Dose-related airway-selective epithelial toxicity of 1-nitronaphthalene in rats

Nonciliated ("Clara") cells of terminal bronchioles are one of the principal targets of bioactivated pulmonary toxicants. However, we have recently observed cytotoxicity in proximal tracheobronchial airways with high doses of naphthalene. To test if this was true for other xenobiotics, 1-nitronaphthalene (25, 50, 100, or 150 mg/kg) was injected i.p. into male Sprague-Dawley rats and cytotoxicity characterized 24 hr later by high-resolution histopathology along a defined airway path extending from the trachea to the terminal bronchioles. At 25 mg/kg, only nonciliated cells in minor daughter airways were swollen and necrotic. At 50 mg/kg there was near complete loss of nonciliated cells in most bronchioles, minor daughter airways, and tracheas. Marked damage to ciliated cells was observed at doses of 100 and 150 mg/kg. Denudation of the basement membrane was common in the trachea. We conclude for 1-nitronaphthalene cytotoxicity in the lung that: (1) nonciliated cells of the distal bronchioles are not the only target, (2) the threshold for injury in nonciliated cells is lower than that for ciliated cells, (3) the response is airway selective, (4) the response is dose-related.