Pulmonary osteoclast-like cells in silica induced pulmonary fibrosis.

The pathophysiology of silicosis is poorly understood, limiting development of therapies for those who have been exposed to the respirable particle. We explored mechanisms of silica-induced pulmonary fibrosis in human lung samples collected from patients with occupational exposure to silica and in a longitudinal mouse model of silicosis using multiple modalities including whole-lung single-cell RNA sequencing and histological, biochemical, and physiologic assessments. In addition to pulmonary inflammation and fibrosis, intratracheal silica challenge induced osteoclast-like differentiation of alveolar macrophages and recruited monocytes, driven by induction of the osteoclastogenic cytokine, receptor activator of nuclear factor κΒ ligand (RANKL) in pulmonary lymphocytes, and alveolar type II cells. Anti-RANKL monoclonal antibody treatment suppressed silica-induced osteoclast-like differentiation in the lung and attenuated pulmonary fibrosis. We conclude that silica induces differentiation of pulmonary osteoclast-like cells leading to progressive lung injury, likely due to sustained elaboration of bone-resorbing proteases and hydrochloric acid. Interrupting osteoclast-like differentiation may therefore constitute a promising avenue for moderating lung damage in silicosis.

From Engineered Stone Slab to Silicosis: A Synthesis of Exposure Science and Medical Evidence.

Engineered stone (ES) is a popular building product, due to its architectural versatility and generally lower cost. However, the fabrication of organic resin-based ES kitchen benchtops from slabs has been associated with alarming rates of silicosis among workers. In 2024, fifteen years after the first reported ES-related cases in the world, Australia became the first country to ban the use and importation of ES. A range of interacting factors are relevant for ES-associated silicosis, including ES material composition, characteristics of dust exposure and lung cell-particle response. In turn, these are influenced by consumer demand, work practices, particle size and chemistry, dust control measures, industry regulation and worker-related characteristics. This literature review provides an evidence synthesis using a narrative approach, with the themes of product, exposure and host. Exposure pathways and pathogenesis are explored. Apart from crystalline silica content, consideration is given to non-siliceous ES components such as resins and metals that may modify chemical interactions and disease risk. Preventive effort can be aligned with each theme and associated evidence.

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

BACKGROUND: Silicosis, 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. METHODS: The 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. RESULTS: This 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. CONCLUSIONS: This study uncovers a natural compound, HKL, with significant anti-fibrotic properties through activating sirt3, shedding light on silicosis pathogenesis and treatment avenues.

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.

Low-Level Respirable Crystalline Silica and Silicosis: Long-Term Follow-Up of Vermont Granite Workers.

The lifetime risk of silicosis associated with low-level occupational exposure to respirable crystalline silica remains unclear because most previous radiographic studies included workers with varying exposure concentrations and durations. This study assessed the prevalence of silicosis after lengthy exposure to respirable crystalline silica at levels ≤ 0.10 mg/m3. Vermont granite workers employed any time during 1979-1987 were traced and chest radiographs were obtained for 356 who were alive in 2017 and residing in Vermont. Work history, smoking habits and respiratory symptoms were obtained by interview, and exposure was estimated using a previously developed job-exposure matrix. Associations between radiographic findings, exposure, and respiratory symptoms were assessed by ANOVA, chi-square tests and binary regression. Fourteen workers (3.9%) had radiographic evidence of silicosis, and all had been employed ≥30 years. They were more likely to have been stone cutters or carvers and their average exposure concentrations and cumulative exposures to respirable crystalline silica were significantly higher than workers with similar durations of employment and no classifiable parenchymal abnormalities. This provides direct evidence that workers with long-term exposure to low-level respirable crystalline silica (≤0.10 mg/m3) are at risk of developing silicosis.

Association of smoking cessation with airflow obstruction in workers with silicosis: A cohort study.

BACKGROUND: Studies in general population reported a positive association between tobacco smoking and airflow obstruction (AFO), a hallmark of chronic obstructive pulmonary disease (COPD). However, this attempt was less addressed in silica dust-exposed workers. METHODS: This retrospective cohort study consisted of 4481 silicotic workers attending the Pneumoconiosis Clinic during 1981-2019. The lifelong work history and smoking habits of these workers were extracted from medical records. Spirometry was carried out at the diagnosis of silicosis (n = 4177) and reperformed after an average of 9.4 years of follow-up (n = 2648). AFO was defined as forced expiratory volume in one second (FEV1)/force vital capacity (FVC) less than lower limit of normal (LLN). The association of AFO with smoking status was determined using multivariate logistics regression, and the effect of smoking cessation on the development of AFO was evaluated Cox regression. RESULTS: Smoking was significantly associated with AFO (current smokers: OR = 1.92, 95% CI 1.51-2.44; former smokers: OR = 2.09, 95% CI 1.65-2.66). The risk of AFO significantly increased in the first 3 years of quitting smoking (OR = 1.23, 95% CI 1.02-1.47) but decreased afterwards with increasing years of cessation. Smoking cessation reduced the risk of developing AFO no matter before or after the confirmation of silicosis (pre-silicosis cessation: HR = 0.58, 95% CI 0.46-0.74; post-silicosis cessation: HR = 0.62, 95% CI 0.48-0.79). CONCLUSIONS: Smoking cessation significantly reduced the risk of AFO in the workers with silicosis, although the health benefit was not observed until 3 years of abstinence. These findings highlight the importance of early and long-term smoking cessation among silicotic or silica dust-exposed workers.

Update on Silicosis.

Although silicosis has been an established disease with a recognized cause for more than 100 years, many workers continue to be exposed to silica and new outbreaks of disease continue to occur. This article describes some of the well-established and new exposures, including denim sandblasting, artificial stone cutting, and some forms of "coal worker's pneumoconiosis." The authors review the imaging and pathology of acute silicosis (silicoproteinosis), simple silicosis, and progressive massive fibrosis and summarize known and putative associations of silica exposure, including tuberculosis, lung cancer, connective tissue disease (especially systemic sclerosis), and vasculitis.

Dose-response relationship between lung function and chest imaging response to silica exposures in artificial stone manufacturing workers.

BACKGROUND: Occupational exposure to artificial stone, a popular material used for countertops, can cause accelerated silicosis, but the precise relationship between silica dose and disease development is unclear. OBJECTIVES: This study evaluated the impact of silica exposure on lung function and chest imaging in artificial stone manufacturing workers. METHODS: Questionnaire and spirometry assessments were administered to workers in two plants. A high-exposure subset underwent further evaluation, including chest CT and DLco. Weighting factors, assigned as proxies for silica exposure, were based on work tasks. Individual cumulative exposures were estimated using area concentration measurements and time spent in specific areas. Exposure-response associations were analyzed using linear and logistic regression models. RESULTS: Among 65 participants, the mean cumulative silica exposure was 3.61 mg/m3-year (range 0.0001 to 44.4). Each 1 mg/m3-year increase was associated with a 0.46% reduction in FVC, a 0.45% reduction in FEV1, and increased lung function abnormality risk (aOR = 1.27, 95% CI = 1.03-1.56). Weighting factors correlated with cumulative exposures (Spearman correlation = 0.59, p < 0.0001), and weighted tenure was associated with lung function abnormalities (aOR = 1.04, 95% CI = 1.01-1.09). Of 37 high-exposure workers, 19 underwent chest CT, with 12 (63%) showing abnormal opacities. Combining respiratory symptoms, lung function, and chest X-ray achieved 91.7% sensitivity and 75% specificity for predicting chest CT abnormalities. CONCLUSION: Lung function and chest CT abnormalities occur commonly in artificial stone workers. For high-exposure individuals, abnormalities on health screening could prompt further chest CT examination to facilitate early silicosis detection.

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.

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.

Systemic inflammation indices as hematological biomarkers of inflammatory response in non-silicotic workers exposed to respirable silica dust.

This cross-sectional study was performed to assess whether systemic inflammatory indices, including systemic inflammation response index (SIRI), systemic immune­inflammation index (SII), and aggregate index of systemic inflammation (AISI), can be considered as possible inflammatory markers in silica-exposed workers with no diagnosis of silicosis. We studied 371 non-silicotic workers exposed to respirable silica dust (RSD) and 1422 reference workers. The workers' exposure to RSD were assessed and the inflammatory indices were compared between subgroups of the exposed workers based on the severity and duration of exposure. Correlations between inflammatory indices and the pulmonary function parameters were investigated. Also, the receiver operating characteristic (ROC) curve and Youden index were used to determine the cut-off values of the SII, SIRI, and AISI. Significant dose-response relationships were observed between duration of exposure and all indices except monocytes and LMR. No significant interaction was observed between duration of exposure to RSD and smoking. Borderline significant correlations were observed between AISI and SIRI with forced expiratory volume (FEV1) and FEV1 to forced vital capacity (FVC) ratio. Higher AUCs were obtained for SII and AISI, respectively. The cut-off values for these biomarkers to be considered abnormal were > 348.48 for SII, > 183.78 for AISI, and > 0.768 for SIRI. Overall, the present study showed for the first time, that SII, AISI, and SIRI might be considered as available, easy-to-obtain, and non-expensive markers of inflammation in non-silicotic workers with a long duration of exposure to RSD who are at risk of developing silicosis in subsequent years.

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.

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.

Targeting progranulin alleviated silica particles-induced pulmonary inflammation and fibrosis via decreasing Il-6 and Tgf-ß1/Smad.

Long term exposure to silica particles leads to various diseases, among which silicosis is of great concern. Silicosis is an interstitial lung disease caused by inhalation of silica particles in production environments. However, the mechanisms underlying silicosis remains unclear. Our previous studies revealed that progranulin (Pgrn) promoted the expression of pro-inflammatory factors in alveolar macrophages treated with silica particles and the secretion of extracellular matrix of pulmonary fibroblasts. Nevertheless, the role of Pgrn in silica particles-induced silicosis in vivo was unknown. This study found that silica particles increased Pgrn expression in silicosis patients. Pgrn deficiency reduced lung inflammation and fibrosis in silica particles-induced silicosis mouse models. Subsequently, based on transcriptional sequencing and interleukin (Il) -6 knockout mouse models, results demonstrated that Pgrn deficiency might decrease silicosis inflammation by reducing the production of Il-6, thereby modulating pulmonary fibrosis in the early stage of silicosis mouse models. Furthermore, another mechanism through which Pgrn deficiency reduced fibrosis in silicosis mouse models was the regulation of the transforming growth factor (Tgf) -ß1/Smad signaling pathway. Conclusively, Pgrn contributed to silicosis inflammation and fibrosis induced by silica particles, indicating that Pgrn could be a promising therapeutic target.

Prolonged cough and dyspnea following a single episode of intense silica exposure.

Long term exposure to silica at worksites can cause silicosis. This typically has two radiographic forms, simple silicosis and complicated or conglomerate silicosis. Patients with acute silicosis have rapid progression of disease with fulminant respiratory failure over months rather than years. The patient described in this case report had a one-time 4 to 5-h exposure to silica and sand dust at work when his mask malfunctioned. He developed cough and shortness of breath. During his initial clinic visit he had significant cough. His chest examination was clear without crackles or wheezes. His pulmonary function tests were within normal limits. His chest x-ray was clear. Both symptoms, especially the cough, persisted over the next 6+ months even after treatment with oral corticosteroids and inhaled corticosteroids and long-acting beta agonists. Consequently, this patient developed severe cough following a one-time exposure to silica particulates. Laboratory studies have demonstrated that silica exposure can cause reactive oxygen species which potentially could have activated transient receptor potential vanilloid 1 channels in the afferent sensory nerves in his bronchial epithelium. This could cause sustained cough for more than 6 months. His symptoms improved but did not resolve with corticosteroid treatment. Therefore, this case demonstrates that acute silica exposure can cause sustained airway symptoms in healthy workers.

Knowledge, Attitudes, and Practices of Artisanal and Small-Scale Miners regarding Tuberculosis, Human Immunodeficiency Virus, and Silicosis in Zimbabwe.

In Zimbabwe, artisanal and small-scale miners (ASMs) have a high prevalence of tuberculosis (TB), human immunodeficiency virus (HIV), and silicosis. Previous studies on ASMs utilised programme data, and it was not possible to understand reasons for the high prevalence of these comorbidities. We conducted a cross-sectional study to investigate the knowledge, attitudes, and practices of ASMs regarding TB, HIV, and silicosis. We enrolled a convenience sample of 652 ASMs. Their mean (standard deviation) age was 34.2 (10.8) years. There were 602 (92%) men and over 75% had attained secondary education. A total of 504 (80%) of the ASMs knew that TB is a curable disease, and 564 (87%) knew that they were at higher risk of TB than the general population. However, they were less likely to know that HIV increases the risk of TB disease, 340 (52%), with only 226 (35%) who perceived the risk of TB infection to be high among ASMs. Only 564 (59%) were aware that silica dust causes permanent and incurable lung diseases. Six hundred and twenty (97%) showed a positive attitude towards healthcare when they were sick, and 97% were willing to use special respirators to prevent dust inhalation. On practices, only 159 (30%) reported consistent use of either cloth or respirators to prevent dust inhalation. Three hundred and five (49%) ASMs reported consistent use of condoms outside their homes and 323 (50%) reported use of water to suppress dust. Only 480 (75%) of ASMs sought healthcare services when sick. ASMs cited challenges of accessing healthcare services due to lack of money to pay for healthcare (50%), long distances to clinics (17%), and the shortage of medicines at clinics (11%). Effective control of TB, silicosis, and HIV among ASMs requires addressing the identified knowledge gaps and barriers that are faced by ASMs in accessing personal protective equipment and healthcare services. This will require multisector collaboration and the involvement of ASMs in co-designing a package of healthcare services that are tailored for them.