Am. J. Respir. Cell Mol. Biol.,
Volume 20, Number 2, February, 1999 303-311
Centriacinar Remodeling and Sustained Procollagen Gene Expression
after Exposure to Ozone and Nitrogen Dioxide
Cindy A.
Farman,
Karen
Watkins,
Brent
van Hoozen,
Jerold A.
Last,
Hanspeter
Witschi,
and
Kent E.
Pinkerton
California Regional Primate Research Center, School of Veterinary Medicine, Institute of Toxicology and
Environmental Health and Pulmonary/Critical Care Medicine, Department of Internal Medicine,
School of Medicine, University of California, Davis, California
Sprague-Dawley rats were exposed to 0.8 ppm ozone (O3), to 14.4 ppm nitrogen dioxide (NO2), or to both
gases simultaneously for 6 h per day for up to 90 d. The extent of histopathologic changes within the central acinus of the lungs was compared after 7 or 78 to 90 d of exposure using morphometric analysis by
placement of concentric arcs radiating outward from a single reference point at the level of the bronchiole-
alveolar duct junction. Lesions in the lungs of rats exposed to the mixture of gases extended approximately
twice as far into the acinus as in those exposed to each individual gas. The extent of tissue involvement
was the same at 78 to 90 d as noted at 7 d in all exposure groups. At the end of exposure, in situ hybridization for procollagen types I and III demonstrated high levels of messenger RNA within central acini in the
lungs of animals exposed to the combination of O3 and NO2. In contrast, animals exposed to each individual gas had a similar pattern of message expression compared with that seen in control animals, although
centriacinar histologic changes were still significantly different from control animals. We conclude that
the progressive pulmonary fibrosis that occurs in rats exposed to the combination of O3 and NO2 is due to
sustained, elevated expression of the genes for procollagen types I and III. This effect at the gene level is
correlated with the more severe histologic lesions seen in animals exposed to both O3 and NO2 compared
with those exposed to each individual gas. In contrast, the sustained expression of the procollagen genes is
not associated with a shift in the distribution of the lesions because the area of change in each group after 7 d
of exposure was the same as after 78 to 90 d of exposure.
