Enhanced nitric oxide and reactive oxygen species production and damage after inhalation of silica

1 Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505; and 2 Division of Applied Research and Technology, National Institute for Occupational Safety and Health, Cincinnati, Ohio 45226 In previous reports from this study, measurements of pulmonary inflammation, bronchoalveolar lavage cell cytokine production and nuclear factor- B activation, cytotoxic damage, and fibrosis were detailed. In this study, we investigated the temporal relationship between silica inhalation, nitric oxide (NO), and reactive oxygen species (ROS) production, and damage mediated by these radicals in the rat. Rats were exposed to a silica aerosol (15 mg/m 3 silica, 6 h/day, 5 days/wk) for 116 days. We report time-dependent changes in 1 ) activation of alveolar macrophages and concomitant production of NO and ROS, 2 ) immunohistochemical localization of inducible NO synthase and the NO-induced damage product nitrotyrosine, 3 ) bronchoalveolar lavage fluid NO x and superoxide dismutase concentrations, and 4 ) lung lipid peroxidation levels. The major observations made in this study are as follows: 1 ) NO and ROS production and resultant damage increased during silica exposure, and 2 ) the sites of inducible NO synthase activation and NO-mediated damage are associated anatomically with pathological lesions in the lungs. silicosis; fibrosis; oxidant injury; nitrotyrosine