Fibroblast proliferation induced by silica-exposed human alveolar macrophages.

Inhalation of silica dust is an important cause of pulmonary fibrosis. In these studies, we demonstrate that supernatants of silica-stimulated human alveolar macrophages cause significantly (p less than 0.05) greater amounts of fibroblast proliferation than do supernatants of macrophages stimulated with optimal amounts of endotoxin (LPS). The amount of fibroblast proliferation was similar (p greater than 0.2) in the presence of supernatants of LPS-stimulated macrophages and supernatants of unstimulated adherent macrophages. When macrophages were stimulated with LPS in the presence of indomethacin (to inhibit the cyclooxygenase pathway of arachidonic acid), the supernatants stimulated the same amount of proliferation of fibroblasts as did supernatants of silica-stimulated macrophages. Indomethacin did not increase the growth factor activity of supernatants of silica-stimulated or unstimulated macrophages. Consistent with these observations, supernatants of LPS-stimulated macrophages contained 25.5 +/- 3.8 nM of PGE2, whereas supernatants of silica-stimulated macrophages and unstimulated macrophages contained essentially no PGE2. These findings were confirmed by high performance liquid chromatography. The amounts of PGE2 present in supernatants of LPS-stimulated macrophages were sufficient to cause a 75% reduction in the proliferation of maximally stimulated fibroblasts. These studies suggest that silica may be a very effective stimulus for fibroblast proliferation in vivo since it causes macrophages to release growth factors for fibroblasts without triggering the release of PGE2, an inhibitor of fibroblast proliferation.