Abstract
Particulate matter (PM) air pollution is a global environmental health problem contributing to more severe lung inflammation and injury. However, the molecular and cellular mechanisms of PM-induced exacerbation of lung barrier dysfunction and injury are not well understood. In the current study, we tested a hypothesis that PM exacerbates vascular barrier dysfunction via ROS-induced generation of truncated oxidized phospholipids (Tr-OxPLs). Treatment of human pulmonary endothelial cells with PM caused endothelial cell barrier disruption in a dose-dependent fashion. Biochemical analysis showed destabilization of cell junctions by PM via tyrosine phosphorylation and internalization of VE-cadherin. These events were accompanied by PM-induced generation of Tr-OxPLs, detected by mass spectrometry analysis. Furthermore, purified Tr-OxPLs: POVPC, PGPC and lyso-PC alone, caused a rapid increase in endothelial permeability and augmented pulmonary endothelial barrier dysfunction induced by submaximal doses of PM. In support of a role of TR-OxPLs-dependent mechanism in mediation of PM effects, ectopic expression of intracellular type 2 platelet-activating factor acetylhydrolase (PAFAH2), which specifically hydrolyzes Tr-OxPLs, significantly attenuated PM-induced endothelial hyperpermeability. In summary, this study uncovered a novel mechanism of PM-induced sustained dysfunction of pulmonary endothelial cell barrier which is driven by PM-induced generation of truncated products of phospholipid oxidation causing destabilization of cell junctions.
Highlights
Particulate matter (PM) is the most common air pollutant with a serious global health threat contributing to millions of premature deaths annually worldwide
We assessed the effects of PM on EC barrier function by measuring endothelial permeability with two complementary approaches: measurement of transendothelial electrical resistance (TER) using ECIS array and evaluation of endothelial cell monolayer permeability for FITCavidin as described in Methods
To test whether PM-induced EC barrier disruption was accompanied by changes in AJ integrity, we performed immunofluorescence staining of VE-cadherin in pulmonary endothelial monolayers
Summary
Particulate matter (PM) is the most common air pollutant with a serious global health threat contributing to millions of premature deaths annually worldwide. The role of PM air pollution in the development or exacerbation of various heart and lung diseases is becoming increasingly recognized [1,2,3]. Among these diseases, two third include cardiovascular diseases such as ischemic heart disease, congestive heart failure etc. Truncated phospholipids define barrier-disruptive effects of particulate matter as chronic obstructive pulmonary disease, acute lower respiratory tract infections, pneumonia, asthma and lung cancer [3,4,5,6,7,8]. PM exposure induces epigenetic modifications especially DNA methylation and controls the expression of various inflammatory and oxidant stressrelated genes [17,18,19,20]
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