Crystalline silica stimulates macrophages in vitro to release interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and nitric oxide (NO) and induces apoptosis of macrophages. Because the fibrogenic potential of a particulate paralleled its ability to induce apoptosis in macrophages, we investigated the underlying mechanisms by which IL-1β and NO mediate apoptosis and inflammation in murine silicosis. First, we demonstrated that silica induced NO production and apoptosis in vitro using the IC-21 macrophage cell line. Both NO release and apoptosis could be inhibited by neutralizing anti-IL-Iβ antibody or the NO synthase (NOS) inhibitor NG-nitro-L-arginine-methyl ester (L-NAME), demonstrating the requirement for IL-1β-mediated NO release in silica-induced apoptosis. We exposed IL-1β knockout (IL-1β-/-) mice, inducible NOS knockout (iNOS-/-) mice, and wild-type mice to 250 mg/m3 silica for 5 h/d for 10 d using an inhalation chamber. Exposure of wild-type mice to silica resulted in lung inflammation, apoptosis, and significantly larger and more numerous silicotic lesions than in IL-1β-/- mice over a 12-wk course. We also exposed iNOS-/- mice via inhalation in the same protocol and compared with wild-type mice and demonstrated that iNOS-/- mice had significantly reduced apoptosis and inflammation. These results demonstrated an association between apoptosis and inflammation in murine silicosis and support a potential role for IL-1β-dependent NO-mediated apoptosis in the evolution of silicosis.
|Number of pages
|American Journal of Respiratory and Critical Care Medicine
|Published - 15 Feb 2002
- Nitric oxide