Effects of Bisenzylisoquinoline Alkoloids on AlveolarMacrophages: Correlation Between Binding Affinity, Inhibitory Potency, and Antifibrotic Potential

"Effects of Bisbenzylisoquinoline Alkaloids on Alveolar Macrophages: Correlation between Binding Affinity. Inhibitory Potency and Antifibrotic Potential. CASTRANOVA, V., KANG, J-H., MA. J. K. H., Mo, C-H., MALANGA, L. J., MOORE M. D., SCHWEGLER-BERRY, D.. AND MA. J. Y. C. (1991). Toxicol. Appl. Pharmacol 108, 242-252. The Chinese have conducted extensive studies concerning the medicinal properties of plant products. In this investigation the ability of three bisbenzylisoquinoline alkaloids to inhibit particle-induced activation of alveolar macrophages was evaluated and this inhibitory potential was correlated with the ability of those drugs to bind to membrane components. Tetrandrine. i.e.. an herbal medicine used as an antifibrotic agent in China, was a potent inhibitor of particle-stimulated oxygen consumption, superoxide release, and hydrogen peroxide secretion by alveolar macrophages. Tetrandrine also exhibited substantial binding affinity for membrane lipids and alveolar macrophages. In contrast, tubocurine, an analogue with little antifibrotic potential, exhibited low binding affinity and had little effect on macrophage activation. Methoxyadiantifoline, an alkaloid of unknown antifibrotic potential, exhibited inhibitory and binding properties similar to those of tetrandrine. The data indicate that a strong relationship exists between the antifibrotic potential of these alkaloids and their ability to bind to alveolar macrophages and inhibit particle-induced activation of these phagocytes. These drugs should serve as useful probes to evaluate the role of alveolar macrophages in pulmonary fibrosis. © 1991 Academic Press, Inc.Chronic silicosis is a fibrotic disease resulting from occupational exposure to silica dust. It is manifested initially by an increase in the quantity of pulmonary surfactant (Dethloff et al., 1986). However, in later stages it is characterized by an increase in collagen formation and the development of concentric hyalinized nodular lesions in the lung (Ziskind et al., 1976). Although mechanisms for the progression of silicosis have not yet been completely defined, activation of alveolar macrophages by respirable silica particles is believed to play an important role in the etiology of this disease. Studies from our laboratory have shown that both in vitro and in vivo silica exposures result in a stimulation of macrophage release of reactive products capable of damaging the lung parenchyma (Castranova et al., 1990; Goodman et al., 1990). In addition, exposure of al¬veolar macrophages to silica results in the release of fibrogenic factors which enhance the proliferation of fibroblasts and the synthesis of collagen by these pneumocytes (Leibovich and Ross, 1976; Bitterman et al., 1982, 1983).The bisbenzylisoquinoline alkaloids, which represent the largest group among the iso-quinoline compounds isolated from the plant kingdom, are known to exhibit a broad rangeof pharmacological activities. Tetrandrine, for example, an alkaloid isolated from the root of Stephania tetrandra, has been tested for its antitumor, antihypertensive, and antisilicotic effects (Kupchan and Atland, 1973; Zeng et al., 1985; Yu et al., 1983). It is currently used in China as a treatment for angina, hypertension, and silica-induced pulmonary fibrosis (Li et al., 1981). Several related bisbenzylisoquinoline alkaloids such as methoxyadiantifoline and tubocurine have also been evaluated for medicinal effects. Methoxyadiantifoline has been shown to exhibit effects on the cardiovascular system similar to those reported for tetrandrine (Jia et al., 1988). However, to date, the antifibrotic activity of methoxyadiantifoline has not been evaluated. In contrast to tetrandrine, tubocurine, a structural analogue of this drug, has been reported to be relatively ineffective against fibrosis (Mo et al., 1982)."