Pharmaceutical Considerations in the Use of Tetrandrine to Treat Silicosis

AN OVERVIEW OF THE ACTION OF TETRANDRINE ON SILICOSISBecause of the persistent presence of silica dust in the lungs silicosis is a progressive and irreversible disease. At present, there is no proven effective therapy for silicosis. Limited choices of therapeutic intervention with corticosteroids and other immunosuppressive regimens 1,2 have been accepted for some forms of pulmonary fibrosis. These treatments are only minimally effective, and the results provide little understanding of the disease state due to the lack of correlation between drug activity and the mechanism of fibrosis. Thus, continuing effort must be made in the search for effective antifibrotic agents, which may be used to provide a sequential analysis of the fibrotic process and to open the door for further research and clinical development. Tetrandrine is one of hundreds of drugs screened for antifibrotic activity by Chinese scientists. It has been used in China as a treatment for silicosis in open clinical trials3 and in laboratory animals. The action of tetrandrine on pulmonary fibrosis has been attributed to its ability to inhibit particle stimulation of alveolar macrophages, a key cell type central to the fibrotic process, to release oxygen radicals and inflammatory cytokines. Alveolar macrophages (AM) residing on the alveolar wall, are the predominant phagocytic cells of the lungs responsible for pulmonary defense against inhaled microorganisms and other particles and thus play an important role in maintaining the homeostasis of the lungs. 7 Ample evidence suggests that cells of the monocyte-macrophage series play an important role in the immunopathogenesis of pulmonary fibrosis. When upregulated by silica, alveolar macrophages generate reactive oxygen metabolites8·9 which can damage lung parenchyma and release fibrogenic growth factors and cytokines, 10,11 such as interleukin 1 (IL-1), which can induce fibroblast proliferation and collagen synthesis. The cytokine-mediated fibroblast proliferation and collagen synthesis are key steps in the development and progression of pulmonary fibrosis .11 Previous studies by our group have shown that tetrandrine exhibits strong binding affinity to AM and inhibits particle-stimulated respiratory burst activity (oxygen consumption, superoxide anion release, and hydrogen peroxide secretion) in these cells. 13 In addition, studies by Kang et al. 14 have reported that tetrandrine inhibits silica-induced release of fibrogenic factors such as IL-1 which are capable of inducing fibroblast proliferation and collagen synthesis. Reist et al. 15 further suggested that the antifibrotic action of tetrandrine may be mediated in part by the direct effect of this drug on the ability of fibroblasts to respond to proliferative agents. These results indicate that the mechanism of silicosis involves activation of AM and fibroblasts by silica, resulting in abnormal collagen production due to miscommunications between the cell types. Tetrandrine may interrupt this process by direct interaction with the lung cells.