Fibrogenic and Redox-Related but not Proinflammatory Genes are Upregulated in Lewis Rat Model of Chronic Silicosis

Abstract

Silicosis, a fibrotic granulomatous lung disease, may occur through accidental high-dose or occupational inhalation of silica, leading to acute/accelerated and chronic silicosis, respectively. While chronic silicosis has a long asymptomatic latency, lung inflammation and apoptosis are hallmarks of acute silicosis. In animal models, histiocytic granulomas develop within days after high-dose intratracheal (IT) silica instillation. However, following chronic inhalation of occupationally relevant doses of silica, discrete granulomas resembling human silicosis arise months after the final exposure without significant lung inflammation/apoptosis. To identify molecular events associated with chronic silicosis, lung RNAs from controls or sub-chronic silica-exposed rats were analyzed by Affymetrix at 28 weeks after silica exposures. Results suggested a significant upregulation of 144 genes and downregulation of 7 genes. The upregulated genes included complement cascade, chemokines/chemokine receptors, G-protein signaling components, metalloproteases, and genes associated with oxidative stress. To examine the kinetics of gene expression relevant to silicosis, qPCR, ELISA, Luminex-bead assays, Western blotting, and/or zymography were performed on lung tissues from 4 day, 28 week, and intermediate times after sub-chronic silica exposure and compared with 14 day acute silicosis samples. Results indicated that genes regulating fibrosis (secreted phosphoprotein-1, Ccl2, and Ccl7), redox enzymes (superoxide dismutase-2 and arginase-1), and the enzymatic activities of matrix metalloproteinases 2 and 9 were upregulated in acute and chronic silicosis models. However, proinflammatory cytokines were strongly upregulated only in acute silicosis. Thus, inflammatory cytokines are associated with acute but not chronic silicosis. Data suggest that genes regulating fibrosis, oxidative stress, and metalloproteases may contribute to both acute and chronic silicosis.

Predictive hazard markers for the ranking of pulmonary toxicity of nanomaterials

“…Langley et al found that CCL2 and CCL7 were persistently upregulated in rat lungs exposed to inhaled crystalline silica, a dust with high toxicity [32]. Fujita et al also reported that CCL2 and CCL7 were upregulated in the lungs of rats injected intratracheally with in ammogenetic SWCNT [27,33].…”

Secreted Phosphoprotein 1 and Sex-Specific Differences in Silica-Induced Pulmonary Fibrosis in Mice

“…SPP1 contributes to human fibrotic lung disease, and increases in SPP1 are associated with pulmonary fibrosis ( Foster et al 2015 ; Nau et al 1997 ; Pardo et al 2005 ) and with the development of fibrosis in a number of animal models ( Berman et al 2004 ; Langley et al 2011 ; Ma et al 2012 ; Mangum et al 2004 ; Miyazaki et al 1995 ; Oh et al 2015 ; Sabo-Attwood et al 2011 ; Takahashi et al 2001 ). For example, bleomycin treatment of mice results in an increase in SPP1 mRNA and protein at 14 days post-exposure, and treatment with an antibody that blocks SPP1 function partially protects against fibrosis development ( Takahashi et al 2001 ).…”

“…SPP1 also mediates fibroblast migration through integrin- ( Anwar et al 2012 ; Li et al 2000 ) and matrix metalloproteinase–dependent mechanisms ( Lund et al 2009 ). Lung SPP1 increases in humans with pulmonary fibrosis ( Foster et al 2015 ; Nau et al 1997 ; Pardo et al 2005 ) and in mouse ( Berman et al 2004 ; Miyazaki et al 1995 ; Oh et al 2015 ; Sabo-Attwood et al 2011 ; Takahashi et al 2001 ) and rat ( Langley et al 2011 ; Ma et al 2012 ; Mangum et al 2004 ) models of pulmonary fibrosis. In addition, SPP1 may be a useful biomarker for the development and progression of fibrotic lung diseases ( Boon et al 2009 ; Kadota et al 2005 ; Kelly et al 2006 ; O’Regan et al 2006 ; Pardo et al 2005 ; Selman et al 2006 ; Vij and Noth 2012 ).…”

Case of accelerated silicosis in a sandblaster

“…According to the literature, increasing evidence shows that lung inflammation and apoptosis are hallmarks of acute silicosis 14 ) . In animal models of acute silicosis, severe lung inflammation, alveolar lipoproteinosis, apoptosis, induction of reactive oxygen species, production of proinflammatory cytokine/chemokine, and tissue destruction were found 14 ) . The accelerated acute inhalation model also led to the development of acute-like injury (e.g.…”

“…apoptosis, inflammation, tissue destruction) 15 ) . Animal models have shown that genes regulating fibrosis, oxidative stress, and metalloproteases contribute to both acute and chronic silicosis, but proinflammatory cytokines are associated with acute but not chronic silicosis 14 ) .…”