We have established animal models to elucidate the basic cellular mechanisms associated with interstitial fibrosis caused by inhalation of asbestos and silica. The initial deposition sites of the particles and the nature of the earliest lesions consequent to deposition have been demonstrated. Autoradiography and ultrastructural morphometry have been used to show the cellular alterations which occur at alveolar duct bifurcations (i.e., sites of particle deposition) at varying times after a brief exposure (1 or 5 hrs) to chrysotile asbestos. Within 24 hrs after a 5-hr exposure, there was a highly significant increase in macrophage accumulation at the bifurcation of alveolar ducts. Now we have shown for the first time that concurrent with macrophage accumulation increased numbers of terminal bronchiolar epithelial cells, proximal alveolar duct epithelial cells and alveolar duct bifurcation epithelial cells incorporated tritiated thiymidine (3HTdr) into nuclei. In addition, there were significant increases in the number and volume of epithelial and interstitial cells in all three anatomic compartments. We have attempted to establish the biochemical and cellular mechanisms through which these initial pulmonary lesions are induced. We postulate that the pulmonary macrophages which accumulate in association with inhaled asbestos produce growth factors that are mitogenic for interstitial fibroblasts and possibly for epithelial cells. We have demonstrated in vitro that rat pulmonary macrophages secrete a growth factor for early passage rat lung fibroblasts when stimulated with a variety of particles. This macrophage-derived growth factor has several biochemical characteristics similar to platelet-derived growth factor and is chemotactic for other pulmonary macrophages. Ongoing studies are designed to establish whether or not this factor is secreted by macrophages in vivo and if it plays a role in the pathogenesis of pulmonary fibrosis.
