Abstract
Silicosis remains one of the most serious diseases worldwide, with no effective drug for its treatment. Our research results have indicated that arctiin and arctigenin could increase the mitochondrial membrane potential, which in turn reduces the production of reactive oxygen species (ROS), blocks the polarization of macrophages, and inhibits the differentiation of myofibroblasts to reduce oxidative stress, inflammation, and fibrosis. Further, our study revealed that arctiin and arctigenin suppressed the activation of NLRP3 inflammasome through the TLR-4/Myd88/NF-κB pathway and the silica-induced secretion of TNF-α, IL-1β, TGF-β, and α-SMA. Besides, the silica-induced increase in the levels of serum ceruloplasmin and HYP was also inhibited. Results of metabolomics indicated that arctiin and arctigenin could regulate the abnormal metabolic pathways associated with the development of silicosis, which involve pantothenate and CoA biosynthesis, cysteine and methionine metabolism, linoleic acid metabolism, and arginine and proline metabolism successively. Furthermore, the analysis of metabolomics, together with network topological analysis in different phases of silicosis, revealed that urine myristic acid, serum 4-hydroxyproline, and L-arginine could be regarded as diagnosis biomarkers in the early phase and formation of pulmonary fibrosis in the latter phases of silicosis. Arctiin and arctigenin could downregulate the increased levels of myristic acid in the early phase and serum 4-hydroxyproline in the latter phase of silicosis. Interestingly, the integration of TLR-4/NLRP3/TGF-β signaling and metabolomics verified the importance of macrophage polarization in the silicosis fibrosis process. To the best of our knowledge, this is the first study reporting that arctiin and arctigenin both can ameliorate silicosis effectively, and the former is a little stronger than its aglycone arctigenin because of its high oral bioavailability, low toxicity, and multimolecular active metabolites as determined by AdmetSAR and molecular docking analysis.
Highlights
Silicosis is an occupational disease characterized by chronic lung inflammation, progressive pulmonary fibrosis, and systemic immune dysfunction [1,2,3]
Our results indicated that the increased expression levels of iNOS and Arg-1 induced by silica in the arctiin group (ARC) group and the arctigenin group (ARG) group were both downregulated, indicating that the effects of the ARC group and the ARG group on silicosis may be associated with the blocking of the Toll-like receptors (TLRs)-4/NLRP3/TGF-β signaling pathway (Figures 3(a)–3(g))
Based on the abovementioned research results of metabolomics and signal transduction, we found that oxidative stress, inflammation, and enhanced innate immune responses were the main reactions after silica was phagocytosed by macrophages in the early phase
Summary
Silicosis is an occupational disease characterized by chronic lung inflammation, progressive pulmonary fibrosis, and systemic immune dysfunction [1,2,3]. The innate and adaptive immune systems are regarded to play key regulatory roles in early phases of silicosis [4]. Previous studies have indicated that silica can damage macrophages, activate the innate immune system, and initiate an inflammatory response in the lungs. Fibrosis and inflammation occur together; oxygen- and nitrogen-derived free radicals play a major role in silica-induced lung injury and fibrosis [5]. Silicosis is usually ignored or misdiagnosed as other diseases because only inflammation occurs at its early phase. X-ray is the primary method for diagnosing silicosis, but it is not suitable for early diagnosis as the image shadows only show the fibrosis formation.
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