期刊
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
卷 165, 期 4, 页码 527-533出版社
AMER THORACIC SOC
DOI: 10.1164/ajrccm.165.4.2106009
关键词
interleukin-1 beta; nitric oxide; inflammation; apoptosis; silicosis
资金
- NHLBI NIH HHS [HL59832, HL62055] Funding Source: Medline
- NIEHS NIH HHS [ES09161] Funding Source: Medline
- CCR NIH HHS [GCRC M0100096] Funding Source: Medline
Crystalline silica stimulates macrophages in vitro to release interleukin-1beta 3 (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 N-G-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/m(3) silica for 5 h/d for 10 d using an inhalation chamber. Exposure of wildtype mice to silica resulted in lung inflammation, apoptosis, and significantly larger and more numerous silicotic lesions than in IL1beta(-/-) 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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