K. Yasuhara et al., MICE WITH FOCAL PULMONARY FIBROSIS CAUSED BY MONOCROTALINE ARE INSENSITIVE TO URETHANE INDUCTION OF LUNG TUMORIGENESIS, Toxicologic pathology, 25(6), 1997, pp. 574-581
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.