Effects of long-term nitrogen dioxide exposure on rat lung: morphological observations.

Rats continuously exposed to NO2 at 0.04, 0.4, and 4.0 ppm for as long as 27 months were submitted to morphological observation and electronmicroscopic morphometry of the lung. At 4 ppm exposure for 9 months, bronchial epithelium showed typical proliferation, which progressed further at 18 months. At this stage, proliferation of type II alveolar epithelium and edematous extension of interstitial tissue were evident and yielded fibrosis at 27 months. At 0.4 ppm, morphological changes in 18-month specimens were still ambiguous, although a tendency toward epithelial changes, as well as interstitial edema of the alveolar wall, was noticed under the electron microscope. Slight but definite alteration of the epithelium became evident after 27 months. At 0.04 ppm there were no remarkable changes throughout the entire exposure period. The morphometry revealed concentration- and duration-dependent increases in arithmetic mean thickness (AMT) of the alveolar wall. At 4 ppm, increase of AMT started as early as 9 months, became significant at 18 months, and showed a slight decrease at 27 months. This decrease was interpreted as a recovery of alveolar epithelium and decreased amount of septal edema, which in turn led to fibrosis. At 0.4 ppm, a slight increase of AMT started at 18 months and extended significantly in 27 months. A similar but insignificant tendency was found even at 0.04 ppm. The morphological alterations were parallel to the concentration and duration of exposure. These findings suggested that an intensive study should be conducted to confirm whether alterations were due to prolonged exposure and/or due to elevated sensitivity of the aged lung.