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Environmental exposure to crystalline silica (CS) particles is common and occurs during natural, industrial, and agricultural activities. Prolonged inhalation of CS particles can cause silicosis, a serious and incurable pulmonary fibrosis disease. However, the underlying mechanisms remain veiled. Herein, we aim to elucidate the novel mechanisms of interleukin-11 (IL-11) driving fibroblast metabolic reprogramming during the development of silicosis. We observed that CS exposure induced lung fibrosis in mice and activated fibroblasts, accompanied by increased IL-11 expression and metabolic reprogramming switched from mitochondrial respiration to glycolysis. Besides, we innovatively uncovered that elevated IL-11 promoted the glycolysis process, thereby facilitating the fibroblast-myofibroblast transition (FMT). Mechanistically, CS-stimulated IL-11 activated the extracellular signal-regulated kinase (ERK) pathway and the latter increased the expression of hypoxia inducible factor-1α (HIF-1α) via promoting the translation and delaying the degradation of the protein. HIF-1α further facilitated glycolysis, driving the FMT process and ultimately the formation of silicosis. Moreover, either silence or neutralization of IL-11 inhibited glycolysis augmentation and attenuated CS-induced lung myofibroblast generation and fibrosis. Overall, our findings elucidate the role of IL-11 in promoting fibroblast metabolic reprogramming through the ERK-HIF-1α axis during CS-induced lung fibrosis, providing novel insights into the molecular mechanisms and potential therapeutic targets of silicosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Silica particles are commonly encountered in natural and industrial activities. Long-term environmental exposure to silica can result in silicosis, which is characterized by chronic inflammation and abnormal tissue repair in lung. To uncover the role of m 6 A modification in silica-induced pulmonary inflammation, we conducted this study using established mouse and macrophage models. In this study, the aerodynamic diameter of silica particles was approximately 1-2 µm. We demonstrated that silica exposure in mice caused pulmonary inflammation and increased global m 6 A modification levels, the downregulation of alkB homolog 5 (ALKBH5) might contribute to this alteration. Besides, we found that F4/80, a macrophage-specific biomarker, was co-expressed with ALKBH5 through dual immunofluorescent staining. In vitro studies using MeRIP assays suggested that Slamf7 was a target gene regulated by m 6 A modification, and specific inhibition of ALKBH5 increased Slamf7 expression. Mechanistically, ALKBH5 promoted m 6 A modification of Slamf7, which decreased Slamf7 mRNA stability in an m 6 A-dependent manner, ultimately regulating Slamf7 expression. In addition, silica exposure activated PI3K/AKT and induced macrophage autophagy. Inhibition of Slamf7 promoted autophagy, reduced the secretion of pro-inflammatory cytokines, and improved silica-induced pulmonary inflammation. In summary, ALKBH5 can regulate silica-induced pulmonary inflammation by modulating Slamf7 m 6 A modification and affecting the function of macrophage autophagy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Inhalation of crystalline silica (CS) can cause silicosis, which is one of the most serious interstitial lung diseases worldwide. Autophagy dysfunction is an essential step in silicosis progression. In this study, we aim to identify the effect of growth arrest-specific protein 6 (Gas6) during autophagy induction and macrophage inflammatory response caused by CS. After RAW 264.7 macrophages exposed to CS, the levels of Gas6 and autophagy markers (p62, Beclin1, and LC3-II/LC3-I) were increased, accompanied with enhanced inflammatory cytokines secretion. Using autophagy activator (rapamycin) repressed, whereas autophagy inhibitor (3-methyladenine) promoted inflammatory cytokines release. Besides, inhibition of Gas6 aggravated CS-induced inflammatory response, and autophagy inhibition facilitated the promoted effect of Gas6 silencing, resulting in elevated expression of inflammatory cytokines. These findings reveal the protective effects of Gas6 and autophagy in macrophages in response to CS exposure, and highlight the autophagy regulated by Gas6 may be a potential prevention target for CS-induced lung inflammatory response., (© 2022 Wiley Periodicals LLC.)

Published evidences have shown that autophagy plays an important role in silica-induced lung inflammation and collagen deposition. Our previous study found that the level of growth arrest-specific protein 6 (Gas6) in bronchoalveolar lavage fluid was increased after silica exposure. However, it is unclear whether Gas6 is involved in the regulation of silica-induced autophagy dysfunction. In this study, we observed an autophagosomes accumulation in wild-type C57BL/6 (WT) mice lung after silica intratracheal instillation and then investigated whether genetic loss of Gas6 (Gas6 -/- ) could ameliorate it. Our data showed that Gas6 -/- mice exhibited a limited autophagosomes accumulation from days 7-84 after silica exposure, revealed by reduced induction and increased degradation of autophagosomes in mice lung tissue. Interestingly, silica particles could elevate the expression of Mer receptor, which was significantly decreased in Gas6 -/- mice (P < 0.05). Furthermore, we found that Mer deficiency (Mer -/- ) could also reduce the formation of autophagosomes and restore the function of impaired lysosomes in silica-treated mice. Taken together, our results indicate that genetic loss of Gas6 attenuates silica-induced autophagosomes accumulation partly through down-regulating the expression of Mer receptor. Targeting Gas6/Mer-mediated autophagy pathway may provide a novel insight into the prevention and therapy of silica-induced pulmonary fibrosis., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Alveolar macrophage (AM) injury and inflammatory response are key processes in pathological damage caused by silica. However, the role of triiodothyronine (T3) in silica-induced AM oxidative stress, inflammation, and mitochondrial apoptosis remained unknown. To investigate the possible effects and underlying mechanism of T3 in silica-induced macrophage damage, differentiated human acute monocytic leukemia cells (THP-1) were exposed to different silica concentrations (0, 50, 100, 200, and 400 μg/mL) for 24 h. Additionally, silica-activated THP-1 macrophages were treated with gradient-dose T3 (0, 5, 10, 20, and 40 nM) for 24 h. To illuminate the potential mechanism, we used short hairpin RNA to knock down the thyroid hormone receptor α (TRα) in the differentiated THP-1 macrophages. The results showed that T3 decreased lactate dehydrogenase and reactive oxygen species levels, while increasing cell viability and superoxide dismutase in silica-induced THP-1 macrophages. In addition, silica increased the expression of interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α), and T3 treatment reduced those pro-inflammatory cytokines secretion. Compared with silica-alone treated groups, cells treated with silica and T3 restored the mitochondrial membrane potential loss and had reduced levels of cytochrome c and cleaved caspase-3 expressions. Lastly, we observed that TRα-knockdown inhibited the protective effects of T3 silica-induced THP-1 macrophages. Together, these findings revealed that T3 could serve as a potential therapeutic target for protection against silica-induced oxidative stress, inflammatory response, and mitochondrial apoptosis, which are mediated by the activation of the T3/TRα signal pathway.

Importance: The joint association of long-term silica dust exposure and cigarette smoking with mortality has not been well established., Objective: To evaluate the joint association of silica dust exposure and cigarette smoking with mortality in a large cohort of workers at mines and factories in China., Design, Setting, and Participants: This cohort study included 44 708 adults who were employed in 20 metal mines and 9 pottery factories in central and southern China for at least 1 year between January 1, 1960, and December 31, 1974. Participants were retrospectively followed up to January 1, 1960, and prospectively followed up to December 31, 2003. Data analysis was conducted from April 5, 2019, to October 26, 2019., Exposures: Cumulative respirable silica dust exposure was estimated by linking a job-exposure matrix to participants' personal work histories. Cigarette smoking data were collected through participant questionnaires., Main Outcomes and Measures: The main outcome was mortality, with codes from the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) used to categorize diseases associated with mortality., Results: Among 44 708 participants, 38 221 (85.49%) were men, with a mean (SD) age at cohort entrance of 26.9 (8.1) years. A total of 13 700 deaths were observed during 1 534 005 person-years of follow-up, with a median follow-up period of 34.9 years (range, 4.8-43.9 years). Silica exposure was associated with a higher risk of mortality among individuals with all diseases, lung cancer, respiratory tuberculosis, cardiovascular diseases, and diseases of the respiratory system; cigarette smoking was associated with an increased risk of mortality among individuals with all diseases, lung cancer, respiratory tuberculosis, cerebrovascular diseases, and diseases of the respiratory tract. The hazard ratios for the joint association of silica dust exposure and cigarette smoking with mortality were 4.51 (95% CI, 3.23-6.29) for lung cancer, 3.21 (95% CI, 2.53-4.08) for certain infectious and parasitic diseases, 3.93 (95% CI, 2.99-5.15) for respiratory tuberculosis, 6.27 (95% CI, 4.83-8.15) for diseases of the respiratory system, and 12.52 (95% CI, 7.92-19.80) for pneumoconiosis, with a significant additive interaction (P < .001). The proportions of the joint association for the additive interaction of silica dust exposure and cigarette smoking were 21.63% for lung cancer, 42.12% for certain infectious and parasitic diseases, 42.25% for respiratory tuberculosis, 29.55% for diseases of the respiratory system, and 36.46% for pneumoconiosis., Conclusions and Relevance: These findings suggest that cigarette smoking is associated with an increased risk of mortality in individuals exposed to silica dust. Smoking cessation and the control of silica dust concentrations may be important for reducing the risk of mortality among individuals exposed to silica.

Pulmonary fibrosis induced by prolonged exposure to silica particles is a chronic and irreversible lung disease without effective treatment till now. Our previous study has shown that early intervention with MARCO antagonist PolyG could alleviate pulmonary fibrosis in silica-exposed rats. However, the therapeutic effects of PolyG on silica-induced pulmonary fibrosis have rarely been reported. In this study, we explored the effects of administration (on the 28th day after silica exposure) of PolyG (MARCO inhibitor) on an established rat silicosis model. The lungs were analyzed histopathologically in rats using HE and Masson staining. The silica-induced ERS-related apoptosis, EMT and fibrosis were evaluated using western blotting, qRT-PCR and immunohistochemical analyses. The results suggested that silica exposure could increase the MARCO activity, and induce ERS and EMT in lung tissues. Pharmacological targeting of MARCO with PolyG attenuated the development of pulmonary fibrosis in silica-exposed rats. Further study indicated that PolyG could inhibit silica-induced ERS-related apoptosis and EMT process. Together, our findings reveal an essential function of ERS-related apoptosis and EMT in the processes of pulmonary fibrosis caused by silica, and identify MARCO as a potential therapeutic pharmacological target for silicosis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Both cigarette smoking and long-term exposure to crystalline silica dust were reported to be associated with increased mortality. However, the combined effect of both factors has not been well evaluated., Methods: We investigated a retro-prospective cohort of 7,665 workers from one Chinese iron mine with a median follow-up of 42.8 years. Cumulative silica exposure was estimated for each worker by linking work histories with a job-exposure matrix. Cigarette smoking information was collected through face-to-face questionnaires. Hazard ratios (HRs) for total and cause-specific mortality due to silica exposure and smoking were estimated using Cox proportional hazards models., Results: A total of 2,814 deaths occurred during 315,772.9 person-years of follow-up. Significantly elevated mortality from all causes, cardiovascular disease, non-malignant respiratory disease and lung cancer was observed among silica-exposed workers, while elevated mortality from non-malignant respiratory disease and lung cancer was observed among smokers. Combined exposure to silica dust and cigarette smoking elevated the proportion of mortality and accounted for 21.2, 76.0, 35.7 and 81.4% of all causes, non-malignant respiratory disease, cardiovascular disease, and lung cancer, respectively. Significant additive joint effects of silica exposure and cigarette smoking on mortality from lung cancer (HR 1.893, 95% CI 0.628 to 3.441) and pneumoconiosis (6.457, 0.725 to 39.114), together with a significant multiplicative joint effect from all causes (1.002, 1.000 to 1.004) were observed., Conclusions: The present findings indicated that silica exposure in combination with cigarette smoking accounted for a fraction of extra deaths in our cohort. Our research showed the urgent need for smoking cessation and silica control among iron miners.

Objective: The aim of this study was to explore the potential role of extracellular matrix (ECM) regulated by miRNAs in lung function decline., Methods: We convened 270 silica dust exposed subjects and divided them into three groups according to lung function data. MiRNAs were measured by real-time quantitative polymerase chain reaction detecting system and ECM-related proteins were detected by enzyme linked immunosorbent assay. Data were analyzed by t test, Chi-squared tests, nonparametric Mann-Whitney U test, and Spearman rank correlation coefficient., Results: Lower miR-200c and miR-29c were observed in subjects with severe lung function decline and higher ECM proteins were observed in subjects with mild or severe lung function decline. MiRNA and ECM were significantly correlated with FVC%, FEV1%, MMF%, and PEF% (r: 0.204 to 0.458, P < 0.01) and that miRNA were significantly correlated with ECM (r: 0.309 to 0.687, P < 0.01)., Conclusion: The abnormal ECM regulated by miRNAs may play an important role in lung function decline associated with silica dust exposure.

The association between low-level crystalline silica (silica) exposure and mortality risk is not well understood. We investigated a cohort of 44,807 Chinese workers who had worked in metal mines or pottery factories for at least 1 year from January 1, 1960, to December 31, 1974, and were followed through 2003. Low-level silica exposure was defined as having a lifetime highest annual mean silica exposure at or under a permissible exposure limit (PEL). We considered 3 widely used PELs, including 0.05 mg/m3, 0.10 mg/m3, and 0.35 mg/m3. Cumulative silica exposure was estimated by linking a job exposure matrix with each participant's work history. For the 0.10-mg/m3 exposure level, Cox proportional hazards models showed significantly increased risk of mortality from all diseases (for each 1-ln mg/m3-years increase in logged cumulative silica exposure, hazard ratio (HR) = 1.05, 95% confidence interval (CI): 1.03, 1.07), malignant neoplasms (HR = 1.06, 95% CI: 1.03, 1.09), lung cancer (HR = 1.08, 95% CI: 1.02, 1.14), ischemic heart disease (HR = 1.09, 95% CI: 1.02, 1.16), pulmonary heart disease (HR = 1.08, 95% CI: 1.00, 1.16), and respiratory disease (HR = 1.20, 95% CI: 1.14, 1.26). The 0.05-mg/m3 and 0.35-mg/m3 exposure levels yielded similar associations. Long-term exposure to low levels (PELs ≤0.05 mg/m3, ≤0.10 mg/m3, or ≤0.35 mg/m3) of silica is associated with increased total and certain cause-specific mortality risk. Control of ambient silica levels and use of personal protective equipment should be emphasized in practice., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Crystalline silica is considered as one of the most common and serious occupational hazards to workers' health. Although its association with lung cancer has been studied for many decades, the conclusion remains somewhat controversial. Our objectives are to review and summarize the epidemiological evidence on the relationship between occupational silica exposure and risk of lung cancer and to provide an update on this major occupational health concern., Methods: Eligible studies up to 29 April 2016 were identified. Pooled effect estimates were calculated according to the reported outcome and the study design. Cohort, case control and proportional mortality studies were examined separately. Studies reporting results according to silicotic status were grouped together and analyzed. Due to the significant amount of heterogeneity expected, random effects models were implemented. Subgroup and meta-regression analyses (both univariate and multivariate) were performed in an attempt to explain heterogeneity. Studies which had adequate exposure characterization were selected to find out whether there was an exposure-response relationship between silica and lung cancer., Results: The risk of lung cancer was found to be elevated in both silicotics and non-silicotics. The pooled standardized mortality ratio (SMR) was 2.32 with a 95 % confidence interval (95 % CI) of 1.91-2.81 and 1.78 (95 % CI 1.07-2.96) respectively. The pooled standardized incidence ratio (SIR) was 2.49 (95 % CI 1.87-3.33) and 1.18 (95 % CI 0.86-1.62) respectively. Subgroup analysis showed that workers in the mining industry had the highest risk of lung cancer with a pooled SMR of 1.48 (95 % CI 1.18-1.86) and the weakest association was seen in potteries with a pooled SMR of 1.14 (95 % CI 1.05-1.23). A positive exposure-response relation was found between cumulative silica exposure and risk of lung cancer., Conclusion: The results of our meta-analysis supported the carcinogenic role of silica on the lungs, which was more pronounced at higher levels of exposure, in the presence of silicosis and in the mining industry. Further research is needed to evaluate whether non-silicotics are truly at risk, whether a predisposing factor would explain this potential risk, and to determine the mechanism of carcinogenicity of silica in humans.

Growth arrest specific 6 (Gas6) has been reported to be related to the modulation of innate immunity. To investigate the potential effect of Gas6 on the regulation of inflammations induced by silica, differentiated THP-1 macrophages were exposed to different concentrations of silica for 6h and 24h. Additionally, silica-activated macrophages were treated with Gas6 antibody and Gas6 respectively. Expression levels of Gas6 and inflammatory cytokines (TNF-α, IL-1β and IL-6) were measured. Our results showed that both cell viability and Gas6 expression were suppressed by silica in dose-dependent manners. After pretreatment with Gas6 antibody, silica induced a significant decrease in cell viability and a significant increase in inflammatory cytokines at two time points. Moreover, addition of Gas6 significantly suppressed silica induced TNF-α, IL-1β and IL-6 levels in negative dose-dependent manners, not only in mRNA levels but also in protein levels. Our results suggested that exogenous Gas6 might attenuate inflammations induced by silica on macrophages., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Current epidemiological studies suggest that crystalline silica exposure is associated with an increased risk of cardiovascular and renal disease; however, the potential pathological damage of the heart and kidney and its underlying mechanisms have not been completely elucidated. This study tried to investigate the silica-induced inflammatory and fibrotic changes in the heart and kidney and evaluate the role of interleukin (IL)-1 beta (β) in silica-induced cardiac and renal damage. In this study, a silica-exposed model was generated by intratracheally instilling silica dust in mice. The anti-IL-1β monoclonal antibody (mAb) was used to neutralise IL-1β in the pulmonary alveolus and serum. The real-time PCR studies showed that (1) inhalational silica induced inflammatory responses in the heart and kidney by elevated mRNA levels of TNF-α, IL-6 and MCP-1; (2) early fibrotic responses in the heart were observed as elevated mRNA levels of collagen I and fibronectin. What is more, fibrosis of the kidney was demonstrated by pathological results and significantly increased mRNA levels of TGF-β, collagen I, collagen III and fibronectin. Further studies showed that usage of anti-IL-1β mAb decreased the inflammatory response of the heart and kidney induced by inhalational silica and also attenuated fibrosis in the mouse kidney. In conclusion, this study found that inhaled silica induced inflammatory and early fibrotic responses in the mouse heart and inflammatory response and fibrosis in the mouse kidney. Neutralisation of IL-1β attenuated the silica-induced inflammatory response of the heart and kidney and decreased fibrosis in the mouse kidney.

Objective: To investigate oxidative stress and mitochondria-related cell apoptosis induced by silica dust in human normal bronchial epithelial 16HBE cells., Methods: Cell viability, lactate dehydrogenase (LDH), superoxide dismutase (SOD), cell apoptotic rate, the expression level of Bax and Bcl-2 mRNA were measured after 16HBE cells were exposed to 37.5, 75, 150, 300 µg/mL respirable silica dust (diameter<2 µm, d50=1 µm)for 24 h in vitro. Reactive oxygen species (ROS)were tested after 16HBE cells were exposed to silica dust at above concentrations for 1.5, 3, 6, 12 h, respectively., Results: Dose-dependent decreases of cell viability and the activity of SOD were observed when silica concentrations increased. The activity of LDH increased when silica concentrations elevated. Compared with the control group, cell viability significantly reduced in 75, 150, 300 µg/mL silica-treated groups (P<0.05). The activity of LDH significantly increased in 150, 300 µg/mL silica-treated groups when compared with the control group (P<0.05). The activity of SOD in all silica-treated groups were significantly lower in comparison with controls (P<0.05). Intracellular ROS levels reached peak values at 1.5 h of silica exposure and gradually dropped to the base level at 12 h. The relationship between ROS levels and silica exposure were dose-response at 1.5 h, 3 h and 6 h of exposure (P<0.05). Similar dose-dependent increase were observed for apoptotic rate and silica exposure (P<0.05). The expression levels of Bcl-2 mRNA decreased, and the expression levels of Bax mRNA increased when silica concentrations increased. The results showed that significantly positive correlations between ROS level and apoptotic rate (r=0.892,P<0.05)or the expression level of Bax mRNA (r=0.850,P<0.05). There was a negative correlation between ROS level and the expression level of Bcl-2 mRNA (r=-0.703,P<0.05)., Conclusion: Silica dust could induce cytotoxicity, oxidative stress and mitochondria-related cell apoptosis in 16HBE cells. Oxidative stress may play role in the processes of mitochondria-related apoptosis.

The main characteristic of silicosis is irreversible fibrosis. Certain studies have shown that epithelial-mesenchymal transition (EMT) regulated by transforming growth factor-β (TGF-β) is involved in fibrosis. Thus, we suggest that TGF-β regulated EMT may play an important role in silicosis. In this study, we determined the expression of TGF-β-Smad2/3, EMT- and ECM-related markers in lung epithelial cells treated with silica particle by RT-PCR, western-blot and ELISA. In order to explore the role of TGF-β, we used TGF-β inhibitor in the cell model. We found that the cells lost the expression of epithelial phenotypic markers and acquired increased expression of mesenchymal cells markers with ECM deposition after treatment with silica particle. Moreover, the changes of EMT-related event was restricted in response to TGF-β inhibitor. These findings suggest that EMT is essentially involved in the pathogenesis of fibrosis induced by silica particles and down-regulating the TGF-β expression can inhibit the process of EMT., (Copyright © 2015 Elsevier B.V. All rights reserved.)

This study aims to develop a prognostic risk prediction model for the development of silicosis among workers exposed to silica dust in China. The prediction model was performed by using retrospective cohort of 3,492 workers exposed to silica in an iron ore, with 33 years of follow-up. We developed a risk score system using a linear combination of the predictors weighted by the LASSO penalized Cox regression coefficients. The model's predictive accuracy was evaluated using time-dependent ROC curves. Six predictors were selected into the final prediction model (age at entry of the cohort, mean concentration of respirable silica, net years of dust exposure, smoking, illiteracy, and no. of jobs). We classified workers into three risk groups according to the quartile (Q1, Q3) of risk score; 203 (23.28%) incident silicosis cases were derived from the high risk group (risk score ≥ 5.91), whilst only 4 (0.46%) cases were from the low risk group (risk score < 3.97). The score system was regarded as accurate given the range of AUCs (83-96%). This study developed a unique score system with a good internal validity, which provides scientific guidance to the clinicians to identify high-risk workers, thus has important cost efficient implications.

To investigate the regulated role of IL-1β in initiating and maintaining inflammation, PMA-differentiated THP-1 macrophages were exposed to two micro-sized crystalline silica particles (Si3-5μm and Si1μm) from 3h to 24h, respectively. Cytotoxicity and inflammatory cytokines (IL-1β, TNF-α and IL-6) expressions measured showed that they were induced by both silica particles in positive dose-dependent manners. The levels of inflammatory cytokines induced by Si1μm were higher than those induced by Si3-5μm at low concentration. When pretreated with anti-human IL-1β, not only the high levels of IL-1β but also elevated TNF-α and IL-6 induced by both silica particles were remarkably blocked, especially Si1μm particle. In addition, recombinant human IL-1β protein could induce macrophages to strikingly augment TNF-α and IL-6 expressions. Our data suggest that IL-1β could play a critical role of switching regulation in the downstream inflammation induced by micro-sized silica particles., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Pneumoconiosis is the most serious occupational disease in China and its leading cause is occupational silica exposure. Pneumoconiosis takes several years to develop depending on the exposure level of silica. However, individual variation in the susceptibility to pneumoconiosis has been observed among the subjects with similar exposure. We conducted a genome-wide screening with 710,999 single nucleotide polymorphisms (SNPs) in a cohort of 400 coal workers (202 cases and 198 exposed controls) for pneumoconiosis susceptible loci. Seven promising variants were evaluated in an independent cohort of 568 coal workers (323 cases and 245 exposed controls), followed by a second replication on 463 iron ore workers (167 cases and 296 exposed controls). By pooling all of the genome-wide association studies and replication stages together, we found a genome-wide significant (P < 5.0 × 10(-8)) association for rs73329476 (P = 1.74 × 10(-8), OR = 2.17, 95% CI = 1.66-2.85) and two additional replicated associations for rs4320486 (P < 0.05) and rs117626015 (P < 0.05) with combined P-values of 4.29 × 10(-6) and 5.05 × 10(-6), respectively. In addition, the risk allele T of rs73329476 was significantly associated with lower mRNA expression levels of carboxypeptidase M (CPM) in total cellular RNA from whole blood of 156 healthy individuals (P = 0.0252). The identified pneumoconiosis susceptibility loci may provide new insights into the pathogenesis of pneumoconiosis, and may also have some clinical utility for risk prediction for pneumoconiosis and high-risk population screening for workers with occupational silica exposure., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The association between crystalline silica exposure and risk of heart disease mortality remains less clear., Methods: We investigated a cohort of 42,572 Chinese workers who were potentially exposed to crystalline silica and followed from 1960 to 2003. Cumulative silica exposure was estimated by linking a job-exposure matrix to each person's work history. Low-level silica exposure was defined as never having held a job with an exposure higher than 0.1 mg/m. We estimated hazard ratios (HRs) in exposure-response analyses using Cox proportional hazards model., Results: We identified 2846 deaths from heart disease during an average of 35 years follow-up. Positive exposure-response trends were observed for cumulative silica exposure associated with mortality from total heart disease (HRs for increasing quartiles of cumulative silica exposure compared with the unexposed group = 0.89, 1.09, 1.32, 2.10; P for linear trend < 0.001) and pulmonary heart disease (0.92, 1.39, 2.47, 5.46; P for linear trend < 0.001). These positive trends remained among workers with both high- and low-level silica exposure. There was also a positive trend for ischemic heart disease among workers with low-level exposure, with quartile HRs of 1.04, 1.13, 1.52, and 1.60 (P for linear trend < 0.001)., Conclusion: Low-level crystalline silica exposure was associated with increased mortality from heart disease, including pulmonary heart disease and ischemic heart disease, whereas high-level exposure mainly increased mortality from pulmonary heart disease. Current permissible exposure limits for crystalline silica in many countries may be insufficient to protect people from deaths due to heart disease.

Crystalline silica has been classified as a human carcinogen by the International Agency for Research on Cancer (Lyon, France); however, few previous studies have provided quantitative data on silica exposure, silicosis, and/or smoking. We investigated a cohort in China (in 1960-2003) of 34,018 workers without exposure to carcinogenic confounders. Cumulative silica exposure was estimated by linking a job-exposure matrix to work history. Cox proportional hazards model was used to conduct exposure-response analysis and risk assessment. During a mean 34.5-year follow-up, 546 lung cancer deaths were identified. Categorical analyses by quartiles of cumulative silica exposure (using a 25-year lag) yielded hazard ratios of 1.26, 1.54, 1.68, and 1.70, respectively, compared with the unexposed group. Monotonic exposure-response trends were observed among nonsilicotics (P for trend < 0.001). Analyses using splines showed similar trends. The joint effect of silica and smoking was more than additive and close to multiplicative. For workers exposed from ages 20 to 65 years at 0.1 mg/m(3) of silica exposure, the estimated excess lifetime risk (through age 75 years) was 0.51%. These findings confirm silica as a human carcinogen and suggest that current exposure limits in many countries might be insufficient to protect workers from lung cancer. They also indicate that smoking cessation could help reduce lung cancer risk for silica-exposed individuals.

Epidemiological evidence reports silica dust exposure has been associated with increased risk of cardiovascular diseases, but the mechanisms are largely unknown. In this study, endothelial cells were exposed to increasing concentrations of two sizes silica particles and the soluble mediators released by macrophages treated with the same particles for 24 h. Expression and release of cytokines (IL-1β, TNF-α and IL-6) were measured by using ELISA. Cytotoxicity was measured by MTT assay and LDH release. We show that both ways induced increases in cell toxicity and cytokines in a dose-dependent manner. For smaller particles, the soluble mediators are more capable of increasing cytokines compared with the effect of particles directly. For larger particles, evaluating results of these two ways are similar. Either way, smaller particles make the increasing action of cell toxicity and cytokines more remarkable. Our results indicate both silica particle and macrophage-derived mediators can induce endothelial cell injury and inflammation and demonstrate the potential importance of the particle sizes in this effect., (Copyright © 2013. Published by Elsevier B.V.)

The inflammation and fibrosis induced by silica dust are considered to be substantial responses in silicosis progression. Interleukin-1 beta (IL-1β) plays an important role in silica-induced lung inflammation, but the mechanisms that underlie the influence of IL-1β on the progression of silicosis remain unclear. In this study, the role of IL-1β in silica-induced inflammation and fibrosis was evaluated by administering a suspension of 2.5-mg silica dust, either with or without 40 μg anti-mouse IL-1β monoclonal antibody (mAb), to the lungs of male C57BL/6 mice. Silica + anti-IL-1β mAb-treated mice showed the depletion of IL-1β as well as the attenuation of inflammation, as evaluated in the bronchoalveolar lavage fluid (BALF) and histological sections from 1 to 84 days after silica exposure. Further study of the BALF indicated that inhibition of IL-1β could reduce the contents of tumor necrosis factor-alpha and monocyte chemoattractant protein-1. The real-time PCR and pathology results showed that the neutralization of IL-1β attenuated silica-induced fibrosis by inhibiting the gene expression of transforming growth factor-beta 1, collagen I and fibronectin. The examination of Th1-cytokine and Th2-cytokine suggested that depletion of IL-1β decelerated the Th1/Th2 balance toward a Th2-dominant response. In conclusion, the present study suggests that the neutralization of IL-1β attenuates silica-induced inflammation and fibrosis by inhibiting other inflammatory and fibrogenic mediators and modulating the Th1/Th2 balance.

BACKGROUND.: The detailed lung radiographic response to silica exposure has not been described. In estimating the exposure-response relationship in silicosis with statistical models, the absence of baseline (unattributable) risk can disable relative-rate estimation or produce widely varying estimates. This obstructs identification of optimum exposure metrics and invalidates comparisons and meta-analyses, which assume a common background rate. METHODS.: A cohort of 3,000 Chinese tin miners with more than 1,000 cases of silicosis was analyzed for the period 1961-1994. Regular surveillance documented three stages of silicosis. To examine the exposure-response relationship, the intercept in relative-rate models was fixed to correspond to 1% of the observed silicosis rate. Exposure metrics for contributions in different time-windows were simultaneously evaluated, as were burden and cumulative burden metrics. RESULTS.: Silica exposures that most contributed to silicosis onset occurred in the period 5-10 years prior (excess annual rate per 10 mg-year/m(3) , ER = 0.158, 95% CI = 0.125-0.192, or 16% per year). During 10-20 year prior, the excess rate contribution was much smaller (ER = 0.048, 95% CI = 0.037-0.060) but larger again during 20-30 year prior to onset (ER = 0.112, 95% CI = 0.098-0.126). For advanced silicosis, all time periods contributed about equally to the rate of onset. CONCLUSIONS.: Reliable estimates of parameters were observed, demonstrating exposure contributions over time. Burden metrics with different half-lives suggested some reversibility for silicosis onset with a half-life of 20 years. Advanced silicosis was best predicted with a cumulative burden metric which was consistent with prior observations that previously deposited silica continues to cause pulmonary damage., (Copyright © 2012 Wiley Periodicals, Inc.)

Silicosis is a fibrotic lung disease caused by inhalation of free crystalline silicon dioxide or silica. Occupational exposure to respirable crystalline silica dust particles occurs in many industries. Phagocytosis of crystalline silica in the lung causes lysosomal damage, activating the NALP3 inflammasome and triggering the inflammatory cascade with subsequent fibrosis. Impairment of lung function increases with disease progression, even after the patient is no longer exposed. Diagnosis of silicosis needs carefully documented records of occupational exposure and radiological features, with exclusion of other competing diagnoses. Mycobacterial diseases, airway obstruction, and lung cancer are associated with silica dust exposure. As yet, no curative treatment exists, but comprehensive management strategies help to improve quality of life and slow deterioration. Further efforts are needed for recognition and control of silica hazards, especially in developing countries., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To evaluate proinflammatory responses induced by respirable silica dust samples and to analyze the role of those responses in explaining adverse health effects among dust-exposed workers in pottery factoryies and tungsten and tin mines., Methods: Proinflammatory cytokines of cells were determined after being treated with silica dust samples. Adverse health effects of workers were calculated on the basis of a cohort study., Results: Incidence and mortality of silicosis among tungsten miners were higher than those in other workers. The incidence of interleukin-1β levels was highest in tungsten mines, which was consistent with the incidence of silicosis in tungsten miners. The higher levels of TNF-α and interleukin-6 released from macrophages might be helpful in explaining increased mortalities from lung cancer among tin miners., Conclusions: Interleukin-1β could be a sensitive biomarker in predicting fibrogenic potential of silica dust and the risk of silicosis among dust-exposed workers.

Background: Human exposure to silica dust is very common in both working and living environments. However, the potential long-term health effects have not been well established across different exposure situations., Methods and Findings: We studied 74,040 workers who worked at 29 metal mines and pottery factories in China for 1 y or more between January 1, 1960, and December 31, 1974, with follow-up until December 31, 2003 (median follow-up of 33 y). We estimated the cumulative silica dust exposure (CDE) for each worker by linking work history to a job-exposure matrix. We calculated standardized mortality ratios for underlying causes of death based on Chinese national mortality rates. Hazard ratios (HRs) for selected causes of death associated with CDE were estimated using the Cox proportional hazards model. The population attributable risks were estimated based on the prevalence of workers with silica dust exposure and HRs. The number of deaths attributable to silica dust exposure among Chinese workers was then calculated using the population attributable risk and the national mortality rate. We observed 19,516 deaths during 2,306,428 person-years of follow-up. Mortality from all causes was higher among workers exposed to silica dust than among non-exposed workers (993 versus 551 per 100,000 person-years). We observed significant positive exposure-response relationships between CDE (measured in milligrams/cubic meter-years, i.e., the sum of silica dust concentrations multiplied by the years of silica exposure) and mortality from all causes (HR 1.026, 95% confidence interval 1.023-1.029), respiratory diseases (1.069, 1.064-1.074), respiratory tuberculosis (1.065, 1.059-1.071), and cardiovascular disease (1.031, 1.025-1.036). Significantly elevated standardized mortality ratios were observed for all causes (1.06, 95% confidence interval 1.01-1.11), ischemic heart disease (1.65, 1.35-1.99), and pneumoconiosis (11.01, 7.67-14.95) among workers exposed to respirable silica concentrations equal to or lower than 0.1 mg/m(3). After adjustment for potential confounders, including smoking, silica dust exposure accounted for 15.2% of all deaths in this study. We estimated that 4.2% of deaths (231,104 cases) among Chinese workers were attributable to silica dust exposure. The limitations of this study included a lack of data on dietary patterns and leisure time physical activity, possible underestimation of silica dust exposure for individuals who worked at the mines/factories before 1950, and a small number of deaths (4.3%) where the cause of death was based on oral reports from relatives., Conclusions: Long-term silica dust exposure was associated with substantially increased mortality among Chinese workers. The increased risk was observed not only for deaths due to respiratory diseases and lung cancer, but also for deaths due to cardiovascular disease. Please see later in the article for the Editors' Summary.

An analysis was conducted on a cohort of Chinese pottery workers to estimate the exposure-response relationship between respirable crystalline silica dust exposure and the incidence of radiographically diagnosed silicosis, and to estimate the long-term risk of developing silicosis until the age of 65. The cohort comprised 3,250 employees with a median follow-up duration of around 37 years. Incident cases of silicosis were identified via silicosis registries (Chinese X-ray stage I, similar to International Labor Organisation classification scheme profusion category 1/1). Individual exposure to respirable crystalline silica dust was estimated based on over 100,000 historical dust measurements. The association between dust exposure, incidence and long-time risk of silicosis was quantified by Poisson regression analysis adjusted for age and smoking. The risk of silicosis depended not only on the cumulative respirable crystalline silica dust exposures, but also on the time-dependent respirable crystalline silica dust exposure pattern (long-term average concentration, highest annual concentration ever experienced and time since first exposure). A long-term "excess" risk of silicosis of approximately 1.5/1,000 was estimated among workers with all annual respirable crystalline silica dust concentration estimates less than 0.1 mg/m(3), using the German measurement strategy. This study indicates the importance of proper consideration of exposure information in risk quantification in epidemiological studies.

Objective: The role of silica in the causation of lung cancer is an ongoing debate. In order to explore whether observed association between silica exposure and lung cancer is confounded by exposure to other occupational carcinogens, we updated a previously nested case-control study among a cohort of male workers in 29 Chinese mines and factories on the basis of an extended follow-up., Methods: Five hundred and eleven lung cancer cases and 1,879 matched controls were selected. Exposure to respirable silica as well as relevant occupational confounders were quantitatively assessed based on historical industrial hygiene data. The relationship between exposure to silica and lung cancer was analyzed by conditional logistic regression analysis adjusted for exposure to arsenic, polycyclic aromatic hydrocarbons (PAHs), radon, and smoking., Results: In a crude analysis adjusted for smoking only, a significant trend of increasing risk of lung cancer with exposure to silica was found for tin, iron/copper miners, and pottery workers. But after adjustment for relevant occupational confounders, no relationship between silica and lung cancer can be observed. Instead, there is a significant association between lung cancer mortality and cumulative exposure to inorganic arsenic (OR = 1.86, 95% CI: 1.14, 3.04 for each mg/m(3)-year increase) and carcinogenic PAHs (OR = 1.35, 95% CI: 1.08, 1.69 for each 100 microg/m(3)-year increase)., Conclusion: This analysis does not provide any evidence to show that exposure to silica causes lung cancer in the absence of confounding factors.

Background: Mineral dusts that contain crystalline silica have been associated directly or indirectly with the development of pneumoconiosis or silicosis, non-malignant respiratory diseases, lung cancer, and other diseases. The health impacts on workers with silica mixed dust exposure in tin mines and dose-response relationships between cumulative dust exposure and the mortality from lung cancer are investigated., Methods: A cohort of 7,837 workers registered in the employment records in 4 Chinese tin mines between 1972 and 1974 was identified for this study and the mortality follow-up was traced through 1994. Of the cohort, the cause of death was ascertained for 1,061 (97%) of the 1,094 deceased workers. Standardized mortality ratios (SMRs) were calculated for all workers, non-exposed workers, and dust-exposed workers with different exposure levels, silicotics, and non-silicotics based on Chinese national rates., Results: The mortality from all causes in four tin mines was nearly the same as the national mortality. Malignant neoplasm, cerebrovascular disease, and cardiovascular disease accounted for 68.6% of all deaths. Mortality excess from lung cancer, liver cancer, all malignant diseases, and non-malignant respiratory diseases was observed among dust-exposed workers; a 50-fold excess of pneumoconiosis was observed. There was an upward trend for SMRs of lung cancer was noted from no exposure to low, medium, and high exposure levels (SMRs=1.29, 2.65, 2.66, 3.33). The shape of the exposure-response curve for risk of lung cancer at high exposure levels was inconsistent in these four mines., Conclusions: The findings indicated a positive dose-response relation between exposure to cumulative dust and the mortality of lung cancer. High arsenic content in dust particles, together with crystalline silica, may play an important role in causing increased mortality from lung cancer., (Copyright (c) 2005 Wiley-Liss, Inc.)