Abstract
Using a water-in-oil-in-water multiple emulsion system developed for pulmonary drug targeting, the effectiveness of tetrandrine as an antifibrotic agent and the therapeutic advantage of a tetrandrine emulsion over drug in solution for the treatment of silicosis were investigated in rats. Previously we have shown that the action of tetrandrine is attributed to its ability to inhibit the release of reactive oxygen metabolites and inflammatory cytokines by alveolar macrophages, and that targeted delivery of tetrandrine to alveolar macrophages using a multiple emulsion system minimizes drug toxicity, maintaines the drug's pharmacological activity, and enhances tetrandrine distribution in the lungs while reducing systemic drug distribution. The purpose of the present study is to provide in vivo evidence of emulsion-mediated enhancement of drug action in the lungs against silica-induced lung injury using a rat model. The antifibrotic action of tetrandrine was evaluated by examinations of lung histology, alveolar cell differentials, in vivo drug effect on macrophage respiratory burst, and the measurements of lung weight and collagen content. Tetrandrine was shown to inhibit the macrophage-orchestrated inflammatory process in response to silica exposure, preventing infiltration of neutrophils into the alveolar space. In addition, the drug was also shown to protect the cells from silica-induced toxicity and stimulation, and to restore healthy alveolar macrophage populations in the alveolar region. Intervention of the silica effect with tetrandrine markedly decreased light microscopic lung lesions. These results were also supported by quantitative inhibition of a silica-induced increase in lung weight and collagen content by tetrandrine. In all experiments the tetrandrine emulsion system was shown to be consistently more efficacious than the solution dosage form in the treatment of silica-induced granulomatous pneumonia, alveolar lipoproteinosis consistent with acute silicosis, and fibrosis. These results confirm our hypothesis regarding the functional and morphologic interactions of emulsions with alveolar macrophages in vivo.