Morphological changes and proliferative activity of alveolar epithelium in mouse lungs treated with urethan.

We have observed sequential cellular changes in type II pneumocytes in mouse lungs following oral administration of 0.1% urethan solution. Histologically, scatterings of swollen alveolar cells were first noticed 25 days after administration. These cells continued to swell further, after which they aggregated more compactly to form a papillary structure by day 75. After day 100, distinct tumour nodules were found with atypical large cells in some areas. Necrotic foci appeared in large tumours of more than 4 mm diameter. At day 250, nucleoli became distinct and large bizarre and multinucleated cells were intermingled with some mitotic figures. These morphologies correspond to conventional descriptions; that is, hyperplasia (day 25-75), benign neoplastic changes (day 75-100) and malignant neoplastic changes (day 100-250). The proliferating cell nuclear antigen (PCNA) and nucleolar organizer regions (AgNOR) scores in these lesions increased with time, and proliferative activities during tumour progression seemed continuous. However, proliferative activity of the cells on specific days did not differ statistically from the values on neighboring days. We speculate that the hyperplasia-like lesions seen in our mice are neoplastic in nature from their outset.