PULMONARY INFLAMMATION AND FIBROSIS FOLLOWING SUBACUTE INHALATIONAL EXPOSURE TO SILICA - DETERMINANTS OF PROGRESSION

To evaluate components of the pulmonary cellular response to inhaled s ilica that might be determinants of progression to fibrosis, we develo ped a model of the early stages of chronic human silicosis. Groups of mice were subacutely exposed either to alpha-quartz or to nonfibrogeni c titanium dioxide dust as a control. Induction of lesions by inhaled silica was dependent upon the size distribution and dose of the partic les. A novel observation was that low intensity exposure to silica evo ked reversible inflammatory lesions that were characterized by focal a ggregation of particle-laden alveolar macrophages near terminal airway s. In contrast, higher intensity exposure elicited progressive pulmona ry inflammation, including a significant perivascular influx of T-lymp hocytes early in the response. The airspace inflammatory lesions exhib ited a statistically significant decline in numerical density over tim e. Meanwhile, deposition of collagen was observed at perivascular loca tions, which were anatomically distinct from the initial foci of infla mmation, and the numerical density of fibrotic lesions increased signi ficantly with time. We speculate that this pattern of response might b e related to alveolar clearance mechanisms being overwhelmed, followed by translocation and sequestration of particles in the interstitium, subsequently leading to T-lymphocyte recruitment and ultimately to the development of fibrosis.