EVOLUTION OF LUNG LESIONS IN RATS EXPOSED TO MIXTURES OF OZONE AND NITROGEN-DIOXIDE

In previous work we have shown that rats exposed to 0.8 ppm ozone and 14.4 ppm NO2 for 6 h daily develop progressive bronchiolitis and pulmo nary fibrosis after about 8-10 wk of exposure, with a high level of mo rtality. To begin to understand the mechanisms of fibrogenesis in this animal model, and especially what processes are occurring during the approximately 2- to 2.5-month long period of lesion development, we ha ve determined the time course of evolution of fibrotic lesions in rats exposed to ozone and NO2. Rats were sampled weekly for 9 wk from the onset of exposure, and biochemical and histopathological evaluations w ere performed. We also quantified the reparative potential of the airw ay epithelium after 4 and a wk of exposure by in vivo labeling with br omodeoxyuridine (BrdU). Histopathological evaluation by a variety of p arameters indicated a triphasic response temporally: Inflammatory and fibrotic changes increased mildly for the first 3 wk of exposure, stab ilized or apparently decreased during wk 4-6, and demonstrated severe increases over wk 7-9. Body weight data for these animals were consist ent with an ongoing process starting from the first week of exposure. Biochemical quantification of lung 4-hydroxyproline (collagen) content showed a pattern consistent with the histopathology: no significant d ifferences from controls for the tint 3 wk of exposure, significant in creases in collagen content after 4-5 wk of exposure, and a stabilizat ion of lung collagen content after 6 wk of exposure. The latter observ ation presumably reflects a balance of increased synthesis and increas ed degradation of collagen occurring simultaneously in the lungs of th ese rats. In vivo determination of cumulative labeling indexes showed normal (or slightly decreased) repair of the small airway and alveolar epithelium after 4 wk of exposure, with significantly diminished repa rative capacity after 8 wk. We suggest that the diminished reparative capacity of the bronchiolar and alveolar epithelium may be causally li nked with the rapid, progressive fibrosis that occurs in this model af ter about 7-8 wk of exposure to ozone plus NO2.