Silica refers to crystalline particles formed by the combination of silicon with oxygen. chronic silicosis is associated with an increased risk of lung cancer. In animals, the initial inflammation induced by silica exposure is followed by the development of an immunosuppressive microenvironment that supports the growth of lung tumors. This work will review our current knowledge of silica-associated lung cancers, highlighting how recent mechanistic insights support the use of cutting-edge approaches to diagnose and treat silica-related Staurosporine tyrosianse inhibitor lung cancer. capable of secreting biologically active HO-1. In animal models, this biologic Staurosporine tyrosianse inhibitor approach showed promise for the treatment of inflammatory diseases characterized by oxidative stress and could be useful in high-risk silicosis patients with low serum HO-1 levels.39 Anti-inflammatory agents may also be used to treat silicosis. In a study of 34 individuals with silicosis complicated by COPD, systemic treatment with prednisolone led to a significant improvement in pulmonary function (as measured Staurosporine tyrosianse inhibitor by increased diffusing capacity and oxygenation) when compared with patients receiving supportive therapy alone.40,41 To date, there have been no large randomized clinical trials evaluating the effect of systemic glucocorticoid therapy in patients with silicosis. Murine studies were performed to evaluate the use of bone marrow-derived mononuclear or mesenchymal cells to treat silicosis. Results showed that such cells could Staurosporine tyrosianse inhibitor reduce pulmonary inflammation and improve lung function.17,42C44 Based on those findings, two clinical trials involving cell-based therapy were conducted.45,46 Morales et al performed a pilot safety study using bone marrow-derived mononuclear cells from five patients with silicosis and documented good tolerability.46 In a second study involving mesenchymal cells from four patients genetically modified to express hepatocyte growth factor results showed that treatment could 1) ameliorate symptoms, 2) improve pulmonary function and 3) partially reverse radiographically detectable fibrotic changes.45 Another potential strategy for limiting the production of inflammatory cytokines and ROS following silica exposure involves treatment with immunosuppressive oligodeoxynucleotides (ODNs).26 Immunosuppressive ODNs contain repetitive TTAGGG motifs that inhibit the production of inflammatory cytokines and p47 phagocytic oxidase (p47phox, the primary component of NADPH oxidase) when murine macrophages are exposed to silica in vitro.26 Importantly, the upregulation of p47phox contributes to the inflammatory pathology observed in many diseases including cancer, raising the possibility that immunosuppressive ODNs might reduce the risk of inflammation-associated tumorigenesis.47,48 Immunosuppressive ODNs were found to inhibit ERK activation in human lung cancer cells, leading to cell cycle arrest in G1 and a marked reduction in proliferation.49 Staurosporine tyrosianse inhibitor Thus, immunosuppressive ODNs have the potential to reduce ERK-mediated tumorigenesis.32,33 There is recent evidence that silica-induced lung fibrosis mediated by the infiltration of macrophages and Th17 cells is promoted by the mineral dust-induced gene (mdig).50 Impairment of mdig gene function ameliorated fibrogenic changes by reducing the infiltration of macrophages and Th17 cells into the lungs while enhancing the accumulation of immune suppressive regulatory T cells. These findings raise the possibility that a treatment strategy involving targeting of mdig could be successful. Silica and lung cancer risk: experimental evidence In rodents, the intra-pulmonary delivery of silica particles induces a strong inflammatory response characterized by cellular infiltration of the lungs. The main cell types involved are macrophages and neutrophils (Figure 1). Upon activation, these cells produce a variety of chemokines, cytokines and ROS.25,51,52 Lung tumors subsequently develop in mice and rats into which silica particles are delivered by inhalation or instillation.53C58 Inflammation is considered the primary mechanism underlying this carcinogenicity, although ROS may also have a toxic effect on lung epithelial cells (Figure 1).25,59 A recent study by Wang et al documented the strong association between inflammation and carcinogenesis by generating mice in which GPRC5A (the G protein-coupled receptor family Mouse monoclonal to RICTOR C group 5 type A that is predominantly expressed in lung epithelial cells) was knocked out.60 GPRC5A-KO mice exposed to silica had increased sensitivity to both lung injury and tumorigenesis, with neoplastic lesions in the epithelium correlating with the appearance of intense inflammatory/fibrotic lesions in the lungs.60 Silica can influence the process of epithelial cell damage and subsequent carcinogenesis through several pathways as shown in Figure 1. 1) Activated neutrophils and macrophages cause persistent inflammation that damages epithelial cells; 2) oxidants produced by macrophages indirectly damage epithelial cells and 3) oxidants produced as a consequence of particle uptake by epithelial cells cause direct injury. All these pathways provide inflammatory stimuli and place cells at increased risk of genotoxic (DNA) damage that increases susceptibility to tumor formation.22,61,62 Open in a separate window Figure 1 Proposed mechanism of silica-induced.