Pathogenesis Of Silicosis Research Articles

Formation of a current concept of silicosis pathogenesis (on the 100th birthday anniversar y of RAS academician B. T. Velichkovskiy)

Academician of the Russian Academy of Sciences Boris Tikhonovich Velichkovsky (October 6, 1923 — September 17, 2020) holds a special place among scientists of occupational pathologists and hygienists — Soviet and Russian scientist-hygienist, health organizer, full member of the Academy of Medical Sciences of the USSR (1988), Russian Academy of Medical Sciences, RAS (2013). Doctor of Medical Sciences, Professor B. T. Velichkovsky was born in 1923 in the city of Orel, moved with his parents to Sverdlovsk. In August 1941, he volunteered for the army and was sent to the school of second lieutenants of infantry in Novosibirsk, but did not pass the mandatory commission. As a member of the construction company, he worked on In the Urals, he worked as a miner at the Degtyarsky copper mine and, after a spinal injury, as a grinder at the tool shop of the OCM plant in the city of Revda. He also had an open form of pulmonary tuberculosis.

Transcriptomic profiling of lung fibroblasts in silicosis: Regulatory roles of Nrf2 agonists in a mouse model

Silicosis is an occupational disease caused by long-term inhalation of free silica, resulting in a significant global health burden. Its pathogenesis remains unclear, and there is no effective treatment. Proliferative and activated myofibroblasts play a key role in the development of silicosis. Traditional studies have focused on fibroblast proliferation and collagen secretion, neglecting their functional heterogeneity. With the advancement of omics research, more pathogenic fibroblast subgroups and their functions have been identified. In this study, we applied transcriptomics to analyze gene changes in primary lung fibroblasts during silicosis development using a mouse model. Our results indicate that DEGs are enriched in collagen secretion, ECM synthesis, leukocyte migration, and chemotaxis functions. Altered core genes are associated with immune cell recruitment and cell migration. Nrf2 agonists, known for anti-inflammatory and antioxidant properties, have shown potential therapeutic effects in fibrotic diseases. However, their effects on fibroblasts in silicosis are not fully understood. We used four common Nrf2 agonists to study gene expression changes in lung fibroblasts at the transcriptome level, combined with histopathological and biochemical methods, to investigate their effects on silicosis in mice. Results show that Nrf2 agonists can exert anti-silicosis fibrosis functions by downregulating genes like Fos and Egr1, involved in cell differentiation, proliferation, and inflammation. In conclusion, this study suggests that inflammation-related co-functions of fibroblasts may be a potential mechanism in silicosis pathogenesis. Targeting Nrf2 may be a promising strategy to alleviate oxidative stress and inflammation in silicosis.

A Differential Protein Study on Bronchoalveolar Lavage Fluid at Different Stages of Silicosis.

In this study, by comparing the difference in protein expression in bronchoalveolar lavage fluid between silicosis patients in different stages and healthy controls, the pathogenesis of pneumoconiosis was discussed, and a new idea for the prevention and treatment of pneumoconiosis was provided. The lung lavage fluid was pretreated by 10 K ultrafiltration tube, Agilent 1100 conventional liquid phase separation, strong cation exchange column (SCX) HPLC pre-separation, and C18 reverse phase chromatography desalting purification, and protein was labeled with isotope. GO, KEGG pathway, and PPI analysis of differential proteins were conducted by bioinformatics, and protein types and corresponding signal pathways were obtained. Thermo Q-Exactive mass spectrometry identified 943 proteins. T-test analysis was used to evaluate the different significance of the results, and the different protein of each group was obtained by screening with the Ratio≥1.2 or Ratio≤0.83 and P<0.05. We found that there are 16 kinds of protein throughout the process of silicosis. There are different expressions of protein in stages Ⅲ/control, stages Ⅱ/control, stage Ⅰ/control, stages Ⅲ/ stages Ⅱ, stages Ⅲ/ stage Ⅰ and stages Ⅱ/ stage Ⅰ groups. The results of ontology enrichment analysis of total differential protein genes show that KEGG pathway enrichment analysis of differential protein suggested that there were nine pathways related to silicosis. The main biological changes in the early stage of silicosis are glycolysis or gluconeogenesis, autoimmunity, carbon metabolism, phagocytosis, etc., and microfibril-associated glycoprotein 4 may be involved in the early stage of silicosis. The main biological changes in the late stage of silicosis are autoimmunity, intercellular adhesion, etc. Calcium hippocampus binding protein may participate in the biological changes in the late stage of silicosis. It provides a new idea to understand the pathogenesis of silicosis and also raises new questions for follow-up research.

Exosomal proteomics and cytokine analysis distinguish silicosis cases from controls

Occupational silica exposure caused a serious disease burden of silicosis. There is currently a lack of sensitive and effective biomarkers for silicosis, and the pathogenesis of silicosis is unclear. Exosomes were significant in the pathogenesis of silicosis, and our study was carried out from exosomal proteomics and cytokine analysis. Firstly, the plasma levels of cytokines were detected using a Luminex multiplex assay, and the results indicated that the plasma levels of TNF-α, IL-6, CCL2, CXCL10, and PDGF-AB were significantly higher in silicosis patients than in silica-exposed workers and controls (p < 0.05). After correlation analysis, the plasma levels of cytokines were positively correlated with exosomal protein concentration. Secondly, data-independent acquisition (DIA) was performed on plasma-derived exosomes in the screening population, which identified 88, 151, 293, and 53 differentially expressed proteins (DEPs) in exposure/control, silicosis/control, silicosis/exposure, and silicosis stage Ⅲ/silicosis stage Ⅰ groups respectively. After parallel reaction monitoring (PRM) in an independent verification population, the results indicated that the changing trend of 15 DEPs was coincident in screening and verification results. The result of correlation analysis indicated that the plasma level of TNF-α was negatively correlated with the expression of exosomal DSP, KRT78, SERPINB12, and CALML5. The AUC of combined determination of TNF-α and CALML5 reached 0.900, with a sensitivity of 0.714 and a specificity of 0.933. Overall, our study revealed the exosomal proteomic profiling of silicosis patients, silica-exposed workers, and controls, indicating that exosomes were significant in the pathogenesis of silicosis. It also revealed that the combined of the plasma levels of cytokines and the expression of exosomal DEPs could increase determination efficiency. This study provided directions for the development of silicosis biomarkers and a scientific basis for the pathogenesis research of silicosis in the future.

Role of TRIM59 in regulating PPM1A in the pathogenesis of silicosis and the intervention effect of tanshinone IIA

This study examines the involvement of TRIM59 in silica-induced pulmonary fibrosis and explores the therapeutic efficacy of Tanshinone IIA (Tan IIA). In vivo experiments conducted on rats with silica-induced pulmonary fibrosis unveiled an increase in TRIM59 levels and a decrease in PPM1A levels. Subsequent investigations using in vitro silicosis cell models demonstrated that modulation of TRIM59 expression significantly impacts silicosis fibrosis, influencing the levels of PPM1A and activation of the Smad2/3 signaling pathway. Immunofluorescence and co-immunoprecipitation assays confirmed the interaction between TRIM59 and PPM1A in fibroblasts, wherein TRIM59 facilitated the degradation of PPM1A protein via proteasomal and ubiquitin-mediated pathways. Furthermore, employing a rat model of silica-induced pulmonary fibrosis, Tan IIA exhibited efficacy in mitigating lung tissue damage and fibrosis. Immunohistochemical analysis validated the upregulation of TRIM59 and downregulation of PPM1A in silica-induced pulmonary fibrosis, which Tan IIA alleviated. In vitro studies elucidated the mechanism by which Tan IIA regulates the Smad2/3 signaling pathway through TRIM59-mediated modulation of PPM1A. Treatment with Tan IIA in silica-induced fibrosis cell models resulted in concentration-dependent reductions in fibrotic markers and attenuation of relevant protein expressions. Tan IIA intervention in silica-induced fibrosis cell models mitigated the TRIM59-induced upregulation of fibrotic markers and enhanced PPM1A expression, thereby partially reversing Smad2/3 activation. Overall, the findings indicate that while overexpression of TRIM59 may activate the Smads pathway by suppressing PPM1A expression, treatment with Tan IIA holds promise in counteracting these effects by inhibiting TRIM59 expression.

Silica aggravates pulmonary fibrosis through disrupting lung microbiota and amino acid metabolites

Silicosis, recognized as a severe global public health issue, is an irreversible pulmonary fibrosis caused by the long-term inhalation of silica particles. Given the intricate pathogenesis of silicosis, there is no effective intervention measure, which poses a severe threat to public health. Our previous study reported that dysbiosis of lung microbiota is associated with the development of pulmonary fibrosis, potentially involving the lipopolysaccharides/toll-like receptor 4 pathway. Similarly, the process of pulmonary fibrosis is accompanied by alterations in metabolic pathways. This study employed a combined approach of 16S rDNA sequencing and metabolomic analysis to investigate further the role of lung microbiota in silicosis delving deeper into the potential pathogenesis of silicosis. Silica exposure can lead to dysbiosis of the lung microbiota and the occurrence of pulmonary fibrosis, which was alleviated by a combination antibiotic intervention. Additionally, significant metabolic disturbances were found in silicosis, involving 85 differential metabolites among the three groups, which are mainly focused on amino acid metabolic pathways. The changed lung metabolites showed a substantial correlation with lung microbiota. The relative abundance of Pseudomonas negatively correlated with L-Aspartic acid, L-Glutamic acid, and L-Threonine levels. These results indicate that dysbiosis in pulmonary microbiota exacerbates silica-induced fibrosis through impacts on amino acid metabolism, providing new insights into the potential mechanisms and interventions of silicosis.

Activation of Sirtuin3 by honokiol ameliorates alveolar epithelial cell senescence in experimental silicosis via the cGAS-STING pathway

BackgroundSilicosis, characterized by interstitial lung inflammation and fibrosis, poses a significant health threat. ATII cells play a crucial role in alveolar epithelial repair and structural integrity maintenance. Inhibiting ATII cell senescence has shown promise in silicosis treatment.However, the mechanism behind silica-induced senescence remains elusive. MethodsThe study employed male C57BL/6 N mice and A549 human alveolar epithelial cells to investigate silicosis and its potential treatment. Silicosis was induced in mice via intratracheal instillation of crystalline silica particles, with honokiol administered intraperitoneally for 14 days. Silica-induced senescence in A549 cells was confirmed, and SIRT3 knockout and overexpression cell lines were generated. Various analyses were conducted, including immunoblotting, qRT-PCR, histology, and transmission electron microscopy. Statistical significance was determined using one-way ANOVA with Tukey's post-hoc test. ResultsThis study elucidates how silica induces ATII cell senescence, emphasizing mtDNA damage. Notably, honokiol (HKL) emerges as a promising anti-senescence and anti-fibrosis agent, acting through sirt3. honokiol effectively attenuated senescence in ATII cells, dependent on sirt3 expression, while mitigating mtDNA damage. Sirt3, a class III histone deacetylase, regulates senescence and mitochondrial stress. HKL activates sirt3, protecting against pulmonary fibrosis and mitochondrial damage. Additionally, HKL downregulated cGAS expression in senescent ATII cells induced by silica, suggesting sirt3's role as an upstream regulator of the cGAS/STING signaling pathway. Moreover, honokiol treatment inhibited the activation of the NF-κB signaling pathway, associated with reduced oxidative stress and mtDNA damage. Notably, HKL enhanced the activity of SOD2, crucial for mitochondrial function, through sirt3-mediated deacetylation. Additionally, HKL promoted the deacetylation activity of sirt3, further safeguarding mtDNA integrity. ConclusionsThis study uncovers a natural compound, HKL, with significant anti-fibrotic properties through activating sirt3, shedding light on silicosis pathogenesis and treatment avenues.

FAP expression dynamics and role in silicosis: Insights from epidemiological and experimental models

Prolonged exposure to free silica leads to the development of silicosis, wherein activated fibroblasts play a pivotal role in its pathogenesis and progression. Fibroblast Activation Protein (FAP), as a biomarker for activated fibroblasts, its expression pattern and role in key aspects of silicosis pathogenesis remain unclear. This study elucidated the expression pattern and function of FAP through population-based epidemiological investigations, establishment of mouse models of silicosis, and in vitro cellular models. Results indicated a significant elevation of FAP in plasma from silicosis patients and lung tissues from mouse models of silicosis. In the cellular model, we observed a sharp increase in FAP expression early in the differentiation process, which remained high expression. Inhibition of FAP suppressed fibroblast differentiation, while overexpression of FAP produced the opposite effect. Moreover, fibroblast-derived FAP can alter the phenotype and function of neighboring macrophages. In summary, we revealed a high expression pattern of FAP in silicosis and its potential mechanistic role in fibrosis, suggesting FAP as a potential therapeutic target for silicosis.

Analysis of Immune Cell Subsets in Peripheral Blood from Patients with Engineered Stone Silica-Induced Lung Inflammation.

Silicosis caused by engineered stone (ES-silicosis) is an emerging worldwide issue characterized by inflammation and fibrosis in the lungs. To our knowledge, only a few reports have investigated leukocyte/lymphocyte subsets in ES-silicosis patients. The present study was designed to explore the proportions of the main lymphocyte subsets in ES-silicosis patients stratified into two groups, one with simple silicosis (SS) and the other with a more advanced state of the disease, defined as progressive massive fibrosis (PMF). The proportions of B (memory and plasmablasts) cells, T (helper, cytotoxic, regulatory) cells, and natural killer (NK) (regulatory and cytotoxic) cells were investigated by multiparameter flow cytometry in 91 ES-silicosis patients (53 SS patients and 38 PMF patients) and 22 healthy controls (HC). Although the total number of leukocytes did not differ between the groups studied, lymphopenia was observed in patients compared to healthy controls. Compared with those in healthy controls, the proportions of memory B cells, naïve helper T cells, and the CD4+/CD8+ T cells' ratio in the peripheral blood of patients with silicosis were significantly decreased, while the percentages of plasma cells, memory helper T cells, and regulatory T cells were significantly increased. For the NK cell subsets, no significant differences were found between the groups studied. These results revealed altered cellular immune processes in the peripheral blood of patients with ES-silicosis and provided further insight into silicosis pathogenesis.

The multifaceted role of macrophage mitophagy in SiO2-induced pulmonary fibrosis: A brief review.

Prolonged exposure to environments with high concentrations of crystalline silica (CS) can lead to silicosis. Macrophages play a crucial role in the pathogenesis of silicosis. In the process of silicosis, silica (SiO2) invades alveolar macrophages (AMs) and induces mitophagy which usually exists in three states: normal, excessive, and/or deficiency. Different mitophagy states lead to corresponding toxic responses, including successful macrophage repair, injury, necrosis, apoptosis, and even pulmonary fibrosis. This is a complex process accompanied by various cytokines. Unfortunately, the details have not been fully systematically summarized. Therefore, it is necessary to elucidate the role of macrophage mitophagy in SiO2-induced pulmonary fibrosis by systematic analysis on the literature reports. In this review, we first summarized the current data on the macrophage mitophagy in the development of SiO2-induced pulmonary fibrosis. Then, we introduce the molecular mechanism on how SiO2-inducedmitophagy causes pulmonary fibrosis. Finally, we focus on introducing new therapies based on newly developed mitophagy-inducing strategies. We conclude that macrophage mitophagy plays a multifaceted role in the progression of SiO2-induced pulmonary fibrosis, and reprogramming the macrophage mitophagy state accordingly may be a potential means of preventing and treating pulmonary fibrosis.

Exposure to micron-grade silica particles triggers pulmonary fibrosis through cell-to-cell delivery of exosomal miR-107

Long-term exposure to inhalable silica particles may lead to severe systemic pulmonary disease, such as silicosis. Exosomes have been demonstrated to dominate the pathogenesis of silicosis, but the underlying mechanisms remain unclear. Therefore, this study aimed to explore the roles of exosomes by transmitting miR-107, which has been linked to the toxic pulmonary effects of silica particles. We found that miR-107, miR-122-5p, miR-125a-5p, miR-126-5p, and miR-335-5p were elevated in exosomes extracted from the serum of patients with silicosis. Notably, an increase in miR-107 in serum exosomes and lung tissue was observed in the experimental silicosis mouse model, while the inhibition of miR-107 reduced pulmonary fibrosis. Moreover, exosomes helped the migration of miR-107 from macrophages to lung fibroblasts, triggering the transdifferentiation of cell phenotypes. Further experiments demonstrated that miR-107 targets CDK6 and suppresses the expression of retinoblastoma protein phosphorylation and E2F1, resulting in cell-cycle arrest. Overall, micron-grade silica particles induced lung fibrosis through exosomal miR-107 negatively regulating the cell cycle signaling pathway. These findings may open a new avenue for understanding how silicosis is regulated by exosome-mediated cell-to-cell communication and suggest the prospect of exosomes as therapeutic targets.

LncRNA MRAK052509 competitively adsorbs miR-204-3p to regulate silica dust-induced EMT process.

Silicosis is a systemic disease caused by long-term inhalation of free SiO2 and retention in the lungs. At present, it is still the most important occupational health hazard disease in the world. Existing studies have shown that non-coding RNA can also participate in complex fibrosis regulatory networks. However, its role in regulating silicotic fibrosis is still unclear. In this study, we constructed a NR8383/RLE-6TN co-culture system to simulate the pathogenesis of silicosis in vitro. Design of miR-204-3p mimics and inhibitors to overexpress or downregulate miR-204-3p in RLE-6TN cells. Design of short hairpin RNA (sh-RNA) to downregulate MRAK052509 in RLE-6TN cells. The regulatory mechanism of miR-204-3p and LncRNA MRAK052509 on EMT process was studied by Quantitative real-time PCR, Western blotting, Immunofluorescence and Cell scratch test. The results revealed that miR-204-3p affects the occurrence of silica dust-induced cellular EMT process mainly through regulating TGF-βRΙ, a key molecule of TGF-β signaling pathway. In contrast, Lnc MRAK052509 promotes the EMT process in epithelial cells by competitively adsorbing miR-204-3p and reducing its inhibitory effect on the target gene TGF-βRΙ, which may influence the development of silicosis fibrosis. This study perfects the targeted regulation relationship between LncRNA MRAK052509, miR-204-3p and TGF-βRΙ, and may provide a new strategy for the study of the pathogenesis and treatment of silicosis.

Salt Lake Aerosol Overview: Emissions, Chemical Composition and Health Impacts under the Changing Climate

Salt Lakes, having a salt concentration higher than that of seawater and hosting unique extremophiles, are predominantly located in drought-prone zones worldwide, accumulating diverse salts and continuously emitting salt dust or aerosols. However, knowledge on emission, chemical composition, and health impacts of Salt Lake aerosols under climate change is scarce. This review delves into the intricate dynamics of Salt Lake aerosols in the context of climate change, pointing out that, as global warming develops and weather patterns shift, Salt Lakes undergo notable changes in water levels, salinity, and overall hydrological balance, leading to a significant alteration of Salt Lake aerosols in generation and emission patterns, physicochemical characteristics, and transportation. Linked to rising temperatures and intensified evaporation, a marked increase will occur in aerosol emissions from breaking waves on the Salt Lake surface and in saline dust emission from dry lakebeds. The hygroscopic nature of these aerosols, coupled with the emission of sulfate aerosols, will impart light-scattering properties and a cooling effect. The rising temperature and wind speed; increase in extreme weather in regard to the number of events; and blooms of aquatic microorganisms, phytoplankton, and artemia salina in and around Salt Lakes, will lead to the release of more organic substances or biogenic compounds, which contribute to the alteration of saline aerosols in regard to their quantitative and chemical composition. Although the inhalation of saline aerosols from Salt Lakes and fine salt particles suspended in the air due to salt dust storms raises potential health concerns, particularly causing respiratory and cardiovascular disease and leading to eye and skin discomfort, rock salt aerosol therapy is proved to be a good treatment and rehabilitation method for the prevention and treatment of pneumoconiosis and chronic obstructive pulmonary disease (COPD). It is implied that the Salt Lake aerosols, at a certain exposure concentration, likely can delay the pathogenesis of silicosis by regulating oxidative stress and reducing interstitial fibrosis of the lungs. It emphasizes the interconnectedness of climate changes, chemical composition, and health aspects, advocating for a comprehensive and practical approach to address the challenges faced by Salt Lake aerosols in an ever-changing global climate.

Lipid characteristics of lung tissue in silicosis rat model were studied based on lipid metabolomics

Silicosis is a common occupational disease caused by the long-term inhalation of large amounts of silica dust. Lipid metabolism plays an important role in the progression of silicosis, but its contributing mechanism remains unclear. The aim of this study was to investigate the differential lipid metabolites and active metabolic pathways in silicosis rat lung tissue. We first constructed a silicosis rat model, and randomly divided 24 male SD rats into control group (C), silicosis group for 1 week (S1W), silicosis group for 2 weeks (S2W) and silicosis group for 4 weeks (S4W) with 6 rats in each group. 1 mL SiO2 suspension (50 mg/mL) or normal saline were injected into the trachea, and the rats were killed at 1 week, 2 weeks and 4 weeks, respectively. The lung tissue pathology of the rats was observed by HE staining and VG staining, and the plasma TC and FC levels were detected by the kit. Western blot was used to detect the expression of lipid-related factors CD36, PGC1α and LXR. In addition, lipidomics analysis of lung tissue samples was performed using UPLC-IMS-QTOF mass spectrometer to screen out potential differential metabolites in silicosis models and analyze lipid enrichment, and verified the expression of differential gene CHPT1 in the metabolic pathway. HE and VG staining showed that the number of nodules and fibrosis increased in a time-dependent manner in the silicosis model group, and the levels of TC, FC and CE in silicosis plasma increased. Western blot results showed that PGC1α and LXR decreased in the silicosis model group, while CD36 expression increased. In addition, metabolomics screened out 28 differential metabolites in the S1W group, 32 in the S2W group, and 22 in the S4W group, and found that the differential metabolites were mainly enriched in metabolic pathways such as glycerophospholipid metabolism and ether lipid metabolism, and the expression of differential gene CHPT1 in the metabolic pathway was decreased in the silicosis model group. These results suggest that there are significant changes in lipid metabolites in lung tissue in silicosis rat models, and glycerophospholipid metabolism was significantly enriched, suggesting that glycerophospholipids play an important role in the progression of silicosis. The differential metabolites and pathways reported in this study may provide new ideas for the pathogenesis of silicosis.

Silica-exposed macrophages-secreted exosomal miR125a-5p induces Th1/Th2 and Treg/Th17 cell imbalance and promotes fibroblast transdifferentiation

Until now, the specific pathogenesis of silicosis is not clear. Exosomal miRNAs, as a newly discovered intercellular communication medium, play an important role in many diseases. Our previous research found that serum exosomal miR125a-5p was increased in silicosis patients by miRNAs high-throughput sequencing. TRAF6, is a target gene of miR125a-5p, which is involved in T-cell differentiation. Furthermore, results from animal study indicate that knockdown of miR-125a-5p can regulate T lymphocyte subsets and significantly reduce pulmonary fibrosis by targeting TRAF6. However, the level of serum exosomal miR125a-5p in silicosis patients has not been reported, the role of macrophages-secreted exosomal miR-125a-5p in regulating T cell differentiation to promote fibroblast transdifferentiation (FMT) remains unknown. In this study, the levels of serum exosomal miR125a-5p and serum TGF-β1, IL-17A, IL-4 cytokines in silicosis patients were elevated, with the progression of silicosis, the level of serum exosomal miR125a-5p and serum IL-4 were increased; thus, the serum level of IFN-γ was negatively correlated with the progression of silicosis. In vitro, the levels of miR125a-5p in macrophages, exosomes, and T cells stimulated by silica were significantly increased. When the mimic was transfected into T cells, which directly suppressed TRAF6 and caused the imbalance of T cells differentiation, induced FMT. To sum up, these results indicate that exosomal miR-125a-5p may by targeting TRAF6 of T cells, induces the activation and apoptosis of T cells and the remodeling of Th1/Th2 and Th17/Tregs distribution, ultimately promotes FMT. Suggesting that exosomal miR-125a-5p may be a potential therapeutic target for silicosis.

Silicon dioxide-induced endoplasmic reticulum stress of alveolar macrophages and its role on the formation of silicosis fibrosis: a review article.

Silicosis is a chronic lung inflammatory disease induced by long-term inhalation of high concentrations of silicon dioxide (SiO2), characterized by pulmonary fibrosis. Inhalation of silica invades alveolar macrophages (AMs) and changes the micro-environment of the cell, resulting in abnormal morphology and dysfunction of the endoplasmic reticulum (ER). Once beyond the range of cell regulation, the endoplasmic reticulum stress (ERS) will occur, which will lead to cell damage, necrosis, and apoptosis, eventually causing silicosis fibrosis through various mechanisms. This is a complex and delicate process accompanied by various macrophage-derived cytokines. Unfortunately, the details have not been systematically summarized yet. In this review, we systematically introduce the basic two processes: the process of inducing ERS by inhaling SiO2 and the process of inducing pulmonary fibrosis by ERS. Moreover, the underlying mechanism of the above two sequential events is also be discussed. We conclude that the ERS of alveolar macrophages caused by silica dust are involved deeply in the pathogenesis of silicosis. Therefore, changing the states of SiO2-induced ERS of macrophage may be an attractive therapeutic target for silicosis fibrosis.

Emerging trends in silicosis research: a scientometric review.

Silicosis is a global disease whose prevention efforts cannot be ignored today. Although numerous silicosis-related data have been published recently, emphasizing the characteristics and nature of silicosis, a summary of the developmental laws of research is lacking, especially in the visual analysis of the literature. We aim to address this issue through a scientometric review. The Web of Science Core Collection and the All Databases were searched with "silicosis" as the topic, excluding unrelated publications, and obtained data from 9802 and 1613 publications, respectively. The data was then analyzed using the Web of Science's online scientometric analysis function and CiteSpace's visual analysis functionality, including publication volume analysis, co-occurrence analysis, co-citation analysis, cluster analysis, and explosive detection. The results identify the "respiratory system" as the most influential area over a century. Furthermore, the publication's number was correlated with the gross domestic product. We ranked countries and institutions based on the frequency of publications and discovered that Europe, the USA, and China are the leading regions for silicosis research, with the USA and Europe having a stronger influence. Many reports related to artificial stone and denim jean production have been studied through citation analysis, indicating new epidemic trends in silicosis. Besides, silicosis-related diseases and the pathogenesis of silicosis were the research hotspots of silicosis through co-occurrence keyword analysis and outbreak detection. Furthermore, related diseases include coal workers' pneumoconiosis and tuberculosis, while the mechanism of silicosis includes studies on inflammation and fibrosis, oxidative stress, alveolar macrophages, apoptosis, and pathways.

Crystalline Silica-Induced Proinflammatory Interstitial Macrophage Recruitment through Notch3 Signaling Promotes the Pathogenesis of Silicosis.

Crystalline silica (CS) particles are ubiquitous in the environment, especially in occupational conditions, and exposure to respirable CS causes silicosis. The initial response to CS is mediated by innate immunity, where pulmonary macrophages act as central orchestrators. However, the repercussions of CS on functionally distinct macrophage subsets remain to be inconclusive. Herein, to study the effects of inhaled CS, we divided macrophages into three subsets: circulating monocytes, interstitial macrophages (IMs), and alveolar macrophages (AMs). CS-induced massive IMs increase in the lung, the phenotype and function of which differed from those of tissue-resident AMs and circulating monocytes. The augmented IMs were driven by recruitment of circulating macrophages rather than cell proliferation in situ. Moreover, the IMs predominantly exerted a classic activated (M1) phenotype and expressed proinflammatory cytokines, contributing to CS-induced lung injury. Notably, we demonstrated that IMs augmented Notch3 expression. Mechanistically, using myeloid-specific Notch3-knockout mice, we demonstrated that Notch3 signaling not only promoted IMs recruitment by regulating CCR2 expression but also manipulated the proinflammatory phenotype. Mice with conditional Notch3-knockout exhibited alleviation of CS-induced inflammation and fibrosis in lung. Overall, our study identifies IMs as critical mediators in response to CS and highlights the role of Notch3 in IMs recruitment and activation, providing new insights into CS toxicological effects in the lung.

The role of mitochondrial dysfunction in macrophages on SiO2 -induced pulmonary fibrosis: A review.

Several epidemiologic and toxicological studies have widely regarded that mitochondrial dysfunction is a popular molecular event in the process of silicosis from different perspectives, but the details have not been systematically summarized yet. Thus, it is necessary to investigate how silica dust leads to pulmonary fibrosis by damaging the mitochondria of macrophages. In this review, we first introduce the molecular mechanisms that silica dust induce mitochondrial morphological and functional abnormalities and then introduce the main molecular mechanisms that silica-damaged mitochondria induce pulmonary fibrosis. Finally, we conclude that the mitochondrial abnormalities of alveolar macrophages caused by silica dust are involved deeply in the pathogenesis of silicosis through these two sequential mechanisms. Therefore, reducing the silica-damaged mitochondria will prevent the potential occurrence and fatality of the disease in the future.

Integrated mRNA and microRNA profiling in lung tissue and blood from human silicosis.

The overwhelming majority of subjects in the current silicosis mRNA and microRNA (miRNA) expression profile are of human blood, lung cells or a rat model, which puts limits on the understanding of silicosis pathogenesis and therapy. To address the limitations, our investigation was focused on differentially expressed mRNA and miRNA profiles in lung tissue from silicosis patients to explore potential biomarker for early detection of silicosis. A transcriptome study was conducted based on lung tissue from 15 silicosis patients and eight normal people, and blood samples from 404 silicosis patients and 177 normal people. Three early stage silicosis, five advanced silicosis and four normal lung tissues were randomly selected for microarray processing and analyze. The differentially expressed mRNAs were further used to conduct Gene Ontology and pathway analyses. Series test of cluster was performed to explore possible changes in differentially expressed mRNA and miRNA expression patterns during the process of silicosis. The blood samples and remaining lung tissues were used in a quantitative real-time PCR (RT-qPCR) (RT-qPCR). In total, 1417 and 241 differentially expressed mRNAs and miRNAs were identified between lung tissue from silicosis patients and normal people (p < 0.05). However, there was no significant difference in most mRNA or miRNA expression between early stage and advanced stage silicosis lung tissues. RT-qPCR validation results in lung tissues showed expression of four mRNAs (HIF1A, SOCS3, GNAI3 and PTEN) and seven miRNAs was significantly down-regulated compared to those of control group. Nevertheless, PTEN and GNAI3 expression was significantly up-regulated (p < 0.001) in blood samples. The bisulfite sequencing PCR demonstrated that PTEN had significantly decreased the methylation rate in blood samples of silicosis patients. PTEN might be a potential biomarker for silicosis as a result of low methylation in the blood.