Abstract
BackgroundExposure 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.ObjectivesWe explored the role of tight junction proteins as targets for PM-induced loss of lung endothelial cell (EC) barrier integrity and enhanced cardiopulmonary dysfunction.MethodsChanges 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.ResultsPM 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.ConclusionsThese 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.
Highlights
Exposure to particulate matter (PM) is a significant risk factor for increased cardiopulmonary morbidity and mortality
PM-activated calpain is responsible for Zona occludens-1 (ZO-1) degradation and endothelial cell (EC) barrier disruption
Overexpression of ZO-1 attenuated PM-induced endothelial barrier disruption and vascular hyperpermeability in vivo and in vitro. These results demonstrate that PM induces marked increases in vascular permeability via ROS-mediated calcium leakage via activated transient receptor potential cation channel M2 (TRPM2), and via ZO-1 degradation by activated calpain
Summary
Exposure to particulate matter (PM) is a significant risk factor for increased cardiopulmonary morbidity and mortality. Epidemiological studies have shown associations of exposure to low levels of urban particulate matter with increased. Exposure of airway epithelium to airborne PM causes altered cytokine/chemokine gene expression and increased production of IL-1β, IL-6, IL-8 and TNF-α [5,6]. Exposure of the endothelium to PM or its active components in the systemic circulation induces significant systemic endothelial inflammation and dysfunction, even at low levels of exposure [7,8]. Bioavailable transition metals present in urban PM catalyze redox reactions in human lung endothelium, which cause oxidative stress, increase the production of inflammatory cytokines, and increase the activation of NF-κB signaling pathways, all of which trigger further endothelial damage [9]. Increased endothelial monolayer permeability is observed in inflammatory pulmonary conditions such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and sepsis; devastating lung disorders with mortality exceeding 30%, as well as in more subacute and chronic inflammatory disorders such as asthma [10,11]
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