Crucial role of interleukin-1β and nitric oxide synthase in silica-induced inflammation and apoptosis in mice
Crucial role of interleukin-1β and nitric oxide synthase in silica-induced inflammation and apoptosis in mice
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DOI：
10.1164/ajrccm.165.4.2106009
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发表时间：
2002-02-15
影响因子：
24.7
通讯作者：
Tchou-Wong, KM
中科院分区：
文献类型：
--
作者：
Srivastava, KD;Rom, WN;Tchou-Wong, KM
结晶二氧化硅在体外刺激巨噬细胞释放白细胞介素-1β 3 (IL-1β)、肿瘤坏死因子-α (TNF-α) 和一氧化氮 (NO)，并诱导巨噬细胞凋亡。由于颗粒的纤维化潜力与其诱导巨噬细胞凋亡的能力平行，因此我们研究了 IL-1β 和 NO 介导小鼠矽肺病细胞凋亡和炎症的潜在机制。首先，我们使用 IC-21 巨噬细胞系证明二氧化硅在体外诱导 NO 产生和细胞凋亡。中和抗 IL-1β 抗体或 NO 合酶 (NOS) 抑制剂 N-G-硝基-L-精氨酸甲酯 (L-NAME) 可以抑制 NO 释放和细胞凋亡，这表明二氧化硅诱导细胞凋亡需要 IL-1β 介导的 NO 释放。我们使用吸入室将 IL-1beta 敲除 (IL-1beta(-/-)) 小鼠、诱导型 NOS 敲除 (iNOS(-/-)) 小鼠和野生型小鼠暴露于 250 mg/m(3) 二氧化硅中，每天 5 小时，持续 10 天。在 12 周的过程中，与 IL1beta(-/-) 小鼠相比，野生型小鼠暴露于二氧化硅会导致肺部炎症、细胞凋亡以及明显更大和更多的硅质病变。我们还以相同的方案通过吸入暴露 iNOS(-/-) 小鼠，并与野生型小鼠进行比较，证明 iNOS-/- 小鼠的细胞凋亡和炎症显着减少。这些结果证明了小鼠矽肺中细胞凋亡与炎症之间的关联，并支持 IL-1β 依赖性 NO 介导的细胞凋亡在矽肺演变中的潜在作用。
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.