Ultrafine particles alter endothelial phenotype through oxidant signaling

• Main Author: Snow, Samantha Jean
• Format: Dissertation
• Language: English
• Subjects: health sciences, toxicology
• ISBN: 1303104385; 9781303104381

Mechanisms that underlie the strong association between air pollution exposure and cardiovascular (CV) morbidity and mortality remain unknown. Particulate matter (PM) is a major component of air pollution and ultrafine (UF) particles, which are the smallest diameter particle, are of particular importance in CV dysfunction caused by exposure to air pollution. UF particles can deposit in the heavily vascularized region of the lung and the soluble components of UF particles (soluble UF) are able to cross from the lung into the circulation and adversely affect cells of the vasculature such as endothelial cells. Endothelial cell activation, as characterized by an increase in reactive oxygen species (ROS) production, initiation of coagulation, and induction in inflammation, is a pathophysiological mechanism that could link inhaled air pollutants to vascular dysfunction. This project will test the hypothesis that soluble UF cause altered endothelial cell phenotype through activation of oxidant signaling that mediates procoagulant and proinflammatory responses. EA cells, an immortalized endothelial cell line, and primary human coronary artery endothelial cells (HCAEC) were assessed for their production of ROS, procoagulant activity, and proinflammatory responses following exposure to non-cytotoxic doses of soluble UF. We show that exposure to soluble UF results in immediate increases in extra- and intracellular H2O2 production from NADPH oxidase (NOX) enzymes in endothelial cells. Furthermore, soluble UF PM increased the expression of proinflammatory mediators and induced endothelial procoagulant activity via a tissue factor (TF)-dependent mechanism. Pretreatment with antioxidants and NOX inhibitors attenuated the soluble UF-induced upregulation of the procoagulant protein TF, the proinflammatory cytokine IL-1β, and the oxidant stress-inducible protein HO-1, linking the procoagulant and proinflammatory responses to ROS formation from NOX enzymes. These novel findings provide mechanistic insight into the endothelial dysfunction and enhanced thrombosis that underly increased risk for CV morbidity and mortality associated with air pollution exposure.