Alterations in Alveolar Type II Cell Metabolism Induced by Tetrandrine and Other Alkaloids

"The bisbenzylisoquinoline alkaloids are compounds which can be isolated from plants and which exhibit a broad range of pharmacological activities. Perhaps the best known alkaloid of this group is tetrandrine (TT), a compound isolated from the root of a traditional Chinese medicinal herb, Stephania tetrandra. It has been tested for its effects on the cardiovascular system, tumors, and the lungs. For example, tetrandrine has been shown to act as a calcium entry blocker in cardiac sarcolemmal vesicles (King et a/., 1988) and has been used in China as a treatment for angina and hypertension. Its possible effects as a tumor-inhibitory substance have also been investigated (Kupchan and Atland, 1973). In addition, there are several lines of evidence to suggest that it is a possible therapeutic agent for the treatment of silicosis. Yu et a/. (1983) have shown that TT inhibits the development of experimental silicosis in rats when it is administered orally after intratracheal instillation of quartz. Other studies have shown that the alkaloid inhibits the synthesis of collagen by fibroblasts and the formation of silicotic nodules in rats exposed to silica (Huang et al., 1981; Liu et al., 1983). In fact, tetrandrine has been used clinically in China as an antifibrotic agent and has been shown to improve both the appearance of chest radiographs and the measurements of diffusing capacity in patients with silicosis (Li et al., 1981).Since tetrandrine may have a potential use as a therapeutic agent for fibrotic lung diseases, its effects on various pulmonary cells and tissues should be studied. Alveolar type II cells are located in the alveolar regions of the lungs and are important because they are responsible for the synthesis and secretion of pulmonary surfactant (Dobbs et al., 1982; King, 1984), regeneration of the alveolar epithelium after lung injury (Kauffman et al., 1974), and metabolism of foreign compounds (Bend et al., 1985). Furthermore, in silicosis, for which TT has been suggested as a treatment, there are increased amounts of pulmonary surfactant produced (Dethloff et al., 1986a,b) as a result of increased rates of surfactant synthesis by type II cells (Dethloff et a/., 1989; Miller et al., 1988). Because type II cells play a critical role in maintaining normal lung function and because type II cells are affected in silicosis, for which 'TT has been used as a treatment, we studied the effects of tetrandrine on energy metabolism in these cells in vitro. Energy metabolism was chosen because it is a basic cellular function which is neces-sary for other cellular processes to occur. Since type II cells depend on mitochondrial metabolism for energy production (Fisher et al., 1980), we examined the effects of tetrandrine on cellular and mitochondrial ATP production and oxygen consumption. Additional experiments were performed in an effort to determine if intracellular calcium levels may be involved in the TT-induced effects. A preliminary report of those results has appeared previously (Ma et al., 1991)."