Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0037116 (silicosis)
 1,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alveolar macrophages play a key role in the development of silicosis by releasing a host of mediators, such as, cytokines and chemokines, which contribute to a complex network of interactions that result in the onset of lung injury, inflammation, and potentially fibrosis. Using a murine macrophage cell line, RAW 264.7, we exposed the cells to cristobalite-silica (35 micrograms/cm(2)) in the presence or absence of antioxidants and various modifiers of cellular antioxidant status. Treatment with dimethyl sulfoxide, extracellular glutathione, or N-acetyl-L-cysteine (NAC) decreased cristobalite-induced tumor necrosis factor (TNF)-alpha mRNA levels by 40%, 20%, and 42%, respectively. TNF-alpha protein levels were decreased by 90%, 32%, and 53%, respectively. Cristobalite-induced macrophage inflammatory protein (MIP)-2 mRNA levels were reduced by 52%, 38%, and 57%, with DMSO, GSH, and NAC treatment, respectively. Both MIP-1alpha and MIP-1beta mRNA levels were reduced at a magnitude similar to the reduction in TNF-alpha mRNA levels, whereas monocyte chemotactic protein (MCP)-1 mRNA levels were reduced at a magnitude similar to the reduction in MIP-2 mRNA levels following antioxidant treatment. These results suggests that the macrophage response to cristobalite exposure is mediated at least in part by oxidant stress.
 ...
PMID:Antioxidant treatment attenuates cytokine and chemokine levels in murine macrophages following silica exposure. 1043 54

Inhalation of crystalline silica results in pulmonary fibrosis and silicosis. It has been suggested that mast cells play a role in these conditions. How mast cells would influence pathology is unknown. We thus explored mast cell interactions with silica in vitro and in B6.Cg-kit(W-sh) mast cell-deficient mice. B6.Cg-kit(W-sh) mice did not develop inflammation or significant collagen deposition after instillation of silica, while C57Bl/6 wild-type mice did have these findings. Given this supporting evidence of a role for mast cells in the development of silicosis, we examined the ability of silica to activate mouse bone marrow-derived mast cells (BMMC), including degranulation (beta-hexosaminidase release); production of reactive oxygen species (ROS) and inflammatory mediators; and the effects of silica on Fc epsilon RI-dependent activation. Silica did not induce mast cell degranulation. However, TNF-alpha, IL-13, monocyte chemotactic protein-1, protease activity, and production of ROS were dose-dependently increased after silica exposure, and production was enhanced after Fc epsilon RI stimulation. This mast cell activation was inhibited by anti-inflammatory compounds. As silica mediates some effects in macrophages through scavenger receptors (SRs), we first determined that mast cells express scavenger receptors; then explored the involvement of SR-A and macrophage receptor with colleagenous structure (MARCO). Silica-induced ROS formation, apoptosis, and TNF-alpha production were reduced in BMMC obtained from SR-A, MARCO, and SR-A/MARCO knockout mice. These findings demonstrate that silica directs mast cell production of inflammatory mediators, in part through SRs, providing insight into critical events in the pathogenesis and potential therapeutic targets in silicosis.
 ...
PMID:Silica-directed mast cell activation is enhanced by scavenger receptors. 1690 92

Silicosis is a systemic disease caused by inhaling silicon dioxide (SiO2). Phagocytosis of SiO2 in the lungs initiates an inflammatory cascade that results in fibroblast proliferation and migration followed by fibrosis. According to previous data from our laboratory, monocyte chemotactic protein-1 (MCP-1) plays a critical role in fibroblast proliferation and migration in conventional two-dimensional (2D) monolayer cultures. The present study aimed to explore the downstream cascade of MCP-1 in both 2D and three-dimensional (3D) cell culture models of silicosis. Experiments using primary cultured adult human pulmonary fibroblasts (HPF-a) demonstrated the following: 1) SiO2 treatment induces expression of MCP-1-induced protein (MCPIP1) in a time- and dose-dependent manner in both 2D and 3D cultures; 2) the MAPK and phosphatidylinositol-3-kinase (PI3K)/Akt pathways are involved in SiO2-induced MCPIP1 expression; and 3) MCPIP1 induction mediates the SiO2-induced increase in cell migration in both 2D and 3D cultures. The effect of MCP-1 in silicosis occurs mainly through MCPIP1, which, in turn, mediates the observed SiO2-induced increase in pulmonary fibroblast migration. However, the time frame for MCPIP1 induction differed between 2D and 3D cultures, indicating that, compared with conventional 2D cell culture systems, 3D culture may be useful for analyses of fibroblast physiology under conditions that more closely resemble in vivo environments. Our study determined the link between fibroblast-derived MCPIP1 and SiO2-induced cell migration, and this finding provides novel evidence of the potential of MCPIP1 in the development of novel therapeutic strategies for silicosis.
...
PMID:MCPIP1 mediates silica-induced cell migration in human pulmonary fibroblasts. 2660 30