Impact of environmental air pollution on arginine metabolism in the lung.

点击翻译按钮获取中文摘要

Transient epigenetic changes in gene expression can occur in response to environmental stressors. We have observed epigenetic changes of the inducible nitric oxide synthase gene (NOS2) (i.e., DNA promoter methylation) in peripheral blood monocytes over the course of 24 hours following exposures of normal healthy human subjects to fine particulate matter (PM2.5). Recent investigations from my laboratory have shown alterations in miRNA profiles that may affect gene expression of L-arginine-related metabolic pathways (i.e., those responsible for L-arginine uptake, production and catabolism of the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine, nitric oxide synthase and arginase), following chronic exposure of mice to diesel particulate matter from two different sources (i.e., PM2.5 collected from a diesel-fueled generator vs. a diesel forklift truck, which produce distinct PM profiles and chemical reactivities). Preliminary data in support of this proposal have shown reduced arginine bioavailability in lungs from mice exposed acutely (4hrs) to PM2.5 + ozone, as well as increased production of endogenous NOS inhibitors (methylarginines and polyamines). These changes in arginine metabolism can affect both lung function (i.e., through impaired production of the airway relaxant, nitric oxide) and cellular function (i.e., ADMA accumulation in the mitochondria can impact cellular respiration and the resultant oxidative stress). Thus, the fundamental hypothesis of this study is that exposure to PM influences the expression of proteins related to arginine metabolism, which can impact lung function and the cellular responses to PM. As a result, the goals of the current proposal are to investigate the impact of air pollution-induced alterations of L-arginine metabolism on the lung (i.e., basic lung function and responsiveness to contractile agonists) and cellular function (i.e., viability, indices of nitrosative and oxidative stress, and mitochondrial energetics). We will investigate the scope of the changes in the arginine metabolome in mice exposed acutely to coarse, fine or ultrafine PM using our unique real-time in vivo air pollution exposure unit as part of the Southern Ontario Centre for Atmospheric Aerosol Research (SOCAAR; www.socaar.utoronto.ca), and chronically using intranasal instillation of size-fractionated PM collected in the concentrated ambient particle exposure unit. We will then determine the impact of acute and chronic PM exposures on changes in the arginine metabolome in airway epithelial cells, grown at the air-liquid interface, focusing on the impact on cellular stress, mitochondrial function and the mechanisms responsible for such alterations. Findings from these investigations will provide important information with respect to the impact of exposures to environmental air pollutants on lung function.