Evolution of lung lesions in rats exposed to mixtures of ozone and nitrogen dioxide

Cynthia A. Farman, Kent E Pinkerton, Padmanabhan Rajini, Hanspeter Witschi, Jerold A Last

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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 pulmonary fibrosis after about 8-10 wk of exposure, with a high level of mortality. 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 have 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 were performed. We also quantified the reparative potential of the airway epithelium after 4 and 8 wk of exposure by in vivo labeling with bromodeoxyuridine (BrdU). Histopathological evaluation by a variety of parameters indicated a triphasic response temporally: Inflammatory and fibrotic changes increased mildly for the first 3 wk of exposure, stabilized or apparently decreased during wk 4-6, and demonstrated severe increases over wk 7-9. Body weight data for these animals were consistent 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 differences from controls for the first 3 wk of exposure, significant increases in collagen content after 4-5 wk of exposure, and a stabilization of lung collagen content after 6 wk of exposure. The latter observation presumably reflects a balance of increased synthesis and increased degradation of collagen occurring simultaneously in the lungs of these 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 reparative capacity after 8 wk. We suggest that the diminished reparative capacity of the bronchiolar and alveolar epithelium may be causally linked with the rapid, progressive fibrosis that occurs in this model after about 7-8 wk of exposure to ozone plus NO2.

Original languageEnglish (US)
Pages (from-to)647-677
Number of pages31
JournalInhalation Toxicology
Issue number7
StatePublished - Sep 1997

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis


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