Proteome, Lysine Acetylome, and Succinylome Identify Posttranslational Modification of STAT1 as a Novel Drug Target in Silicosis.

Inhalation of crystalline silica dust induces incurable lung damage, silicosis, and pulmonary fibrosis. However, the mechanisms of the lung injury remain poorly understood, with limited therapeutic options aside from lung transplantation. Posttranslational modifications can regulate the function of proteins and play an important role in studying disease mechanisms. To investigate changes in posttranslational modifications of proteins in silicosis, combined quantitative proteome, acetylome, and succinylome analyses were performed with lung tissues from silica-injured and healthy mice using liquid chromatography-mass spectrometry. Combined analysis was applied to the three omics datasets to construct a protein landscape. The acetylation and succinylation of the key transcription factor STAT1 were found to play important roles in the silica-induced pathophysiological changes. Modulating the acetylation level of STAT1 with geranylgeranylacetone effectively inhibited the progression of silicosis. This report revealed a comprehensive landscape of posttranslational modifications in silica-injured mouse and presented a novel therapeutic strategy targeting the posttranslational level for silica-induced lung diseases.

Bicyclol attenuates pulmonary fibrosis with silicosis via both canonical and non-canonical TGF-ß1 signaling pathways.

BACKGROUND: Silicosis is an irreversible fibrotic disease of the lung caused by chronic exposure to silica dust, which manifests as infiltration of inflammatory cells, excessive secretion of pro-inflammatory cytokines, and pulmonary diffuse fibrosis. As the disease progresses, lung function further deteriorates, leading to poorer quality of life of patients. Currently, few effective drugs are available for the treatment of silicosis. Bicyclol (BIC) is a compound widely employed to treat chronic viral hepatitis and drug-induced liver injury. While recent studies have demonstrated anti-fibrosis effects of BIC on multiple organs, including liver, lung, and kidney, its therapeutic benefit against silicosis remains unclear. In this study, we established a rat model of silicosis, with the aim of evaluating the potential therapeutic effects of BIC. METHODS: We constructed a silicotic rat model and administered BIC after injury. The FlexiVent instrument with a forced oscillation system was used to detect the pulmonary function of rats. HE and Masson staining were used to assess the effect of BIC on silica-induced rats. Macrophages-inflammatory model of RAW264.7 cells, fibroblast-myofibroblast transition (FMT) model of NIH-3T3 cells, and epithelial-mesenchymal transition (EMT) model of TC-1 cells were established in vitro. And the levels of inflammatory mediators and fibrosis-related proteins were evaluated in vivo and in vitro after BIC treatment by Western Blot analysis, RT-PCR, ELISA, and flow cytometry experiments. RESULTS: BIC significantly improved static compliance of lung and expiratory and inspiratory capacity of silica-induced rats. Moreover, BIC reduced number of inflammatory cells and cytokines as well as collagen deposition in lungs, leading to delayed fibrosis progression in the silicosis rat model. Further exploration of the underlying molecular mechanisms revealed that BIC suppressed the activation, polarization, and apoptosis of RAW264.7 macrophages induced by SiO2. Additionally, BIC inhibited SiO2-mediated secretion of the inflammatory cytokines IL-1ß, IL-6, TNF-α, and TGF-ß1 in macrophages. BIC inhibited FMT of NIH-3T3 as well as EMT of TC-1 in the in vitro silicosis model, resulting in reduced proliferation and migration capability of NIH-3T3 cells. Further investigation of the cytokines secreted by macrophages revealed suppression of both FMT and EMT by BIC through targeting of TGF-ß1. Notably, BIC blocked the activation of JAK2/STAT3 in NIH-3T3 cells required for FMT while preventing both phosphorylation and nuclear translocation of SMAD2/3 in TC-1 cells necessary for the EMT process. CONCLUSION: The collective data suggest that BIC prevents both FMT and EMT processes, in turn, reducing aberrant collagen deposition. Our findings demonstrate for the first time that BIC ameliorates inflammatory cytokine secretion, in particular, TGF-ß1, and consequently inhibits FMT and EMT via TGF-ß1 canonical and non-canonical pathways, ultimately resulting in reduction of aberrant collagen deposition and slower progression of silicosis, supporting its potential as a novel therapeutic agent.

Trigonelline hydrochloride attenuates silica-induced pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation.

BACKGROUND: Silicosis represents a paramount occupational health hazard globally, with its incidence, morbidity, and mortality on an upward trajectory, posing substantial clinical dilemmas due to limited effective treatment options available. Trigonelline (Trig), a plant alkaloid extracted mainly from coffee and fenugreek, have diverse biological properties such as protecting dermal fibroblasts against ultraviolet radiation and has the potential to inhibit collagen synthesis. However, it's unclear whether Trig inhibits fibroblast activation to attenuate silicosis-induced pulmonary fibrosis is unclear. METHODS: To evaluate the therapeutic efficacy of Trig in the context of silicosis-related pulmonary fibrosis, a mouse model of silicosis was utilized. The investigation seeks to elucidated Trig's impact on the progression of silica-induced pulmonary fibrosis by evaluating protein expression, mRNA levels and employing Hematoxylin and Eosin (H&E), Masson's trichrome, and Sirius Red staining. Subsequently, we explored the mechanism underlying of its functions. RESULTS: In vivo experiment, Trig has been demonstrated the significant efficacy in mitigating SiO2-induced silicosis and BLM-induced pulmonary fibrosis, as evidenced by improved histochemical staining and reduced fibrotic marker expressions. Additionally, we showed that the differentiation of fibroblast to myofibroblast was imped in Trig + SiO2 group. In terms of mechanism, we obtained in vitro evidence that Trig inhibited fibroblast-to-myofibroblast differentiation by repressing TGF-ß/Smad signaling according to the in vitro evidence. Notably, our finding indicated that Trig seemed to be safe in mice and fibroblasts. CONCLUSION: In summary, Trig attenuated the severity of silicosis-related pulmonary fibrosis by alleviating the differentiation of myofibroblasts, indicating the development of novel therapeutic approaches for silicosis fibrosis.

Autoimmune diseases, autoantibody status and silicosis in a cohort of 1238 workers from the artificial stone benchtop industry.

OBJECTIVES: Autoimmune disorders are multifactorial but occupational exposures have long been implicated, including respirable crystalline silica (RCS). A modern epidemic of silicosis is emerging internationally, associated with dry processing of engineered stone with high (>90%) RCS content. We aimed to investigate the prevalence of clinical autoimmune disease and common autoantibodies in exposed workers. METHODS: Stone benchtop industry workers in Victoria, Australia were offered free screening for silicosis and related disorders. Symptoms or diagnoses of autoimmune disease were evaluated by questionnaire and blood tests taken for rheumatoid factor (RF), antinuclear antibodies (ANAs) and extractable nuclear antigens (ENAs). RESULTS: Among 1238 workers (93.3% male) screened from 2019 to 2021, 0.9% were confirmed with autoimmune disease. Among those without clinical disease, 24.6% had detectable ANAs (93.5% male), 4.6% detectable ENAs and 2.6% were positive for RF. Silicosis was diagnosed in 253 workers (24.3% of those with diagnostic information available). Of those with ANA readings, 54 (6.6%) had ANA titre >1:320. The likelihood of positive autoantibodies increased with age; smoking; higher exposure to RCS and silicosis diagnosis. CONCLUSION: The proportion of workers with detectable ANAs or ENAs was considerably higher than the 5%-9% expected in the general population. Some of the antibodies detected (eg, Scl-70, CENPB) have high sensitivity and specificity for systemic sclerosis. Long-term follow-up will be needed to estimate incidence. Rheumatologists should explore occupational history in new cases of autoimmune disease. Screening for autoimmune disease is indicated in workers exposed to RCS as these individuals need specialised management and may be entitled to compensation.

Occupational exposure to respirable crystalline silica and incident idiopathic interstitial pneumonias and pulmonary sarcoidosis: a national prospective follow-up study.

BACKGROUND: Respirable crystalline silica is a well-known cause of silicosis but may also be associated with other types of interstitial lung disease. We examined the associations between occupational exposure to respirable crystalline silica and the risk of idiopathic interstitial pneumonias, pulmonary sarcoidosis and silicosis. METHODS: The total Danish working population was followed 1977-2015. Annual individual exposure to respirable crystalline silica was estimated using a quantitative job exposure matrix. Cases were identified in the Danish National Patient Register. We conducted adjusted analyses of exposure-response relations between cumulative silica exposure and other exposure metrics and idiopathic interstitial pneumonias, pulmonary sarcoidosis and silicosis. RESULTS: Mean cumulative exposure was 125 µg/m3-years among exposed workers. We observed increasing incidence rate ratios with increasing cumulative silica exposure for idiopathic interstitial pneumonias, pulmonary sarcoidosis and silicosis. For idiopathic interstitial pneumonias and pulmonary sarcoidosis, trends per 50 µg/m3-years were 1.03 (95% CI 1.02 to 1.03) and 1.06 (95% CI 1.04 to 1.07), respectively. For silicosis, we observed the well-known exposure-response relation with a trend per 50 µg/m3-years of 1.20 (95% CI 1.17 to 1.23). CONCLUSION: This study suggests that silica inhalation may be related to pulmonary sarcoidosis and idiopathic interstitial pneumonias, though these findings may to some extent be explained by diagnostic misclassification. The observed exposure-response relations for silicosis at lower cumulative exposure levels than previously reported need to be corroborated in analyses that address the limitations of this study.

Thin seams and small mines are associated with higher exposures to respirable crystalline silica in US underground coal mines.

OBJECTIVES: Previous radiologic and histopathologic studies suggest respirable crystalline silica (RCS) overexposure has been driving the resurgence of pneumoconiosis among contemporary US coal miners, with a higher prevalence of severe disease in Central Appalachia. We sought to better understand RCS exposure among US underground coal miners. METHODS: We analysed RCS levels, as measured by respirable quartz, from coal mine dust compliance data from 1982 to 2021. RESULTS: We analysed 322 919 respirable quartz samples from 5064 US underground coal mines. Mean mine-level respirable quartz percentage and mass concentrations were consistently higher for Central Appalachian mines than the rest of the USA. Mean mine-level respirable quartz mass concentrations decreased significantly over time, from 0.116 mg/m3 in 1982 to as low as 0.017 mg/m3 for Central Appalachian mines, and from 0.089 mg/m3 in 1983 to 0.015 mg/m3 in 2020 for the rest of the USA. Smaller mine size, location in Central Appalachia, lack of mine safety committee and thinner coal seams were predictive of higher respirable quartz mass concentrations. CONCLUSIONS: These data substantially support the association between RCS overexposure and the resurgence of coal workers' pneumoconiosis in the USA, particularly in smaller mines in Central Appalachia.

Knowledge, attitudes and practices regarding respirable silica exposure and personal protective equipment use among brick kiln workers in Nepal.

OBJECTIVES: Brick kiln workers in Nepal are a neglected population who are exposed to high respirable silica concentrations, and few use interventions to reduce exposure. We aimed to characterise the prevalence of respiratory personal protective equipment (PPE) use, understand knowledge and attitudes towards kiln dust and respiratory PPE and identify factors associated with respiratory PPE use. METHODS: We conducted a cross-sectional study in Bhaktapur, Nepal. We used simple random selection to identify 10 out of 64 total kilns and stratified random sampling of 30 households to enrol workers aged ≥14 years within selected kilns. Field workers surveyed participants using structured questionnaires. Our primary outcome was to characterise the prevalence of current respiratory PPE use and secondary outcomes were summaries of knowledge, attitudes and practice of PPE use. RESULTS: We surveyed 83 workers (mean age 30.8 years, 77.1% male). Of these, 28.9% reported current respiratory PPE use at work, 3.6% heard of silicosis prior to the survey and 24.1% correctly identified the best respiratory PPE (N95, compared with surgical masks and barrier face coverings) for reducing dust exposure. Respiratory PPE users had higher income (mean monthly household income US$206 vs US$145; p=0.04) and education levels (25% vs 5.1% completed more than primary school; p=0.02) compared with non-users. CONCLUSIONS: Respiratory PPE use was low. Workers had poor knowledge of kiln dust health effects and proper respiratory PPE. We highlight important barriers to PPE use, particularly knowledge gaps, which can guide future investigations to reduce the silicosis burden among brick kiln workers.

Evaluating silicosis risk: Assessing dust constitution and influence of water as a primary prevention measure in cutting and polishing of silica agglomerates, granite and marble.

An increasing number of silicosis cases have been reported related to the use of silica agglomerates. Many studies agree on the severity of this disease, which often presents with severe clinical forms in young workers and after a short latency period. Are there differences in the composition of dust generated by cutting and polishing with silica agglomerates versus granite and marble? Does the use of water injection reduce the risk associated with the use of these materials? We carried out a comparative observational-analytical study, measuring the concentration of dust generated during different machining operations on three different materials: granite, marble, and silica agglomerates. The effect of water injection on dust generation was evaluated. Personal sampling pumps were used, connected to a cyclone with polyvinyl chloride filters. The flow rate of the pumps was adjusted using a piston flowmeter. Measurements with a cascade impactor were made to assess the size distribution of respirable crystalline silica particles within the respirable fraction. In addition, environmental measurements with a spectrometer were made. 10 tests were carried out on granite and silica agglomerates for each procedure. In the case of marble, with very low silica content, only 2 tests of each type were carried out. Duration of each measurement was between 6 and 25 min. Cleaning times were set for each of the operations. The amount of dust collected in the respirable fraction was 70.85, 32.50 and 35.78 mg/m3 for dry cutting; 6.50, 3.75 and 3.95 mg/m3 for wet cutting; and 21.35, 13.68 and 17.50 mg/m3 for dry polishing, for granite, marble, and silica agglomerates respectively. Dry procedures in marble, silica agglomerates and granite showed higher dust concentration of particles smaller than 0.5 µm. Silica agglomerates showed higher concentrations of respirable crystalline silica particles than granite and marble, mainly with dry procedures. The greater production of small particles in dry and wet procedures with silica agglomerates shows that water injection is an insufficient preventive measure.

Psychometric properties of the Perceived Stress Scale (PSS-10) in silica-exposed workers from diverse cultural and linguistic backgrounds.

BACKGROUND: The Perceived Stress Scale (PSS-10) has been used in a range of occupational cohorts, but only recently in stone benchtop workers undergoing screening for silicosis. The aim of this study was to compare psychometric properties of the PSS-10 in stone benchtop workers amongst those born overseas or who used an interpreter. METHODS: Stone benchtop workers in Melbourne, Australia completed the PSS-10 as part of their occupational screening for silicosis. Internal consistency was assessed with Cronbach's α for the total score and the positive and negative subscales. Validity was assessed using confirmatory factor analysis (CFA). Analysis was performed for the total group and for subgroups according to sex, interpreter use, overseas-born, and language spoken at home. RESULTS: The results of 682 workers with complete PSS-10 scores were included in analysis. Most participants were male (93%), with mean age 36.9 years (SD 11.4), with just over half (51.6%) born in Australia, 10.1% using an interpreter, and 17.5% using a language other than English at home. Cronbach's α for the overall group (α = 0.878) suggested good internal consistency. DISCUSSION: CFA analysis for validity testing suggested PSS-10 performance was good for both sexes, moderate for country of birth and language spoken at home categories, but poorer for those who used an interpreter. Whilst professional interpreters provide a range of benefits in the clinical setting, the use of translated and validated instruments are important, particularly in cohorts with large numbers of migrant workers. CONCLUSION: This study describes the psychometric properties of the PSS-10 in a population of stone benchtop workers, with good internal consistency, and mixed performance from validity testing across various subgroups.

Understanding the pathogenesis of engineered stone-associated silicosis: The effect of particle chemistry on the lung cell response.

BACKGROUND AND OBJECTIVE: The resurgence of severe and progressive silicosis among engineered stone benchtop industry workers is a global health crisis. We investigated the link between the physico-chemical characteristics of engineered stone dust and lung cell responses to understand components that pose the greatest risk. METHODS: Respirable dust from 50 resin-based engineered stones, 3 natural stones and 2 non-resin-based materials was generated and analysed for mineralogy, morphology, metals, resin, particle size and charge. Human alveolar epithelial cells and macrophages were exposed in vitro to dust and assessed for cytotoxicity and inflammation. Principal component analysis and stepwise linear regression were used to explore the relationship between engineered stone components and the cellular response. RESULTS: Cutting engineered stone generated fine particles of <600 nm. Crystalline silica was the main component with metal elements such as Ti, Cu, Co and Fe also present. There was some evidence to suggest differences in cytotoxicity (p = 0.061) and IL-6 (p = 0.084) between dust samples. However, IL-8 (CXCL8) and TNF-α levels in macrophages were clearly variable (p < 0.05). Quartz explained 11% of the variance (p = 0.019) in macrophage inflammation while Co and Al accounted for 32% of the variance (p < 0.001) in macrophage toxicity, suggesting that crystalline silica only partly explains the cell response. Two of the reduced-silica, non-engineered stone products induced considerable inflammation in macrophages. CONCLUSION: These data suggest that silica is not the only component of concern in these products, highlighting the caution required as alternative materials are produced in an effort to reduce disease risk.

Chest x-ray has low sensitivity to detect silicosis in artificial stone benchtop industry workers.

BACKGROUND AND OBJECTIVE: Chest x-ray (CXR) remains a core component of health monitoring guidelines for workers at risk of exposure to crystalline silica. There has however been a lack of evidence regarding the sensitivity of CXR to detect silicosis in artificial stone benchtop industry workers. METHODS: Paired CXR and high-resolution computed tomography (HRCT) images were acquired from 110 artificial stone benchtop industry workers. Blinded to the clinical diagnosis, each CXR and HRCT was independently read by two thoracic radiologists from a panel of seven, in accordance with International Labour Office (ILO) methodology for CXR and International Classification of HRCT for Occupational and Environmental Respiratory Diseases. Accuracy of screening positive (ILO major category 1, 2 or 3) and negative (ILO major category 0) CXRs were compared with identification of radiological features of silicosis on HRCT. RESULTS: CXR was positive for silicosis in 27/110 (24.5%) workers and HRCT in 40/110 (36.4%). Of the 83 with a negative CXR (ILO category 0), 15 (18.1%) had silicosis on HRCT. All 11 workers with ILO category 2 or 3 CXRs had silicosis on HRCT. In 99 workers ILO category 0 or 1 CXRs, the sensitivity of screening positive CXR compared to silicosis identified by HRCT was 48% (95%CI 29-68) and specificity 97% (90-100). CONCLUSION: Compared to HRCT, sensitivity of CXR was low but specificity was high. Reliance on CXR for health monitoring would provide false reassurance for many workers, delay management and underestimate the prevalence of silicosis in the artificial stone benchtop industry.

Macrophage-derived exosomal HMGB3 regulates silica-induced pulmonary inflammation by promoting M1 macrophage polarization and recruitment.

BACKGROUND: Chronic inflammation and fibrosis are characteristics of silicosis, and the inflammatory mediators involved in silicosis have not been fully elucidated. Recently, macrophage-derived exosomes have been reported to be inflammatory modulators, but their role in silicosis has not been explored. The purpose of the present study was to investigate the role of macrophage-derived exosomal high mobility group box 3 (HMGB3) in silica-induced pulmonary inflammation. METHODS: The induction of the inflammatory response and the recruitment of monocytes/macrophages were evaluated by immunofluorescence, flow cytometry and transwell assays. The expression of inflammatory cytokines was examined by RT-PCR and ELISA, and the signalling pathways involved were examined by western blot analysis. RESULTS: HMGB3 expression was increased in exosomes derived from silica-exposed macrophages. Exosomal HMGB3 significantly upregulated the expression of inflammatory cytokines, activated the STAT3/MAPK (ERK1/2 and p38)/NF-κB pathways in monocytes/macrophages, and promoted the migration of these cells by CCR2. CONCLUSIONS: Exosomal HMGB3 is a proinflammatory modulator of silica-induced inflammation that promotes the inflammatory response and recruitment of monocytes/macrophages by regulating the activation of the STAT3/MAPK/NF-κB/CCR2 pathways.

Differential pulmonary toxicity and autoantibody formation in genetically distinct mouse strains following combined exposure to silica and diesel exhaust particles.

BACKGROUND: Inhalation of airborne particulate matter, such as silica and diesel exhaust particles, poses serious long-term respiratory and systemic health risks. Silica exposure can lead to silicosis and systemic autoimmune diseases, while DEP exposure is linked to asthma and cancer. Combined exposure to silica and DEP, common in mining, may have more severe effects. This study investigates the separate and combined effects of occupational-level silica and ambient-level DEP on lung injury, inflammation, and autoantibody formation in two genetically distinct mouse strains, thereby aiming at understanding the interplay between genetic susceptibility, particulate exposure, and disease outcomes. Silica and diesel exhaust particles were administered to mice via oropharyngeal aspiration. Assessments of lung injury and host response included in vivo lung micro-computed tomography, lung function tests, bronchoalveolar lavage fluid analysis including inflammatory cytokines and antinuclear antibodies, and histopathology with particle colocalization. RESULTS: The findings highlight the distinct effects of silica and diesel exhaust particles (DEP) on lung injury, inflammation, and autoantibody formation in C57BL/6J and NOD/ShiLtJ mice. Silica exposure elicited a well-established inflammatory response marked by inflammatory infiltrates, release of cytokines, and chemokines, alongside mild fibrosis, indicated by collagen deposition in the lungs of both C57BL/6J and NOD/ShilLtJ mice. Notably, these strains exhibited divergent responses in terms of respiratory function and lung volumes, as assessed through micro-computed tomography. Additionally, silica exposure induced airway hyperreactivity and elevated antinuclear antibody levels in bronchoalveolar lavage fluid, particularly prominent in NOD/ShiLtJ mice. Moreover, antinuclear antibodies correlated with extent of lung inflammation in NOD/ShiLTJ mice. Lung tissue analysis revealed DEP loaded macrophages and co-localization of silica and DEP particles. However, aside from contributing to airway hyperreactivity specifically in NOD/ShiLtJ mice, the ambient-level DEP did not significantly amplify the effects induced by silica. There was no evidence of synergistic or additive interaction between these specific doses of silica and DEP in inducing lung damage or inflammation in either of the mouse strains. CONCLUSION: Mouse strain variations exerted a substantial influence on the development of silica induced lung alterations. Furthermore, the additional impact of ambient-level DEP on these silica-induced effects was minimal.

Integration of apaQTL and eQTL analysis reveals novel SNPs associated with occupational pulmonary fibrosis risk.

To explore the association between apaQTL/eQTL-SNPs and the susceptibility to silicosis. A silicosis-related GWAS was initially conducted to screen for single nucleotide polymorphisms (SNPs) associated with the risk of silicosis. Candidate SNPs with apaQTL and eQTL functions were then obtained from the 3'aQTL-atlas and GTEx databases. Subsequently, additional case-control studies were performed to validate the relationship between the candidate apaQTL/eQTL-SNPs and the risk of silicosis. Finally, experiments were conducted to illustrate APA events occurring at different alleles of the identified apaQTL/eQTL-SNPs. The combined results of the GWAS and iMLDR validations indicate that the variant T allele of the rs2974341 located on SMIM19 (additive model: OR = 0.66, the 95% CI = 0.53-0.84, P = 0.001) and the variant T allele of the rs2390488 located on TMTC4 (additive model: OR = 0.72, 95% CI = 0.57-0.90, P = 0.005) were significantly associated with decreased risk of developing silicosis susceptibility. Furthermore, 3'RACE experiments verified the presence of two poly (A) sites (proximal and distal) in SMIM19, rs2974341 may remotely regulate the binding between miRNA-3646 and SMIM19 with its high LD locus rs2974353 to affect the expression level of SMIM19. The rs2974341 variant T allele may contribute to the generation of the shorter 3'UTR transcript of SMIM19 and affect the binding of miRNA-3646 to the target gene SMIM19. The apaQTL/eQTL-SNPs may provide new perspectives for evaluating the regulatory function of SNPs in the development of silicosis.

Multi-omics and multi-stages integration identified a novel variant associated with silicosis risk.

Assessing the association between candidate single-nucleotide polymorphisms (SNPs) identified by multi-omics approaches and susceptibility to silicosis. RNA-seq analysis was performed to screen the differentially expressed mRNAs in the fibrotic lung tissues of mice exposed to silica particles. Following this, we integrated the SNPs located in the above human homologenes with the silicosis-related genome-wide association study (GWAS) data to select the candidate SNPs. Then, expression quantitative trait locus (eQTL)-SNPs were identified by the GTEx database. Next, we validated the associations between the functional eQTL-SNPs and silicosis susceptibility by additional case-control study. And the contribution of the identified SNP and its host gene in the fibrosis process was further validated by functional experiments. A total of 12 eQTL-SNPs were identified in the screening stage. The results of the validation stage suggested that the variant T allele of rs419540 located in IL12RB1 significantly increased the risk of developing silicosis [additive model: odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.11-2.85, P = 0.017]. Furthermore, the combination of GWAS and the results of validation stage also indicated that the variant T allele of rs419540 in IL12RB1 was associated with increased silicosis risk (additive model: OR = 2.07, 95% CI 1.38-3.12, P < 0.001). Additionally, after knockdown or overexpression of IL12RB1, the levels of pro-inflammatory factors, such as IL-12, IFN-γ, and other pro-inflammatory factors, were correspondingly decreased or increased. The novel eQTL-SNP, rs419540, might increase the risk of silicosis by modulating the expression levels of IL12RB1.

Latent tuberculosis infection and infection-associated risk factors for miner workers with silicosis in eastern China.

OBJECTIVES: Silicosis people are at high risk of developing pulmonary tuberculosis. Whether silica exposure increases the likelihood of latent tuberculosis infection (LTBI) was not well understood, and potential factors involved in LTBI risk among silicosis people were not evaluated before. Thus, LTBI among silicosis people and potential risk factors for LTBI among silicosis people were evaluated in this study. METHODS: A cross-sectional study was undertaken for 130 miner workers with silicosis. The QFT-GIT was performed for LTBI detection. RESULTS: The LTBI was high to 31.6% (36/114) for silicosis participants, and 13.1% (13/99) had a history of tuberculosis. Drinking was associated with LTBI risk (OR = 6.92, 95%CI, 1.47-32.66, P = 0.015). Meanwhile, tunneling work was associated with an increased risk of LTBI compared with other mining occupations (OR = 3.91,95%CI,1.20-12.70, P = 0.024). CONCLUSIONS: The LTBI rate of silicosis participants was high and more than 10% had a history of tuberculosis. Drinking alcohol and tunneling were independent risk factors for LTBI in silicosis participants.

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.

The aryl hydrocarbon receptor pathway is a marker of lung cell activation but does not play a central pathologic role in engineered stone-associated silicosis.

Engineered stone-associated silicosis is characterised by a rapid progression of fibrosis linked to a shorter duration of exposure. To date, there is lack of information about molecular pathways that regulates disease development and the aggressiveness of this form of silicosis. Therefore, we compared transcriptome responses to different engineered stone samples and standard silica. We then identified and further tested a stone dust specific pathway (aryl hydrocarbon receptor [AhR]) in relation to mitigation of adverse lung cell responses. Cells (epithelial cells, A549; macrophages, THP-1) were exposed to two different benchtop stone samples, standard silica and vehicle control, followed by RNA sequencing analysis. Bioinformatics analyses were conducted, and the expression of dysregulated AhR pathway genes resulting from engineered stone exposure was then correlated with cytokine responses. Finally, we inhibited AhR pathway in cells pretreated with AhR antagonist and observed how this impacted cell cytotoxicity and inflammation. Through transcriptome analysis, we identified the AhR pathway genes (CYP1A1, CYP1B1 and TIPARP) that showed differential expression that was unique to engineered stones and common between both cell types. The expression of these genes was positively correlated with interleukin-8 production in A549 and THP-1 cells. However, we only observed a mild effect of AhR pathway inhibition on engineered stone dust induced cytokine responses. Given the dual roles of AhR pathway in physiological and pathological processes, our data showed that expression of AhR target genes could be markers for assessing toxicity of engineered stones; however, AhR pathway might not play a significant pathologic role in engineered stone-associated silicosis.

Accelerated silicosis in sandblasters: Pathology, mineralogy, and clinical correlates.

BACKGROUND: With increasing reports of accelerated and acute silicosis, PMF, and autoimmune disease among coal miners and silica-exposed countertop workers, we present previously incompletely-described pulmonary pathology of accelerated silicosis and correlations with mineralogy, radiography, and disease progression in 46 Texas oilfield pipe sandblasters who were biopsied between 1988 and 1995. METHODS: Worker examinations included pulmonary function tests, chest X-ray (CXR), high-resolution computed tomography (HRCT), and Gallium-67 scans. Quantitative mineralogic analysis of pulmonary parenchymal burden of silica, silicates, and metal particles used scanning electron microscopy with energy dispersive x-ray spectroscopy (SEM EDS). RESULTS: Workers had clinical deterioration after <10 years exposure in dusty workplaces. Although initial CXR was normal in 54%, Gallium-67 scans were positive in 68% of those with normal CXR, indicating pulmonary inflammation. The histology of accelerated silicosis is diffuse interstitial infiltration of macrophages filled with weakly birefringent particles with or without silicotic nodules or alveolar proteinosis. Lung silica concentrations were among the highest in our database, showing a dose-response relationship with CXR, HRCT, and pathologic changes (macrophages, fibrosis, and silicotic nodules). Radiographic scores and diffusing capacity worsened during observation. Silica exposure was intensified, patients presented younger, with shorter exposure, more severe clinical abnormalities, higher lung particle burdens, and more rapid progression in a subset of patients exposed to recycled blasting sand. CONCLUSIONS: Accelerated silicosis may present with a normal CXR despite significant histopathology. Multivariable analyses showed silica, and not other particles, is the driver of observed radiologic, physiologic, and histologic outcomes. Eliminating this preventable disease requires higher physician, public health, and societal awareness.

Bioinformatics-based dynamics of cuproptosis -related indicators in experimental silicosis.

Pneumoconiosis is one of the most serious occupational diseases worldwide. Silicosis due to prolonged inhalation of free silica dust during occupational activities is one of the main types. Cuproptosis is a newly discovered mode of programmed cell death characterized by the accumulation of free copper in the cell, which ultimately leads to cell death. Increased copper in the serum of silicosis patients, suggests that the development of silicosis is accompanied by changes in copper metabolism, but whether cuproptosis is involved in the progression of silicosis is actually to be determined. To test this hypothesis, we screened the genetic changes in patients with idiopathic fibrosis by bioinformatics methods and predicted and functionally annotated the cuproptosis-related genes among them. Subsequently, we established a mouse silicosis model and detected the concentration of copper ions and the activity of ceruloplasmin (CP) in serum, as well as changes of the concentration of copper and cuproptosis related genes in mouse lung tissues. We identified 9 cuproptosis-related genes among the differential genes in patients with IPF at different times and the tissue-specific expression levels of ferredoxin 1 (FDX1) and Lipoyl synthase (LIAS) proteins. Furthermore, serum CP activity and copper ion levels in silicosis mice were elevated on days 7th and 56th after silica exposure. The expression of CP in mouse lung tissue elevated at all stages after silica exposure. The mRNA level of FDX1 decreased on days 7th and 56th, and the protein level remained in accordance with the mRNA level on day 56th. LIAS and Dihydrolipoamide dehydrogenase (DLD) levels were downregulated at all times after silica exposure. In addition, Heatshockprotein70 (HSP70) expression was increased on day 56. In brief, our results demonstrate that there may be cellular cuproptosis during the development of experimental silicosis in mice and show synchronization with enhanced copper loading in mice.