Am. J. Respir. Cell Mol. Biol.,
Volume 21, Number 2, August, 1999 185-192
Fibroblast Tropoelastin and 
-Smooth-Muscle Actin Expression Are
Repressed by Particulate-Activated Macrophage-Derived
Tumor Necrosis Factor- in Experimental Silicosis
Thomas J.
Mariani,
Meltem C.
Arikan,
and
Richard A.
Pierce
Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri
Lung elastin synthesis is normally confined to periods of development, is maximal during alveolarization,
and declines to low levels in mature lung. We have previously described an elastogenic response in the
adult rat lung associated with experimental granulomatous disease induced by silica instillation. Reinitiated tropoelastin expression was identified throughout the lung in fibroblasts expressing 
-smooth-muscle
actin, whereas fibroblasts within the granulomatous lesions failed to express both tropoelastin and -smooth-
muscle actin (Mariani and colleagues, Am. J. Pathol. 1995;147:988-1000). We hypothesized that inflammatory cells within the granulomatous lesions produce factors that alter fibroblast phenotype. We found that macrophages accumulating within granulomatous lesions of silicotic rat lungs produce and secrete tumor necrosis factor (TNF)-, a proinflammatory cytokine previously appreciated as a repressor of tropoelastin gene expression. In experimental cell systems, macrophages activated by particulates, either in
vivo or in vitro, conditioned medium with a tropoelastin-repressing activity. This activity repressed both
tropoelastin and -smooth-muscle actin expression in primary cultures of rat lung fibroblasts in a time-
dependent, transient manner. The particulate-activated macrophage-conditioned medium was found to
contain TNF-, which was both necessary and sufficient to induce these changes in lung fibroblast gene
expression. These data indicate that macrophage-derived factors can modulate lung fibroblast tropoelastin
expression in the diseased lung. Furthermore, the findings extend the association between expression by
lung fibroblasts of tropoelastin and -smooth-muscle actin.
