A NEW MODEL OF PROGRESSIVE PULMONARY FIBROSIS IN RATS

Sprague-Dawley rats were exposed for 6 h daily to 0.8 ppm of ozone and 14.4 ppm of nitrogen dioxide. Approximately 7 to 10 wk after the init iation of exposure, animals began to demonstrate respiratory insuffici ency and severe weight loss. About half of the rats died between Days 55 and 78 of exposure; no overt ill effects were observed in animals e xposed to filtered air, to ozone alone, or to nitrogen dioxide. Bioche mical findings in animals exposed to ozone and nitrogen dioxide includ ed increased lung content of DNA, protein, collagen, and elastin, whic h was about 300% higher than the control values. The collagen-specific crosslink hydroxypyridinium, a biomarker for mature collagen in the l ung, was decreased by about 40%. These results are consistent with ext ensive breakdown and remodeling of the lung parenchyma and its associa ted vasculature. Histopathologic evaluation showed severe fibrosis, al veolar collapse, honeycombing, macrophage and mast cell accumulation, vascular smooth muscle hypertrophy, and other indications of severe pr ogressive interstitial pulmonary fibrosis and end-stage lung disease. This unique animal model of progressive pulmonary fibrosis resembles t he final stages of human idiopathic pulmonary fibrosis and should faci litate studying underlying mechanisms and potential therapy of progres sive pulmonary fibrosis.