SiO₂ dust induces inflammation and pulmonary fibrosis in rat lungs through activation of ASMase/ceramide pathway

Abstract

The role of ASMase/ceramide signaling pathway in the development of silicosis needs to be verified by in vivo experiments. We investigated the role of the ASMase/ceramide signaling pathway in the progression of silicosis and the effect of desipramine (DMI) (1 mg/mL) on the development of silicosis, by establishing a silica (1 mL, 50 mg/mL) dust-contaminated rat silicosis model and administering the ASMase inhibitor, DMI, to the dust-contaminated rats. The results showed that the levels of interleukin (IL)-1β and IL-6 were increased in the lung tissues of the rats in the dust-contaminated group at the initial stage after dusting; the inflammatory cell aggregation in the lung tissue was increased. With time progression, the hydroxyproline content in the lung tissue increased, and alpha-smooth muscle actin (α-SMA), collagen I, and vimentin substantially increased, suggesting that silicosis was formed in the lung tissue of the rats 28 days after SiO 2 dust treatment. Moreover, the levels of ASMase, ceramide, and sphingosine-1-phosphate (S1P) were increased in the lung tissue of rats. The expression of β-catenin, fibronectin, and caspase-3 protein was increased, and E-cadherin protein expression was decreased in the lung tissue of the rats in the late stage of dust contamination. The ASMase and ceramide in the lung tissues of the rats in the DMI intervention group were reduced, as were the lung tissue inflammation levels, collagen expression, and lung fibrosis. These results suggest that SiO 2 dust may activate the ASMase/ceramide signaling pathway in rat lung tissue, promoting pulmonary fibrosis. DMI inhibited this activation, attenuated apoptosis, blocked epithelial-mesenchymal transition, and halted silica dust-induced silicofibrosis.

Advances in the Use of N-Acetylcysteine in Chronic Respiratory Diseases

“…Protraction of this process then results in chronic lung inflammation as well as lung fibrosis as pro-inflammatory cytokines such as IL-1, IL-18, and TNFα enhance the recruitment and proliferation of fibroblasts and mesenchymal cells to produce fibroblastic foci and to generate components of the extracellular matrix including collagen, leading to fibrotic scarring of the lung tissue [ 180 ]. As recently demonstrated, the process of silica-induced fibrosis is, besides the TLR-4/NLRP3/TGF-β signaling pathway [ 181 ] and NF-κB signaling pathways [ 182 ], also related to the activation of the acid sphingomyelin (ASM)ase/ceramide signaling pathway [ 183 ] and phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling pathway [ 184 ].…”