Inhibition of Proliferative Activity of Pulmonary Fibroblasts by Tetrandrine

"Silicosis is a fibrotic pulmonary disease produced by inhalation of silica-containing dusts (Peters, 1986). Chronic silicosis may develop 20-40 years after initial exposure to crystalline silica, and the disease may progress from a simple to a complicated form. Few symptoms are evident in simple silicosis with pulmonary function being relatively normal. However, chest radiographs reveal small rounded ·opacities in the upper lobes of the lungs. These silicotic nodules consist of collagen arranged in a distinctive circular pattern. As fibrotic changes become more severe, the disease progresses to complicated silicosis (progressive massive fibrosis). Complicated silicosis is associated with shortness of breath and decreases in pulmonary function characteristic ofrestrictive lung disease. Chest x rays reveal numerous large silicotic nodules which may be associated with scar emphysema. Several mechanisms have been proposed to explain the cellular events which result in silica-induced lung damage and fibrosis (Lapp and Castranova, 1993). They include: ( l) direct cytotoxicity of silica, (2) activation of oxidant and enzyme release from alveolar macrophages, (3) recruitment and activation of polymorphonuclear leukocytes, and (4) stimulation of fibroblast proliferation and collagen synthesis.Tetrandrine is a bisbenzylisoquinoline alkaloid derived from the Chinese herb Radix Stephania tetrandra. It has a molecular weight of 622.73 and an empirical formula of C38H420 6N2. The chemical structure of tetrandrine has been published previously by our laboratory (Castranova et al., 1991 a). Its structure is characterized by methoxy groups at C7 and C12 , uncharged nitrogens at N2 and N’2 and two 17-carbon ring members connected by a double oxygen bridge between Ca-C7 and C11-C12. Tetrandrine has been shown to reduce both silica-induced fibrosis and the elevation of lung collagen content in rats (Huang et al .. 1981; Yu et al., 1983; ldel, 1987). Furthermore, tetrandrine has been used as an antifibrotic agent in Chinese clinical trials (Li et al.. 1981 ). Preliminary results suggest that administration of tetrandrine to patients with silicosis results in substantial improvement of symptoms, increases in diffusion capacity, and decreases in the size of shadows on lung x rays."