Neprilysin (NEP) is a key cell surface peptidase in the maintenance of airway homeostasis and the development of pulmonary disorders. However, little information is available about the effect of particulate matter (PM) on airway NEP. In this controlled human exposure study, changes in induced sputum were measured in 11 subjects at baseline, overshot (OS) mucking, and diesel exhaust (DE) exposure days. Neither OS condition nor DE exposure was found to induce significant changes in total protein, but DE induced significant increases in cell numbers of macrophages and epithelium. Moreover, significant increases in soluble NEP were observed following OS mining dust particulates (0.43 +/- 0.06 nmol/microg protein/min; p = .023) and DE exposure (0.40 +/- 0.03 nmol/microg protein/min; p = .035) when compared with the baseline control (0.30 +/- 0.04 nmol/microg protein/min), with 42% and 31% average net increase, respectively. Pearson's correlation analyses indicated that sputum NEP activity was significantly associated with personal exposure product (elemental carbon concentration [mg/m(3)] x time [min]; C x T). The data suggest that changes in NEP activity may be an early, accurate endpoint for airway epithelial injury and provide a new insight into the mechanism of airway effects following particulate exposure.