MICE WITH FOCAL PULMONARY FIBROSIS CAUSED BY MONOCROTALINE ARE INSENSITIVE TO URETHANE INDUCTION OF LUNG TUMORIGENESIS

To establish the characteristics of an optimized pulmonary fibrosis mo del, male ICR mite were given 4 weekly sc injections of 150 or 0 mg/kg monocrotaline (MCT) and maintained without further treatment for 33 w k (Experiment 1). The final mortality in the MCT group was 64%. Epithe lial cells with large bizarre nuclei and an increased incidence of alv eolar/bronchiolar hyperplasias were typically observed. In areas of pu lmonary fibrosis, the PCNA labeling index (LI) in the alveolar/airway epithelium was significantly elevated. DNA content analysis demonstrat ed a larger range (4-8C) for the ploidy pattern of alveolar epithelium with large bizarre nuclei than in the normal epithelium (2C). In Expe riment 2, the relationship between pulmonary fibrosis development and lung tumorigenesis was investigated. Mice were given 4 weekly sc injec tions of 150 and 0 mg/kg MCT, followed by a single ip injection of 1,0 00 or 500 mg/kg urethane (UR) on week 7, then maintained without furth er treatment for an additional 15 wk. UR following MCT-induced inflamm atory changes, fibrosis, and epithelia with large bizarre nuclei but n o tumorous lesions, in spite of the fact that treatment with UR alone caused a high incidence of pulmonary tumors. Hyperplasias were seen in all groups, but the multiplicity in the combined groups tended to be decreased by the MCT pretreatment. The present study demonstrated that this new protocol is more suitable than previous one for the experime ntal production of pulmonary fibrosis. Furthermore, the induction of l ung tumors by UR was completely depressed in mice with MCT-induced pul monary fibrosis, suggesting that alveolar epithelial cells are resista nt to this lung carcinogen under these conditions.