We have reported previously that crushing or grinding crystalline silica results in the generation of silica-based radicals on the particulate surface and that these radicals can generate hydroxyl radicals in aqueous solution. Data in the present study indicate that freshly ground silica is more cytotoxic and is a more potent activator of alveolar macrophages than comparably sized aged silica. That is, compared to aged silica, fresh silica is 4.2-fold more potent in decreasing the membrane integrity of macrophages; is 50% more potent in activating hydrogen peroxide secretion by macrophages; and is 4.6-fold more potent in stimulating cellular chemiluminescence. Prosil 28, an organosilane material, is an effective coating agent for fresh silica. It decreases the cytotoxicity of fresh silica by as much as 78% and decreases the ability of fresh silica to induce chemiluminescence from alveolar macrophages by 58%. The data suggest that surface radicals associated with freshly cleaved dust may be an important factor in the induction of pulmonary disease. Furthermore, treating dust with coating agents may substantially decrease toxicity.

Tetrandrine is a bisbenzylisoquinoline alkaloid which has been shown to exhibit antifibrotic activity against silicosis. Tetrandrine is characterized by its strong binding to alveolar macrophages and inhibition of particle-induced respiratory burst activity in these phagocytes. In contrast, tubocurine and tubocurarine are structurally similar to tetrandrine but exhibit little effect on fibrosis or activation of alveolar macrophages. The objective of the present study was to test the effect of tetrandrine on macrophage production of monokines in response to occupational dusts, and to determine tetrandrine's effect on monokine-medicated cell growth using a mouse thymocyte proliferation assay and lipopolysaccharide (LPS) as a positive control. Stimulation of alveolar macrophages by respirable silica dust resulted in a release of monokines which caused a fourfold increase in thymocyte proliferation. Coal dust, on the other hand, had no effect on macrophage production of this cytokine. Tetrandrine was found to exhibit a dose-dependent inhibition of monokine release from both silica and LPS-stimulated alveolar macrophages. In experiments where thymocytes were directly treated with tetrandrine, a dose-dependent inhibition of thymocyte proliferation was noted with both interleukin-1-(IL-1) specific and nonspecific mitogenic (concanavalin A) actions. In contrast to the inhibitory potency of tetrandrine, tubocurarine was found to have no effect on either the production of monokines by LPS-stimulated alveolar macrophages or IL-1-mediated thymocyte proliferation. These results provide a correlation between the antifibrotic effect of tetrandrine and inhibition of macrophage activation.

Tetrandrine is an alkaloid obtained from the root of a medicinal herb which is employed in China as a treatment for silicosis. One proposed mechanism for the development of silica-induced fibrosis is lung damage resulting from particle-induced inflammation and secretion of reactive compounds from alveolar phagocytes. Therefore, the objective of the present study was to determine if tetrandrine exhibited the ability to inhibit respiratory burst activity of pulmonary phagocytes. The data indicate that although tetrandrine is not cytotoxic to phagocytic cells, it is a potent inhibitor in vitro of zymosan-stimulated oxygen consumption, superoxide anion release, and hydrogen peroxide secretion by alveolar macrophages. Tetrandrine is also effective in vivo in preventing activation of alveolar macrophages after inhalation or intratracheal instillation of silica. Tetrandrine also inhibits stimulant-induced chemiluminescence by polymorphonuclear leukocytes. Since tetrandrine does not alter stimulant-induced depolarization of phagocytic cells, its inhibitory action is not via interference with receptor-ligand binding but rather must occur elsewhere in the stimulus-secretion coupling scheme.

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