SlLica And Ros

The importance of ROS in mediating silica-induced lung diseases has been well documented in recent years.121122 In aqueous media, silica has been shown to generate 'OH radicals.123 In addition, phagocytosis of silica activates cell membrane NADPH oxidase, inducing the respiratory burst and the generation of superoxide radicals 1 leading to lipoprotein oxidation.124-126 In addition, a major source of in lung cells is also produced by the respiratory chain in mitochondria.

Nitric oxide (NO), another important free radical, and its metabolites have been implicated in the lung tissue damage associated with acute and chronic silica exposure. Van Dyke et al.127 demonstrated that silica caused peroxynitrite-dependent increases in chemiluminescence (CL) of rat lung and bronchoalveolar lavage (BAL) cells. The CL reaction was markedly decreased by N-nitro-L-arginine methyl ester hydrochloride (L-NAME), indicating induction of NO by silica. Studies by Blackford et al.128 suggested that silica was able to up-regulate inducible NO synthase (iNOS) gene expression in rat alveolar macrophages and neutrophils. Immunohistochemical double staining and in situ hybridization demonstrated silica-induced expression of iNOS not only in the alveolar macrophages and neutrophils, but also in the bronchiolar epithelial cells.129 The importance of NO induction in vivo was demonstrated by Srivastava et al.107 in a mouse silicosis model. Inhalation of silica resulted in iNOS gene expression in pulmonary cells and numerous silicotic lung lesions in wild-type mice. The silicotic lesions were significantly reduced in the iNOS gene knock-out mice exposed to silica.

Whereas the induction of NO in vivo by silica has been well documented,130131 the in vitro induction of NO by silica is controversial. Many studies failed to demonstrate that silica was able to induce NO generation in vitro using primary rat alveolar macrophages or macrophage cell lines derived from mice.132 133 Using rat alveolar macrophages, Huffman et al.134 suggested that the induction of NO in vitro by silica required certain cofactors derived from other cells, such as IL-1 and TNF-a.107'135'136

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