Manipulation of injury and repair of the alveolar epithelium using two pneumotoxicants: 3-methylindole and monocrotaline

The role of type II epithelial cell proliferation in repair of diffuse alve olar epithelial injury was examined using two pneumotoxicants, 3-methylindo le (3-MI) and monocrotaline (MCT). It was hypothesized that if MCT inhibits type II epithelial cell mitosis, then pulmonary fibrosis would result afte r diffuse 3-MI-induced type I alveolar cell injury in rats preadministered MCT. Four groups of rats were given vehicle control, MCT, 3-MI, or MCT and 3-MI. Lungs from rats killed 4 days post-treatment were examined subjective ly and quantitatively by light and electron microscopy. Proliferative stimu lus was estimated by bromodeoxyuridine (BrdU) incorporation. Lungs from rat s killed 2 weeks post-treatment were evaluated by light microscopy. At 4 da ys, the number of type II cells in the lungs of 3-MI-treated rats was 3 tim es greater than in the lungs of the dually (MCT/3-MI) treated rats which wa s the same as the control rat lungs. There was no significant difference be tween the MCT/3-MI-treated rats and the 3-MI-treated rats with regard to th e percentage of denuded alveolar basement membrane. The number of BrdU-labe led type II epithelial cells was increased above the control in both 3-MI-t reated groups, but was greater in the 3-MI-treated rat lungs than in the lu ngs of the MCT/3-MI-treated rats. The average type II cell volume in dually treated rats was 3 times the volume in the control animals and 50% greater than that in 3-MI-treated rats, Transmission electron microscopy of the lu ngs of the MCT/3-MI-treated rats demonstrated flattened hypertrophic type I I cells over large portions of the basement membrane. The light microscopic appearance and collagen staining of the lungs of the dually treated rats w ere similar to the negative control rat lungs 2 weeks after dosing with 3-M I. This suggests that despite a proliferative stimulus, MCT inhibits type I I cell division after diffuse alveolar type I cell injury, but that type II cell migration and coverage of the basal lamina proceed. Results of this s tudy suggest that coverage of the denuded basal lamina by any method is suf ficient to prevent interstitial alveolar fibrosis.