitors; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D007093:Imidazoles; D018832:Molecular Chaperones; D052638:Particulate Matter; D011725:Pyridines; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D000111:Acetylcysteine