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Particulate Matter Disrupts Human Lung Endothelial Barrier Integrity via ROS- and p38 MAPK–Dependent Pathways

¹ Department of Medicine, Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois; Departments of ² Epidemiology and ³ Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; and ⁴ Lamont Doherty Earth Observatory, Columbia University, Palisades, New York

Correspondence and requests for reprints should be addressed to Joe G. N. Garcia, M.D., Department of Medicine, University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, W604, Chicago, IL 60637. E-mail: jgarcia{at}medicine.bsd.uchicago.edu

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 µg/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 µM) as well as by reduced expression of either p38 MAPK β 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.

Key Words: endothelial permeability • HSP27 • particulate matter • p38 MAP kinase • ROS

CLINICAL RELEVANCE This study demonstrates that particulate matter (PM) induces reactive oxygen species generation in human lung endothelium, resulting in oxidative stress–mediated endothelial cell barrier disruption via p38 mitogen-activated protein kinase– and HSP27-dependent pathways. These findings support a novel mechanism for PM-induced lung dysfunction and potential adverse cardiovascular outcomes.