Silica Exposure Research Articles

Periodontal conditions and salivary microbiota are potential indicators to distinguish silicosis: an exploratory study

BackgroundSilicosis has always been a serious global occupational health problem. Oral microbiota plays important roles in the development of lung disease. However, few studies have investigated the relationship between periodontal conditions, oral bacteria and silicosis disease.MethodA single-center and cross-sectional study was conducted in 2019 in Sichuan Province, China, including a small sample of silicosis patient group and healthy control group. Demographic data and periodontal examinations measured by clinical attachment loss (CAL), bleeding on probing (BOP) and periodontal pocket (PD) were collected from each participant. Phenotypic changes were detected by histopathological staining. Next-generation sequencing targeting 16S ribosomal RNA was targeted to decipher the salivary microbiome of the two groups. Random forest, Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression and multivariable logistic regression analysis were conducted to find potential indicators to distinguish silicosis.ResultsIn general, 29 male healthy controls and 24 male silicosis patients were included. The proportion of CAL ≥ 3 mm in silicosis group was greater than control group, while the proportion of BOP (+) and PD ≥ 4 mm was reduced in silicosis group. The α-smooth muscle actin and fibronectin expression increased in gingiva of patients. The composition of salivary microbiota exhibited significant differences between the two groups, with silicosis patients demonstrating a lower diversity of salivary microbiota. Genus of Aggregatibacter [odds ratio (OR) = 0.000, p = 0.003] and Catonella (OR = 0.000, p = 0.049) were identified as biomarkers to distinguish silicosis.ConclusionsThe silicosis group exhibited worse CAL, improved BOP and PD, which may be related to the gingival fibrosis found in this study. The composition of the oral microbiota underwent significant changes, accompanied by a decrease in diversity, in patients with silicosis. Our study indicates that respirable crystalline silica exposure affects oral health, and alterations of oral microbiota might be implicated in silicosis. We primarily identified Aggregatibacter and Catonella as the potential indicators to distinguish silicosis patients from healthy controls.

Relationship between cumulative silica exposure and silicosis: a systematic review and dose-response meta-analysis

BackgroundSilicosis, a chronic respiratory disease caused by crystalline silica exposure, is a persistent global lung health issue. No systematic review of the relationship between cumulative respirable crystalline silica (RCS) exposure...

Correlation of spirometry findings and post-six-minute walk test oxygen desaturation in chronic simple silicosis patients with age, duration of silica exposure, smoking pack years, occupation and mean pulmonary artery pressure.

Silicosis is associated with preventable but irreversible lung damage. Early quantifiable assessment of silicosis workers would promote early interventional steps to reduce health deterioration. The objectives of this study were to correlate spirometry findings and post-six-minute walk test oxygen desaturation (post-6MWT OD) in chronic simple silicosis with age, duration of silica exposure (DSE), smoking pack years (SPY), occupation, and mean pulmonary artery pressure. Based on occupational exposure to silica and radiologic confirmation of chronic simple silicosis, 104 patients (all males) were enrolled and grouped based on SPY (nil, 1-10, 11-20, and >20) and occupation (drillers and dressers). They were further investigated with spirometry, post-6MWT OD, and transthoracic echocardiography (TTE), and findings were statistically analyzed. Abnormal spirometry findings were seen in 62.5% of total cases (65/104), with the highest percentage in the >20 SPY group (84%; 21/25) and drillers (68.3%; 28/41). The post-6MWT OD was seen in 50.96% of cases (53/104) with the highest percentage in the >20 SPY group (56%; 14/25) and drillers (63.4%; 26/41). Normal and restrictive patterns were predominant among <20 SPY groups, while obstructive and mixed patterns were prevalent in the >20 SPY group. Normal, obstructive, and restrictive patterns were predominant among dressers, while mixed patterns were in drillers. Mean age and mean DSE were higher for >20 SPY group and dressers; obstructive and mixed patterns; and patients with post-6MWT OD. Pulmonary hypertension was significantly associated with the presence of abnormal spirometry patterns (69.3%; 45/65) and post-6MWT OD (79.3%; 42/53). Mean forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) was significantly lower for the >20 SPY group. Mean FEV1 had an inverse relation with SPY, and mean FVC was lower for drillers than dressers. Spirometry, post-6MWT OD, and TTE assessment give a complete overview of the cardiopulmonary exercise capacity of chronic silicosis patients and facilitate early interventions with special consideration for workers involved in machine-based mining activity.

The evaluation of pneumoconiosis by risk factors gender and age groups in Turkiye, in 1990-2021: incidence, prevalence, deaths, and disability-adjusted life years

Aims: The aim of this study was to evaluate the incidence and prevalence of pneumoconiosis, pneumoconiosis-related disability-adjusted life years (DALY) score, deaths and risk factors by gender and year in Türkiye. Methods: In this study, the estimation data prepared by the Institute for Health Metrics and Evaluation (IHME) for Türkiye in the global burden of disease study covering the years 1990-2021 were used. Descriptive statistics are given as mean and standard deviation. Comparisons according to gender were made with Independent Samples t test. The relationships between numerical variables were analyzed by Pearson correlation coefficient (r). Results: A total of 1755 pneumoconiosis-related deaths occurred in Türkiye between 1990 and 2021. Of the deaths, 687 (39%) were due to silicosis, 489 (28%) to coal worker pneumoconiosis, 451 (26%) to asbestosis and 128 (7%) to other pneumoconiosis. Of those who died, 1619 (92%) were men. The DALY score, incidence and prevalence are also higher in men. The most common risk factor affecting men is silica exposure, while for women it is asbestos exposure. After 2016, incidence and prevalence are decreasing. Conclusion: Pneumoconiosis is more fatal in men and in the 65-80 age group. The effects of the disease vary across countries and even regions within the same country. It is important to take these differences into account in future research on pneumoconiosis. Regulation of working environments in sectors known to cause the disease will both ensure that people are less affected by an important occupational disease and prevent loss of workforce.

Understanding the molecular basis of anti-fibrotic potential of intranasal curcumin and its association with mitochondrial homeostasis in silica-exposed mice

Silicosis is an occupational disease of the lungs brought in by repeated silica dust exposures. Inhalation of crystalline silica leads to persistent lung inflammation characterized by lung lesions due to granuloma formation. The specific molecular mechanism has not yet been identified, though. The Present study investigated the impact of silica-exposed lung fibrosis and probable molecular mechanisms. Here, Curcumin, derived from Curcuma longa shown to be an effective anti-inflammatory and anti-fibrotic molecule has been taken to investigate its therapeutic efficacy in silica-induced lung fibrosis. An experimental model of silicosis was established in mice where curcumin was administered an hour before intranasal silica exposure every alternate day for 35 days. Intranasal Curcumin treatment reduced silica-induced oxidative stress, inflammation marked by inflammatory cell recruitment, and prominent granuloma nodules along with aberrant collagen repair. Its protective benefits were confirmed by reduced MMP9 activities along with EMT markers (Vimentin and α-SMA). It has restored autophagy and suppressed the deposition of damaged mitochondria after silica exposure. Intranasal Curcumin also inhibited oxidative stress by boosting antioxidant enzyme activities and enhanced Nrf2-Keap1 expressions. Higher levels of PINK1, PARKIN, Cyt-c, P62/SQSTM, and damaged mitochondria in the silicosis group were significantly lowered after curcumin and dexamethasone treatments. Curcumin-induced autophagy resulted in reduced silica-induced mitochondria-dependent apoptosis. We report that intranasal curcumin treatment showed protective properties on pathological features prompted by silica particles, suggesting that the compound may constitute a promising strategy for the treatment of silicosis in the near future.

Alterations and associations between lung microbiota and metabolite profiles in silica-induced lung injury

Silicosis, caused by silica exposure, is the most widespread and deadliest occupational disease. However, effective treatments are lacking. Therefore, it is crucial to elucidate the mechanisms and targets involved in the development of silicosis. We investigated the basic processes of silicosis development and onset at different exposure durations (2 or 4 weeks) using various techniques such as histopathology, immunohistochemistry, Enzyme linked immunosorbent assay(ELISA),16 S rRNA, and untargeted metabolomics.These results indicate that exposure to silica leads to progressive damage to lung tissue with significant deterioration observed over time. Time-dependent cytokines such as the IL-4, IL-13, and IL-6 are detected in lung lavage fluid, the model group consistently exhibited elevated levels of these cytokines, indicating a persistent and worsening inflammatory response in the lungs. Meanwhile, HE and Masson results show that 4-week exposure to silica causes more obvious lung injury and pulmonary fibrosis. Besides, the model group consistently exhibited a distinct lung bacterial population, known as the Lachnospiraceae_NK4A136_group, regardless of exposure duration. However, with increasing exposure duration, specific temporal changes were observed in lung bacterial populations, including Haliangium, Allobaculum, and Sandaracinus (at 4 weeks; p < 0.05). Furthermore, our study revealed a strong correlation between the mechanism of silica-induced lung injury and three factors: oxidative stress, impaired lipid metabolism, and imbalanced amino acid metabolism. We observed a close correlation between cytokine levels, changes in lung microbiota, and metabolic disturbances during various exposure periods. These findings propose that a possible mechanism of silica-induced lung injury involves the interplay of cytokines, lung microbiota, and metabolites.

Feasibility of respirable crystalline silica exposure reduction in small-scale tanzanite mining in Tanzania.

Respirable crystalline silica (RCS) exposures in tanzanite gem mining have been linked to tuberculosis and silicosis among miners. We conducted a plot study to assess RCS exposures and to introduce safer mining practices in one small-scale underground tanzanite mine. Personal and area air samples for RCS were collected during tanzanite mining operations before and after improved work practices employed to reduce exposures and analyzed using X-ray diffraction. Area samples were collected at the rest area, located approximately 300 m underground and 100 m from other work activities. Improved practices included the use of wet drilling methods and drilling with new bits. A total of 33 personal and 4 area air samples were collected. Pre-intervention, mean exposures for all operations, drilling operations, non-drilling activities, and area samples were 122 mg/m3, 247 mg/m3, 34.3 mg/m3, and 1.95 mg/m3, respectively which exceeded the U.S. OSHA Permissible Exposure Limit (PEL) by 2,440 times for all operations, by 4,946 times for drilling operations, by 686 times for non-drilling activities and 39 times for area samples collected at an underground rest area. The post-intervention results showed a 99% reduction of RCS exposures for wet drilling operations, 98.5% reduction for non-drilling activities, and 36% reduction for area samples. Despite improvements, post-intervention RCS exposures during drilling had a mean of 2.08 mg/m3 or more than 41 times the OSHA PEL. We successfully piloted a program to work with small-scale tanzanite miners to reduce RCS exposures and raise awareness about the occupational health risks of RCS, though additional measures are recommended to further reduce RCS exposures. Similar programs should be taken to scale throughout underground mining sites in Tanzania and other countries.

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.

Repeated Silica exposures lead to Silicosis severity via PINK1/PARKIN mediated mitochondrial dysfunction in mice model

Background and objectivesSilicosis, one of the occupational health illnesses is caused by inhalation of crystalline silica. Deposition of extracellular matrix and fibroblast proliferation in lungs are linked to silicosis development. Mitochondrial dysfunction plays critical role in some diseases, but how these processes progress and regulated in silicosis, remains limited. Detailed study of silica induced pulmonary fibrosis in mouse model, its progression and severity may be helpful in designing future therapeutic strategies. MethodsIn present study, mice model of silicosis has been developed after repeated silica exposures which may closely resemble clinical symptoms of silicosis in human. In addition to efficiently mimicking the acute/chronic transformation processes of silicosis, this is practical and efficient in terms of time and output, which avoids mechanical injury to the upper respiratory tract due to surgical interventions. Sonicated sterile silica suspension (120 mg/kg) was administered through intranasal route thrice a week at regular intervals (21, 28 and 35 days). ResultsPresence of minute to larger silicotic nodules in H&E-stained lung sections were observed in all silica induced model groups. Enhanced ECM deposition was noted in MT stained lung sections of silica exposure groups as compared to control which were confirmed by significantly higher MMP9 expression levels and hydroxyproline content in silica 35 days group. Increase in Reactive oxygen species (ROS), inflammatory cell recruitment mainly, neutrophils and macrophage were observed in all three silica exposure groups. Transmission electron microscopic analysis has confirmed presence of many aberrant shaped mitochondria (swollen, round shape) in 35 days model where autophagosomes were minimum. Western blot analysis of mitophagy and autophagy markers such as Pink1, Parkin, Cytochrome c, SQSTM1/p62, the ratio of light chain LC3B II/LC3B I was found higher in 21 and 28 days which were significantly reduced in 35 days silica model. ConclusionsHigher MMP9 activity and MMP9 /TIMP1 ratio demonstrate excessive extracellular matrix damage and deposition in 35 days model. Significantly reduced expressions of autophagy and mitophagy markers have also confirmed progression in fibrosis severity and its association with repeated silica exposures in 35 days model group.

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.

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

BackgroundRespirable 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...

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

ObjectivesBrick 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...

123 Respirable crystalline silica exposure in the building materials production: monitoring data over the last 20 years

123 Respirable crystalline silica exposure in the building materials production: monitoring data over the last 20 years

#1700 Clinical presentation and prognosis in ANCA-associated vasculitis with occupational exposure to silica: a monocentric retrospective study

Abstract Background and Aims Exposure to silica is associated with an increased risk of autoimmune diseases, including ANCA-associated vasculitis (AAV) [1–3]. It remains unclear whether silica exposure modifies clinical presentation of AAV, and it is not known whether it affects prognosis. The aim of this work is to address these questions. Method This is a retrospective, monocentric observational study comparing clinical and prognostic features between two groups of patients with ANCA-positive AAV: cases with a well-documented history of occupational exposure to silica (confirmed by industrial hygienists) and controls with no exposure. Each case was matched to 2 controls based on time of diagnosis (± 1 year relative to the case). Clinical features were compared across the two groups using Student's t test or chi-squared test, as appropriate. Clinical outcomes were compared across groups with the log-rank test and Cox proportional hazards regression. Results We identified 25 patients with AAV and a clear-cut history of occupational exposure to silica and 50 controls with no exposure, diagnosed between 2000 and 2023. Compared to controls, patients exposed to silica were more frequently males and smokers (Table). Average age at presentation was 66 ± 14 years and most patients had microscopic polyangiitis and MPO-ANCAs, with no significant differences according to silica exposure (Table). Patterns of organ involvement were also comparable across the two groups (Table). Renal vasculitis was present in almost all patients, probably reflecting a referral bias. Severity of renal impairment at diagnosis (Table) and evolution to end stage renal disease (Figure) were similar between exposed and unexposed individuals. There was a trend for lower survival in patients with exposure to silica (median survival from AAV diagnosis: 172 months in cases and 111 months in controls, log-rank test p = 0.065, Figure). In multivariate Cox regression, the risk of death was independently associated with age at diagnosis (HR 1.09 per year, 95% CI 1.04-1.14, p &amp;lt; 0.001) and not with silica exposure (HR 0.96, 95% CI 0.39-2.41, p = 0.936) or smoking history (HR 2.06, 95% CI 0.80-5.33, p = 0.135). Conclusion Patients with AAV and exposure to silica were more frequently males and smokers, likely reflecting socio-economic factors. We did not identify otherwise distinct clinical features in exposed patients, similarly to other Authors such as Hogan et al [2]. Exposure to silica did not seem to significantly affect renal prognosis or survival either, despite a trend in univariate analysis for higher mortality in individuals with silica exposure. The limited sample size and lack of quantification of silica exposure must be acknowledged and may have reduced statistical power.

Occupational exposures and sarcoidosis: a rapid review of the evidence.

Sarcoidosis is a rare, multisystem, inflammatory condition associated with the formation of granulomas. Diagnosis can be challenging because of non-specific symptoms complicating epidemiological investigations of its aetiology. Despite research efforts, a review of the current state of the evidence is needed. To assess the evidence for an association between occupational exposures and the development of sarcoidosis. To determine if workers in any occupation are at a greater risk of developing sarcoidosis. This rapid review follows the methodology suggested by the World Health Organization. Two electronic databases were systematically searched until April 2022. The methodological quality of the studies was critically appraised, and a best-evidence approach was used to synthesize the results. Titles and abstracts of 2916 articles were screened, with 67 full-text articles reviewed for eligibility. Among the 13 studies eligible for this review, none were of high quality (i.e. low risk of bias). Six studies exploring the association between sarcoidosis and a range of occupations and exposures, and one previous systematic review were of low quality reporting inconsistent findings. Six studies examined the risk of sarcoidosis associated with occupational silica exposure, two of which were of acceptable quality. Overall, the study methodologies and results were inadequate to support causal relationships. There is limited evidence of acceptable methodological quality to assess the risk of sarcoidosis associated with occupational exposures. There is a growing body of research examining occupational exposure to silica and sarcoidosis. Additional high-quality confirmatory research is needed.

Silica's silent threat: Contributing to skin fibrosis in systemic sclerosis by targeting the HDAC4/Smad2/3 pathway

Nowadays, silica products are widely used in daily life, especially in skin applications, which inevitably increases the risk of silica exposure in general population. However, inadequate awareness of silica's potential hazards and lack of self-protection are of concern. Systemic sclerosis (SSc) is characterized by progressive tissue fibrosis under environmental and genetic interactions. Silica exposure is considered an important causative factor for SSc, but its pathogenesis remains unclear. Within this study, we showed that lower doses of silica significantly promoted the proliferation, migration, and activation of human skin fibroblasts (HSFs) within 24 h. Silica injected subcutaneously into mice induced and exacerbated skin fibrosis. Notably, silica increased histone deacetylase-4 (HDAC4) expression by inducing its DNA hypomethylation in normal HSFs. The elevated HDAC4 expression was also confirmed in SSc HSFs. Furthermore, HDAC4 was positively correlated with Smad2/3 phosphorylation and COL1, α-SMA, and CTGF expression. The HDAC4 inhibitor LMK235 mitigated silica-induced upregulation of these factors and alleviated skin fibrosis in SSc mice. Taken together, silica induces and exacerbates skin fibrosis in SSc patients by targeting the HDAC4/Smad2/3 pathway. Our findings provide new insights for evaluating the health hazards of silica exposure and identify HDAC4 as a potential interventional target for silica-induced SSc skin fibrosis.

A study of inflammatory biomarkers in crystalline silica exposed rock drillers

BackgroundCrystalline silica (CS) exposure can cause serious lung disease in humans, but mechanisms of pulmonary toxicity have not been completely elucidated.AimsTo assess pro-inflammatory and anti-inflammatory biomarkers and biomarkers related to the development of chronic obstructive pulmonary disease and fibrosis in serum of rock drillers exposed to CS.MethodsRock drillers (N = 123) exposed to CS and non-specified particulate matter (PM) were compared to 48 referents without current or past exposure to PM in a cross-sectional study.ResultsThe rock drillers had been exposed to CS for 10.7 years on average. Geometric mean (GM) current exposure was estimated to 36 µg/m3. Their GM concentration of matrix metalloproteinase 12 (MMP-12) was significantly higher (16 vs. 13 ng/L; p = 0.04), while interleukin (IL) 6 and IL-8 were significantly lower compared to the referents. Also pentraxin 3 was significantly lower (3558 vs. 4592 ng/L; p = 0.01) in the rock drillers. A dose-response relationship was observed between cumulative exposure to CS and MMP-12, the highest exposed subgroup having significantly higher MMP-12 concentrations than the referents.ConclusionExposure to CS may increase circulating MMP-12 concentrations in a dose-response related fashion. The results may also suggest a down-regulation of pro-inflammatory pathways.

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

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. A cross-sectional study was undertaken for 130 miner workers with silicosis. The QFT-GIT was performed for LTBI detection. 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). 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.

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.

Metabolic landscape of human alveolar type II epithelial cells undergoing epithelial-mesenchymal transition induced directly by silica exposure

Epithelial-mesenchymal transition (EMT) plays an irreplaceable role in the development of silicosis. However, molecular mechanisms of EMT induced by silica exposure still remain to be addressed. Herein, metabolic profiles of human alveolar type II epithelial cells (A549 cells) exposed directly to silica were characterized using non-targeted metabolomic approaches. A total of 84 differential metabolites (DMs) were identified in silica-treated A549 cells undergoing EMT, which were mainly enriched in metabolisms of amino acids (e.g., glutamate, alanine, aspartate), purine metabolism, glycolysis, etc. The number of DMs identified in the A549 cells obviously increased with the elevated exposure concentration of silica. Remarkably, glutamine catabolism was significantly promoted in the silica-treated A549 cells, and the levels of related metabolites (e.g., succinate) and enzymes (e.g., α-ketoglutarate (α-KG) dehydrogenase) were substantially up-regulated, with a preference to α-KG pathway. Supplementation of glutamine into the cell culture could substantially enhance the expression levels of both EMT-related markers and Snail (zinc finger transcription factor). Our results suggest that the EMT of human alveolar epithelial cells directly induced by silica can be essential to the development of silicosis.