Exposure to ozone alters homeostasis of the respiratory system, especially in areas which are susceptible to acute ozone-induced injury. We have established an animal model of progressive pulmonary disease in rats that leads to an end-stage that closely resembles human idiopathic pulmonary fibrosis. This animal model will be further characterized in its evolution by histopathology and by biochemical analysis of lung tissue for hydroxyproline, desmosine and collagen cross-links. To elucidate the mechanism of lung fibrogenesis in this model, we will specifically test two hypothesis: progressive disease may be caused by an exhaustion of the epithelial precursor cell pool in the lung, and event that may trigger fibrotic development. This hypothesis will be approached by cell kinetic analysis. The other hypothesis to be tested will be that depletion of one or more essential lung antioxidant defenses is a critical event. Levels of chemical defense systems (glutathione, vitamins C and E) and activities of selected antioxidant defense enzymes will be measured. Finally we will explore the possibility that in the pathogenesis of progressive lung disease, intermittent exposure is more deleterious than is continuous exposure and that the disease eventually may progress even in the absence of further exposure.
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