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Am. J. Respir. Crit. Care Med., Volume 165, Number 4, February 2002, 527-533

Crucial Role of Interleukin-1beta and Nitric Oxide Synthase in Silica-induced Inflammation and Apoptosis in Mice

KAMAL D. SRIVASTAVA, WILLIAM N. ROM, JAISHREE JAGIRDAR, TING-AN YIE, TERRY GORDON, and KAM-MENG TCHOU-WONG

Division of Pulmonary and Critical Care Medicine, Departments of Environmental Medicine, Medicine, Microbiology, and Pathology, New York University School of Medicine, New York, New York

Crystalline silica stimulates macrophages in vitro to release interleukin-1beta (IL-1beta ), tumor necrosis factor-alpha (TNF-alpha ), 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-1beta 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-1beta antibody or the NO synthase (NOS) inhibitor NG-nitro-L-arginine-methyl ester (L-NAME), demonstrating the requirement for IL-1beta -mediated NO release in silica-induced apoptosis. We exposed IL-1beta knockout (IL-1beta -/-) 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-1beta -/- 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-1beta -dependent NO-mediated apoptosis in the evolution of silicosis.




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