Exposure to ambient air pollutants is associated with increased pulmonary and cardiovascular morbidity and mortality.While regulatory activities aimed at protecting the public health from the adverse effects of air pollution are based primarily on observational studies,a mechanistic understanding of the toxicology of ambient air contaminants provides biological plausibility and is pivotal to reducing complexity by grouping compounds by their mode of action,thus allowing for more effective targeting of mitigation strategies.Our studies have sought to define the links between exposure to air pollutants and the onset of inflammatory and adaptive cellular response that are believed to underlie the pulmonary and cardiovascular effects of inhalation of ambient air contaminants.Oxidant stress is a mechanism of toxic action that is common to a broad range of structurally diverse environmental agents,including relevant metallic,organic electrophiles and oxidant gases commonly found in ambient air.Exposure of cultured human airway epithelial cells to these air contaminants has been shown to disregulate signal transduction processes and lead to inflammatory and adaptive gene expression.A recent focus had been on the elucidation of mechanisms of signal initiation by the model environmental oxidants Zn2+,1,2-naphthoquinone and ozone.Our work has shown that inhibition of protein tyrosine phosphatase activity is a pivotal event leading to signaling activation by these oxidants.We are currently defining the nature of the oxidant responses using live cell imaging of human airway epithelial cells expressing genetically encoded sensors of reactive oxygen species and glutathione redox potential as early readouts in exposures conducted in real time.This work has identified the production of hydrogen peroxide of mitochondrial origin,with an accompanying increase in gluthatione redox potential,as important early indicators of oxidant stress in the cell.Ongoing studies seek to determine intracellular targets of oxidant species in order to gain additional mechanistic insights into the mechanism of action of individual air pollutant compounds and mixtures.