Fibroblast tropoelastin and alpha-smooth-muscle actin expression are repressed by particulate-activated macrophage-derived tumor necrosis factor-alpha in experimental silicosis

Lung elastin synthesis is normally confined to periods of development, is m aximal during alveolarization, and declines to low levels in mature lung. W e have previously described an elastogenic response in the adult rat lung a ssociated with experimental granulomatous disease induced by silica instill ation. Reinitiated tropoelastin expression was identified throughout the lu ng in fibroblasts expressing alpha-smooth-muscle actin, whereas fibroblasts within the granulomatous lesions failed to express both tropoelastin and a lpha-smooth-muscle actin (Mariani and colleagues, Am. J. Pathol. 1995;147:9 88-1000). We hypothesized that inflammatory cells within the granulomatous lesions produce factors that alter fibroblast phenotype, We found that macr ophages accumulating within granulomatous lesions of silicotic rat lungs pr oduce and secrete tumor necrosis factor (TNF)-alpha, a proinflammatory cyto kine previously appreciated as a repressor of tropoelastin gene expression. In experimental cell systems, macrophages activated by particulates, eithe r in vivo or in vitro, conditioned medium with a tropoelastin-repressing ac tivity. This activity repressed both tropoelastin and alpha-smooth-muscle a ctin expression in primary cultures of rat lung fibroblasts in a time depen dent, transient manner. The particulate-activated macrophage-conditioned me dium was found to contain TNF-alpha, which was both necessary and sufficien t to induce these changes in lung fibroblast gene expression. These data in dicate that macrophage-derived factors can modulate lung fibroblast tropoel astin expression in the diseased lung. Furthermore, the findings extend the association between expression by lung fibroblasts of tropoelastin and alp ha-smooth-muscle actin.