Early molecular and cellular events of oxidant-induced pulmonary fibrosis in rats

To evaluate the early molecular events of oxidant-induced pulmonary fibrosi s, rats were continuously exposed to 0.4 ppm ozone and 7 ppm nitrogen dioxi de. The early responses to the combined gases could be divided into three p hases. Acute pulmonary inflammation indicated by an increase in pulmonary e dema as well as an influx of neutrophils into the airspaces first occurred on days 1 to 3 of the exposure. The pulmonary inflammation was reversed by day 8, and no biochemical or morphologic aspects of tissue responses were d etected from days 15 to 45, suggesting that rats adapted to the stimuli dur ing that period. Pulmonary fibrosis could be detected by an increase in the biomarker of lung collagen content at day 60 and by histopathologic evalua tion by day 90. Enhanced expression of macrophage inflammatory protein-2 wa s observed only at day 1, whereas the pulmonary expression of transforming growth factor-beta was upregulated on days 60 and 90 of the exposure. Macro phage expressions of interleukin-1 beta and interleukin-6 were enhanced dur ing acute pulmonary inflammation; however, macrophage expression of tumor n ecrosis factor-alpha was elevated at both day 1 and days 60-90. Activation of nuclear factor-kappa B and increased expression of thioredoxin in the lu ngs was also observed at day 1 and days 60-90. The expression of antioxidan t enzymes, such as manganeous superoxide dismutase and glutathione peroxida se, was not altered during exposure. These results indicate that macrophage activation and the expression of macrophage-derived cytokines may play an important role in the early pulmonary responses against the combined gases, (C) 2000 Academic Press.