Induction of Nitric Oxide and Nitric Oxide Synthase mRNA by Silica and Lipopolysaccharide in PMA-primed THP-1 Cells

The fibrogenic effects of silica in experimental animals and humans has been extensively studied (I 7, 20). However, the pathogenesis and molecular mechanisms underlying lung injury and fibrosis resulting from silica exposure remain to be elucidated. It is well-documented that silica can stimulate monocyte-macrophage lineage cells to produce cytokines and growth factors, including interleukin-I (IL- I) (20), tumor necrosis factor-ex (TNF-cx) (I 7), insulin-like growth factor-I (IGF-1) (4), and transforming growth factor-P (TGF-P) (24). Consequently, it has been suggested that the fibrogenic effect of silica may be mediated by cytokines in the fater stages of silicosis. During the early phase of interaction between silica and the pulmonary alveolar macrophage, several direct and indirect lines of evidence suggest that reactive oxygen intermediates (ROI) may play a pivotal role in silica- induced tissue damage (2I, 22). One of the most important components of and contributors to ROI is nitric oxide (NO) produced from L-arginine and molecular oxygen under the catalytic influence of NO synthase (NOS) (I 9). At present, at least three NOS genes have been cloned: a constitutive neuron NOS, a constitutive endothelial cell NOS and an inducible NOS (iNOS) (16). A number of factors have been shown to differentially induce iNOS gene expression in different cell lines including bacterial cell products and foreign antigens. During inflammation, NO is a double-edged sword in terms of the host immune defense mechanisms and the physiologic response to an inflammatory insult. The macrophage is one of the major cellular sources of NO. During the early phase of acute inflammation, NO produced from the macrophage appears to facilitate the clearance of pathogens and promotes a local relaxation effect on the microcirculation of vascular smooth muscle. When the production of NO is left unattenuated, especially under oxidative stress, direct cytotoxic effects of NO can emerge through the formation of peroxynitrite as a result of a reaction between NO and superoxide (2).