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B-dependent gene expression by silica in
lungs of luciferase reporter mice
1 Department of Pharmaceutical Sciences, University of Connecticut; Storrs, Connecticut 06269; and Departments of 2 Pathology and 3 Medicine, University of Vermont, Burlington, Vermont 05405
Occupational exposure to
crystalline silica is associated with the development of pulmonary
inflammation and silicosis, yet how silica initiates pulmonary fibrosis
and which cell types are involved are unclear. In studies here, we
hypothesized that silica particles interact initially with pulmonary
epithelial cells and alveolar macrophages (AMs) to cause
transcriptional activation of nuclear factor (NF)-
B-regulated genes
encoding inflammatory cytokines. Exposure of NF-B luciferase
reporter mice intratracheally to silica or lipopolysaccharide (LPS),
but not the nonfibrogenic particle titanium dioxide (TiO2),
increased immunoreactivity of luciferase protein in bronchiolar
epithelial cells and AMs. Ribonuclease protection assays revealed
significant (P 
0.05) increases in mRNA levels of
inducible nitric oxide synthase, tumor necrosis factor-
, macrophage
inflammatory protein-2, macrophage chemotactic protein-1 (MCP-1),
interferon-
, interleukin (IL)-6, and IL-12 in lung homogenates of
reporter mice after exposures to silica or LPS. Immunoreactivity of
MCP-1 in these animals was localized to AMs and epithelial cells. These
data are the first to show activation of NF-B in situ by fibrogenic
particles in pulmonary epithelial cells and AMs. Increased expression
of NF-B-related inflammatory cytokines by these cell types, which
first encounter silica after inhalation, may be critical to the
initiation of silica-associated lung diseases, thus providing a
rationale for focusing on NF-B in preventive and therapeutic strategies.
silica; transgenic mice; nuclear factor-B; silicosis; inflammation
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