Mechanisms in the pathogenesis of asbestosis and silicosis.

Interstitial pulmonary fibrosis caused by the inhalation of asbestos fibers or silica particles continues to be an important cause of interstitial lung disease. Although more stringent control of asbestos in the workplace and decreasing industrial use has contributed to declines in the prevalence of asbestosis in the United States (1), new cases continue to be identified. Similarly, silicosis is seen among sandblasters, underground miners, foundry and quarry workers, and in other dust-exposed trades (2). Both diseases, which may have relatively long latency periods, are observed in the clinic today, usually as a result of high occupational exposures in the past, and they are problematic in that treatment with corticosteroids and immunosuppressants, the usual approaches to therapy for fibrotic lung disease, is ineffective (3). Asbestos and silica are complex, naturally occurring minerals that are chemically and physically distinct. Moreover, the pathology of asbestosis and silcosis is dissimilar. However, the pathogenesis of these lesions and the major changes in pulmonary architecture, namely, the laying down of collagen in an interstitial location, appear to be similar to many of the features seen in idiopathic pulmonary fibrosis (IPF). Like IPF and representative animal models of IPF such as bleomycin instillation (4), both asbestosis and silicosis are characterized by a persistent inflammatory response and generation of proinflammatory and profibrotic mediators. Although asbestosis and silicosis have been studied intensely by basic and clinical research scientists, little is known about the crucial cellular mechanisms that initiate and drive the processes of inflammation and fibrogenesis. Many laboratories have developed animal and in vitro models of asbestosis and silicosis to elucidate the cellular events and properties of minerals important in disease causation. Others have explored confounding factors contributing to particulate-induced cell injury as well as cellular and molecular defense mechanisms in response to these minerals. This information has been used to modulate inflammation and fibrosis in expermental animal models in attempts to develop more effective treatment regimens for pulmonary fibroses. This review will briefly address the clinical and pathologic features of asbestosis and silicosis, and consider the mineralogic features of asbestos and silica that may be important in disease causation along with confounding factors such as coexposures to smoking and/or other mineral dusts. The relationship of particle number, type, and size to disease patterns will be reviewed. We will then summarize data published within the past 5 yr on cellular and molecular mechanisms of asbestosis and silicosis and preventive approaches to these diseases in experimental animal models. Lastly, we emphasize in our SUMMARY AND CONCLUSIONS the common mediators and cell types affected in the pathogenesis of both mineral-related and other forms of pulmonary fibrosis and plausible interrelationships between the development of fibrosis and lung cancer, a disease linked to occupational exposures to asbestos and possibly to exposures to silica (1, 5).