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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., 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 Ltd. All rights reserved.)

Objectives: Autoimmune disorders are multifactorial but occupational exposures have long been implicated, including respirable crystalline silica (RCS). A modern epidemic of silicosis is emerging internationally, associated with dry processing of engineered stone with high (>90%) RCS content. We aimed to investigate the prevalence of clinical autoimmune disease and common autoantibodies in exposed workers., Methods: Stone benchtop industry workers in Victoria, Australia were offered free screening for silicosis and related disorders. Symptoms or diagnoses of autoimmune disease were evaluated by questionnaire and blood tests taken for rheumatoid factor (RF), antinuclear antibodies (ANAs) and extractable nuclear antigens (ENAs)., Results: Among 1238 workers (93.3% male) screened from 2019 to 2021, 0.9% were confirmed with autoimmune disease. Among those without clinical disease, 24.6% had detectable ANAs (93.5% male), 4.6% detectable ENAs and 2.6% were positive for RF. Silicosis was diagnosed in 253 workers (24.3% of those with diagnostic information available). Of those with ANA readings, 54 (6.6%) had ANA titre >1:320. The likelihood of positive autoantibodies increased with age; smoking; higher exposure to RCS and silicosis diagnosis., Conclusion: The proportion of workers with detectable ANAs or ENAs was considerably higher than the 5%-9% expected in the general population. Some of the antibodies detected (eg, Scl-70, CENPB) have high sensitivity and specificity for systemic sclerosis. Long-term follow-up will be needed to estimate incidence. Rheumatologists should explore occupational history in new cases of autoimmune disease. Screening for autoimmune disease is indicated in workers exposed to RCS as these individuals need specialised management and may be entitled to compensation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Silicosis is an irreversible and incurable disease. Preventive measures to eliminate exposure are the only effective way to reduce morbidity and mortality. In such situations, having a biomarker for early diagnosis or to predict evolution would be very useful in order to improve control of the disease. The elevation of serum angiotensin-converting enzyme (sACE) in silicosis has been described in previous studies, although its relationship with severity and prognosis is not clear., Aims: To determine the levels of sACE in a cohort of patients with exposure to silica dust with and without silicosis, and to assess their impact on the prognosis of the aforementioned patients., Method: Prospective observational study on patients treated in a silicosis clinic from 2009 to 2018. sACE levels and pulmonary function tests were performed. Radiological progression was assessed in patients who had already had 2 X-rays of the thorax and / or two CT scans with at least a 1-year interval, from the time of inclusion in the study., Results: A total of 413 cases of silicosis were confirmed, as well as 73 with exposure to silica dust but without silicosis. The mean sACE level for healthy subjects was 27.5±7.3U/L, for exposed patients without silicosis it was 49.6±24.2U/L, for simple silicosis it was 57.8±31,3U/L and for complicated silicosis it was 74.5±38.6U/L. Patients with a higher sACE generally progressed radiologically during follow-up (73.3±38.0 vs. 60.4±33.7; p<.001) and so the category of silicosis changed (73,9±38.1 vs. 62.5±34.6; p<.021)., Conclusions: sACE was elevated in patients with silicosis, and the greater its severity, the higher it was, which is associated with disease progression measured radiologically or as a category change of silicosis., (Copyright © 2022 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

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

Long-term exposure to inhaled silica dust induces pneumoconiosis, which remains a heavy burden in developing countries. Modern industry provides new resources of occupational SiO 2 leading to artificial stone silicosis especially in developed countries. This study aimed to characterize the serum metabolic profile of pneumoconiosis and artificial stone silicosis patients. Our case-control study recruited 46 pairs of pneumoconiosis patients and dust-exposed workers. Nontargeted metabolomics and lipidomics by ultra-high-performance liquid chromatography-tandem mass spectrometry platform were conducted to characterize serum metabolic profile in propensity score-matched (PSM) pilot study. 54 differential metabolites were screened, 24 of which showed good screening efficiency through receiver operating characteristics (ROC) in pilot study and validation study (both AUC > 0.75). 4 of the 24 metabolites can predict pneumoconiosis stages, which are 1,2-dioctanoylthiophosphatidylcholine, phosphatidylcholine(O-18:1/20:1), indole-3-acetamide and l-homoarginine. Kynurenine, N-tetradecanoylsphingosine 1-phosphate, 5-methoxytryptophol and phosphatidylethanolamine(22:6/18:1) displayed the potential as specific biomarkers for artificial stone silicosis. Taken together, our results confirmed that tryptophan metabolism is closely related to pneumoconiosis and may be related to disease progression. Hopefully, our results could supplement the biomarkers of pneumoconiosis and provide evidence for the discovery of artificial stone silicosis-specific biomarkers., Competing Interests: Declaration of Competing Interest The authors declare they have no competing financial interests., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To investigate the influence of silica exposure on the expression of connective tissue growth factor (CTGF), transforming growth factor beta-1 (TGF- β 1), and platelet-derived growth factor (PDGF) in lung silicosis rat., Methods: Wistar rats were divided into an experimental group and a control group. In the experimental group, rats were exposed to silica by intratracheal instillation. In the control group, rats were exposed to physiological saline by intratracheal instillation. After 45 days, we compared the level of fibrosis and CTGF, TGF- β 1, and PDGF in the lungs by immunohistochemistry or reverse transcription-polymerase chain reaction between the two groups., Results: The results showed that the expression levels of CTGF, TGF- β 1, and PDGF mRNA were significantly higher in the experimental group than those in the control group ( P < 0.05). The positive staining of CTGF, TGF- β 1, and PDGF mRNA was found in the cytoplasm, especially in the silicotic nodules of the hyalinisation section and cell endochylema of the alveolar macrophages, type II pneumonocytes, and lung tracheal epithelium. There were significantly positive correlations between CTGF, TGF- β 1, and PDGF expressions ( P < 0.05). A protein-protein interaction analysis showed interactions between TGF- β 1, CTGF, and PDGF., Conclusions: TGF- β /CTGF signaling pathway plays an important role in silicosis. Silicon dioxide exposure can induce the expression of CTGF, TGF- β 1, and PDGF., Competing Interests: All of the authors had no any personal, financial, commercial, or academic conflicts of interest separately., (Copyright © 2021 Jie Jiao et al.)

Silicosis is an irreversible, incurable and progressive occupational disease caused by prolonged exposure to crystalline-silica dust while working in the relevant industries. Conventionally diagnosis is done by chest radiology, often in an advanced stage as early symptoms often go unnoticed. Early detection and necessary intervention (secondary prevention) could be a realistic possible control strategy for controlling silicosis as no effective treatment is available to stop and/or reverse the pathological process. Additionally, these patients are also vulnerable to pulmonary tuberculosis, which often becomes difficult to treat and with uncertain treatment outcome. Considering India has a huge burden of silicosis and silico-tuberculosis, a rapid and inexpensive screening method was realized to be an urgent need for early detection of silicosis among silica dust exposed workers. Serum club cell protein 16 (CC16) is evidenced to be a useful proxy screening marker for early detection of silicosis as evidenced from the recent research work of ICMR-National Institute of Occupational Health (ICMR-NIOH), India. In this study a lateral-flow assay for semi-quantitative estimation of serum CC16 level was developed. The detection was performed using gold nanoparticles conjugated anti-CC16 monoclonal antibodies. A sum of 106 serum samples was tested to do the performance evaluation of the assay. A concentration of 6 ng/ml or less produced one band, 6.1-9 ng/ml produced two bands, while more than 9 ng/ml produced all the three bands at the test zone. The sensitivity of the assay was 100% while the specificity was 95%. This assay may be used as a sensitive tool for periodic screening of silica dust exposed vulnerable workers for early detection of silicosis in them., (© 2021. The Author(s).)

Purpose: The degree of silicosis exposure is closely related to the progress of silicosis. At present, we use animal and human studies to explore whether silicon can be an important exposure marker in the development of silicosis., Methods: Rats were randomly divided into 2 groups: (1) controls; and (2) silicosis. Rats in the silicosis group were killed at 4, 8, 12, 16, 24 h, 3, 7, 14, 21, and 28 days. Hematoxylin-eosin (HE) and immunohistochemistry (IHC) were performed to observe the histomorphology of lung tissue. The expression levels of CC16 and SP-D were detected using ELISA kits. In addition, we conducted a population study. Workers who have been selected to work in an iron mine for more than 1 year as research objects. The population was divided into four groups: silicosis exposure group (workers exposed to silica dust for more than 1 year in an iron mine were selected); patients group (silicosis patients); observation group (evidence of disease not meeting formal diagnostic criteria) and control group. Both the levels of trace silicon in the urine and blood of rats and human subjects were measured with ICP-MS., Results: Serum levels of silicon were immediately increased in rats exposed to silicon dust. Similarly, our population study revealed that the silicon level in the silica exposure group and the observing group (exposed but no obvious symptoms) were significantly increased over that of the control group (P < 0.05). In subjects with extended exposure to silica, the serum and urine silicon level in exposed workers appeared to rapidly increase, reaching its peak in 1-5 years, followed by a gradual decline thereafter. Workers exposed to dust for less than 10 years were divided into subgroups by 2-year limit. The levels of serum silicon, urine silicon, TGF-β1, and TNF-α were significantly higher than that of control group., Conclusion: Changes of the serum levels of silicon occurred earlier than the expression of cytokines such as TNF-α, TGF-β 1 , CC16, and SP-D. The level of silicon in workers rapidly increased after exposure to silica, and the change occurred before the expression of TGF-β1 and TNF-α. As a whole, the findings suggest that determining the level of silicon in vivo might be an effective exposure marker in the diagnosis and pathogenesis of silicosis., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Silicosis is a diffuse interstitial lung disease caused by sustained inhalation of silica and silicates. Several cytokines are activated by their inhalation and can mediate the process of pulmonary fibrosis. The identification of biomarkers could allow an early diagnosis before the development of radiological alterations and help monitor the evolution of patients. The objetive of this study was to determine the clinical significance of specific biomarkers, to estimate their association with the development, severity and/or progression of silicosis, and identify determinants of this evolution. We conducted a prospective observational study in patients attending the pulmonology clinic from 2009 to 2018. Serum levels of the following inflammatory mediators were assessed: interleukin-6 (IL-6), interleukin 2 receptor subunit alpha (IL2R) interleukin 1 beta (IL1B), interleukin-8 (IL-8), tumour necrosis factor-alpha (TNF-α), transforming growth factor-beta1 (TGF-β1), alpha-1 antitrypsin (AAT), C-reactive protein (CRP), lactate dehydrogenase (LDH) and ferritin in subjects exposed to silica, with and without silicosis. Association between those inflammatory mediators with lung function measurements and radiological severity of disease and their impact on prognosis were analysed. 337 exposed to silica (278 with silicosis) and 30 subjects in the control group were included. IL-8, α1AT, ferritin, CRP and LDH levels were higher in silicosis than in those exposed to silica without silicosis. IL-8, LDH and AAT levels were associated with progression of silicosis and IL-6, IL-8, LDH, AAT, ferritin, and CRP with vital status. The results of the ROC analysis indicated the potential of IL-8 as a biomarker in the presence of silicosis and for the prediction of mortality.

Background: Silicosis is a progressive pneumoconiosis characterized by interstitial fibrosis following exposure to silica dust. The role of metabolic dysregulation in the pathogenesis of silicosis has not been investigated in detail. This study aimed to identify different metabolic features in the plasma of patients with silicosis and dust-exposed workers without silicosis in metabolomics studies., Methods: Patients with silicosis, dust-exposed workers (DEWs) without silicosis and age-matched healthy controls were recruited in a case-control study. The metabolomics analyses by ultra-high performance liquid chromatography-mass spectrometry were conducted. Distinct metabolic features (DMFs) were identified in the pilot study and were validated in the validation study. The enriched signalling pathways of these DMFs were determined. The ability of DMFs to discriminate among the groups was analysed through receiver operating characteristic (ROC) curves. The correlations between DMFs and clinical features were also explored., Results: Twenty-nine DMFs and 9 DMFs were detected and had the same trend in the pilot study and the validation study in the plasma of the DEW and silicosis groups, respectively. Sphingolipid metabolism was the major metabolic pathway in the DEWs, and arginine and proline metabolism was associated with silicosis. Twenty DMFs in the DEWs and 3 DMFs in the patients with silicosis showed a discriminatory ability with ROC curve analysis. The abundance of kynurenine was higher in Stage III silicosis than in Stage I or Stage II silicosis. L-arginine and kynurenine were both negatively correlated with the percentage of forced vital capacity predicted in silicosis., Conclusions: Distinct metabolic features in the plasma of DEWs and the patients with silicosis were found to be different. Sphingolipid metabolism and arginine and proline metabolism were identified as the major metabolic pathway in the DEW and silicosis groups, respectively. L-arginine and kynurenine were correlated with the severity of silicosis.

Silicosis is a devastating disease caused by inhalation of silica dust that leads to inflammatory cascade and then scarring of the lung tissue. Increasing evidences indicate that soluble receptor for advanced glycation end products (sRAGE) is involved in inflammatory diseases. However, no data on the possible relationship between sRAGE and inflammation of silicosis are available. In this study, serum from subjects with silicosis ( n = 59) or from healthy controls (HC, n = 14) was analyzed for the secretion of sRAGE, tumor necrosis factor- α (TNF- α ), interleukin-1 β (IL-1 β ), interleukin-6 (IL-6), transforming growth factor- β 1 (TGF- β 1), and oxidized low-density lipoprotein (ox-LDL). The associations between sRAGE and cytokines and ox-LDL and lung function were assessed by Pearson's correlation analyses. Mean levels of serum sRAGE were lower in silicosis than those in controls ( p < 0.05). The subjects who had a longer term of occupational exposure had higher levels of sRAGE ( p < 0.05). The secretion of TNF- α , IL-1 β , IL-6, TGF- β 1, and ox-LDL was significantly higher in the silicosis group than that in the HC group ( p < 0.05). Furthermore, the levels of sRAGE were negatively correlated with TNF- α , IL-6, IL-1 β , and ox-LDL. There is no correlation between sRAGE and TGF- β 1 and lung function. The optimal point of sRAGE for differentiating silicosis from healthy controls was 14250.02 pg/ml by ROC curve analysis. A decrease in serum sRAGE and its association with inflammatory response might suggest a role for sRAGE in the pathogenesis of silicosis., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Heliang Liu et al.)

Silicosis is one of the prolonged and irreversible occupational diseases. Crystalline silica dust, which has been linked with silicosis, occurs in different industrial areas such as constructions, ceramic, quarry, and pottery. There are significant numbers of newly diagnosed cases every year in Turkey. Patients with silicosis suffer from inflammatory respiratory disorders and silicosis-related complications such as rheumatoid arthritis, systemic sclerosis, and vasculitis. Oxysterols are defined as 27-carbon intermediates or end products of cholesterol. They are also implicated in the etiology of disease states such as atherosclerosis, neurodegenerative, and inflammatory diseases. The aim of the study is to evaluate cholesterol oxidation products in the patients with silicosis and determination of sphingosine-1-phosphate (S1P) levels which is a sphingolipid metabolite. In addition to these parameters, it is aimed to determine the possible lipid peroxidation by different parameters. For this purpose, blood samples and urine were collected from 47 patients and 30 healthy individual with their consents. In order to evaluate oxysterols, 7-ketocholesterol and cholestan 3β,5α,6β-triol levels were measured by LC-MS/MS method. The measured levels of 7-KC were 0.101 ± 0.005 µmol/l in patient and 0.050 ± 0.003 µmol/l in control plasma samples. Triol levels were measured as 0.038 ± 0.005 µmol/l in patient group and 0.033 ± 0.004 µmol/l in control group (p < 0.001). In addition, lipid peroxidation products were measured by human-8-isoprostane, human-4-hydroxynonenal (4-HNE), and human malondialdehyde (MDA) ELISA kits. The measured levels of HNE in the patient and control groups were 735.14 ± 288.80 pg/ml and 595.72 ± 108.62 pg/ml in plasma and 606.02 + 118.23 pg/ml and 531.84 + 107.18 pg/ml in urine, respectively (p < 0.05). F2-iP results of patients and controls were 450.0 + 101.40 pg/dl and 386.9 + 112.7 pg/ml for urine and 432.7 ± 188,8 pg/dl and 321.9 ± 69.4 pg/dl for plasma, respectively (p < 0.05). MDA levels of plasma were measured as 44.1 ± 14.6 nmol/ml in the patient and 31.9 ± 10.5 nmol/ml in the control (p < 0.05). Levels of MDA for urine samples were 30.15 + 5.06 nmol/ml and 25.15 + 6.07 nmol/ml in patients and controls, respectively (p < 0.05). S1P levels were decreased in patients compared to control group (49.05 ± 10.87 and 67.57 ± 16.25, p < 0.001). The results not only indicate a correlation between cholesterol oxidation, lipid peroxidation, and silicosis, but also provide better understanding of the role of the lipids in the mechanism of this inflammatory disease.

Background: Identification of biomarkers associated with the diagnosis and prognosis of silicosis would be highly advantageous in the clinical setting. The aim of this study is to evaluate inflammatory and oxidative stress biomarkers in subjects exposed to silica., Methods: A cross-sectional study of crystal craftsmen currently (n = 34) or formerly (n = 35) exposed and a group of nonexposed subjects (n = 12) was performed. Personal respirable dust samples were collected. Plasma inflammatory mediators (bone morphogenetic protein- BMP2 and chemokines CXCL16, and CCL5), oxidative stress enzymes (thiobarbituric acid reactive substances [TBARs] and superoxide dismutase [SOD]), and nitrite (NO 2 - ) were analyzed in parallel with nitric oxide in exhaled breath (FeNO)., Results: Being currently or formerly exposed to silica was related to increased levels of CXCL16 and TBARs. Currently, exposed subjects showed decreased levels of SOD. Thirty-seven craftsmen with silicosis (26 formerly and 11 currently exposed) showed higher levels of CXCL16, which was positively associated with the radiological severity of silicosis. Compared with the nonexposed, subjects with silicosis had higher levels of TBARs and those with complicated silicosis had lower levels of SOD. In multivariate analysis, higher levels of CXCL16 were associated with exposure status and radiological severity of silicosis. Smoking was not a confounder. FeNO did not distinguish between the exposure status and the presence of silicosis., Conclusion: CXCL16 emerged as a potential biomarker that could distinguish both silica exposure and silicosis. TBARs were elevated in exposed individuals. However, their clinical applications demand further investigation in follow-up studies of representative samples., (© 2020 Wiley Periodicals, Inc.)

Objective: To investigate the effects of long-term exposure to silica dust on serum CC16 and KL-6 levels. Methods: The patients with stage I silicosis who were hospitalized in our hospital from April 2016 to April 2017 were treated as silicosis group. The silica dust exposed workers without silicosis who were taken the physical examination in our hospital were taken as a dust-exposed group. The healthy control group comes from in the same period of community physical examination did not touch the dust. The levels of CC16 and KL-6 in serum of all subjects were determined by enzyme-linked immunosorbent assay (ELISA) , and the levels of CC16 and KL-6 in serum were compared in three groups. Results: Compared with the control group, the serum levels of CC16 in the silicosis group ( P <0.01) and the dust-exposed group ( P <0.01) were significantly lower. Compared with the control group, the level of serum KL-6 in the silicosis group was significantly decreased ( P <0.01) compared with the control group, while the level of KL-6 in the serum of the dust-exposed group was significantly increased ( P <0.01) . The ROC area of CC16 for diagnosis of silicosis was 0.92 ( P <0.01) , with a sensitivity of 81.37%, specificity of 92.63% and Kappa value of 0.74. Conclusion: Long-term exposure to silica dust may lead to a decrease in serum CC16 levels. Reduced serum CC16 levels may be useful in identifying the diagnosis of silicosis.

Objective: To explore the value of heparin-binding protein (HBP) in early diagnosis of severe infection in silicosis patients. Methods: From January 2017 to June 2018, fifty silicosis patients with severe infection and fity without infection were recruited in the Second Affiliated Hospital of Xuzhou Medical University. In the severe infection group, the time of patients diagnosed with severe infection was set as the reference point for time. Blood samples were selected from the hospital inspection system sample library at the time of 24, 48, and 72 hours prior to the reference point. In the non-infection group, blood samples were selected within 24 hours of admission. The blood samples were tested for the levels of HBP, C-reactive protein (CRP), procalcitonin (PCT), and white blood cell (WBC) count. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve, sensitivity, specificity and Youden index (YI) were used to evaluate the diagnostic efficacy of each indicator. Results: The HBP levels at 72, 48, 24, and 0 hours before the diagnosis in the severe infection group were significantly higher than those in the non-infection group (all of the P values <0.001), and decreased with the prolonged time before diagnosis. The ROC curve showed that the AUC of HBP at 72, 48, 24, and 0 h before the diagnosis in the severe infection group [0.828 (0.750-0.907), 0.966 (0.920-0.998), 0.967 (0.961-0.998), 0.997 (0.994-0.999)] was higher than that of PCT [0.563 (0.450-0.677), 0.687 (0.581-0.794), 0.726 (0.622-0.829), 0.982 (0.973-0.986)] and CRP [0.564 (0.449-0.680), 0.648 (0.535-0.761), 0.705 (0.594-0.817), 0.963 (0.924-0.983)] and WBC [0.492 (0.377-0.607), 0.497 (0.383-0.612), 0.628 (0.519-0.738), 0.700 (0.598-0.802)] at the corresponding time. The sensitivity, specificity and YI of HBP were 88.9%-97.6%, 77.1%-98.4% and 0.66-0.96 at 72, 36, 24 and 0 h before diagnosis, respectively. Conclusion: Heparin-binding protein can be used for early diagnosis of severe infection in silicosis patients.

Silicosis is a typical form of pneumoconiosis and is characterized as a type of lung fibrosis. Silica particles are captured and recognized upon by alveolar macrophages via the macrophage receptor with collagenous structure (MARCO) scavenger receptor, and thereafter the inflammasome is activated. Thereafter, various chemokines/cytokines play their roles to eventually form fibrosis. Additionally, silica particles chronically activate T helper cells which sets the background for the formation of silicosis-associated autoimmune disturbances. The occurrence and progression of lung fibrosis, the extracellular matrix-related molecules such as integrins and their ligands including fibronectin, vitronectin, laminin, and collagens, all play important roles. Here, the roles of these molecules in silicosis-related lung fibrosis are reviewed from the literature. Additionally, the measurement of serum nephronectin (Npnt), a new member of the integrin family of ligands, is discussed, together with investigations attempting to delineate the role of Npnt in silica-induced lung fibrosis. Serum Npnt was found to be higher in silicosis patients compared to healthy volunteers and seems to play a role in the progression of fibrosis with other cytokines. Therefore, serum Npnt levels may be employed as a suitable marker to monitor the progression of fibrosis in silicosis patients.

Respirable crystalline silica (RCS) produced in mining and construction industries can cause life-threatening diseases such as silicosis, lung cancer, and chronic obstructive pulmonary disease (COPD). These diseases could be more effectively treated and prevented if RCS-related biomarkers were identified and measured at an early stage of disease progression, which makes development of a point of care test (POCT) platform extremely desirable for early diagnosis. In this work, a new, highly sensitive lab on a chip (LOC) immunoassay has been designed, developed, and characterized for tumor necrosis factor α (TNF-α), a protein biomarker that causes lung inflammation due to RCS exposure. The designed LOC device is composed of four reservoirs for sample, enzyme conjugated detection antibody, wash buffer, and chemiluminescence substrate in liquid form, along with three spiral reaction chambers for test, positive control, and negative control. All reservoirs and spiral microchannels were connected in series and designed to perform sequential delivery of immunoassay reagents with minimal user intervention. The developed LOC measured TNF-α concentrations as low as 16 pg/mL in plasma from RCS-exposed rats and also had a limit of detection (LOD) of 0.5 pg/mL in spiked artificial serum. In addition, the analysis time was drastically reduced to about 30 min, as opposed to hours in conventional methods. Successful implementation of a highly sensitive, chemiluminescence-based immunoassay on a preloaded LOC with proper quality control, as reported in this work, can pave the way toward developing a new rapid POCT platform for in-field clinical diagnosis.

Objective: This study aims to investigate the changes in CD3 + , CD4 + and CD8 + expression in cells in peripheral blood of silicosis patients, and observe the immunoregulatory effect of thymalfasin., Methods: A total of 80 silicosis patients were enrolled in the study, randomly divided into two groups: treatment group and control group (n=40, each group). In addition, 40 healthy adults, who underwent physical examinations in our hospital, were enrolled into the health examination group. Patients in the control group and treatment group were given anti-infection treatment, according to their conditions. Patients in the treatment group additionally received thymalfasin. Then, the number of peripheral blood T lymphocyte subsets in subjects in all three groups before and after treatment was measured., Results: (1) Before treatment, CD3 + , CD4 + and CD8 + levels in cells were significantly lower in the treatment group and control group than in the health examination group, and the differences were statistically significant ( P <0.05). (2) In the treatment group, the number of CD4 + cells in peripheral blood was significantly higher after one week of treatment, when compared to that before treatment, and the difference was statistically significant ( P <0.05)., Conclusion: In silicosis patients, CD3 + , CD4 + and CD8 + cells in peripheral blood are decreased, and thymalfasin can significantly increase CD4 + cells in peripheral blood of silicosis patients., (© 2019 by the Association of Clinical Scientists, Inc.)

Introduction: Occupational exposure to crystalline silica over time may result in silicosis: a fatal, irreversible occupational disease leading to lung function impairment. A complex inflammatory process, excessive accumulation of mesenchymal cells and collagen production are the primary mechanisms underlying silicosis. Neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR) have emerged as representative indices of systemic inflammation., Objectives: The purpose of the present study was to investigate the relationship between NLR, PLR and silicosis., Methods: We retrospectively analysed the demographic and laboratory data of ceramic workers who were referred to our Hospital between 2010 and 2018. Five hundred and seventy-three patients with silicosis and 222 ceramic workers without silicosis (controls) were included in the study., Results: The radiographic ILO classification of silicosis patients was as follows: category 1 (71.5%), category 2 (19.2%), category 3 (7.5%). NLR and PLR in categories 2 and 3 were significantly higher when compared with the control group (P < .005). FEV 1 , FEV 1 %, FVC, FVC % and PEF were significantly lower in all silicosis patients and also in patients with subcategories (all P < .005). NLR showed a poor positive correlation with CRP (r = 0.095, P < .05) and ESR (r = 0.207, P = .000) while PLR only with ESR (r = 0.317, P = .000) in patients with silicosis. NLR and PLR showed negative correlations with FEV 1 , FVC and PEF (all P < .005)., Conclusion: We conclude that NLR and PLR have significant but poor correlations with pulmonary functions and severity of silicosis, especially in late radiographic profusion categories., (© 2019 John Wiley & Sons Ltd.)

High-mobility group box-1 (HMGB-1) has been associated with fibrotic diseases. However, the role of HMGB-1 in silicosis is still uncertain. In this study, we conducted a case-control study involving 74 patients with silicosis and 107 age/gender-matched healthy controls in China. An Enzyme-linked immunosorbent assay (ELISA) was used to examine the concentrations of plasma HMGB-1 among all subjects. A logistic regression model and receiver operating characteristic curve (ROC) analysis were performed to assess the relationships between HMGB-1 and silicosis. We observed that plasma HMGB-1 concentrations were significantly increased in silicosis patients when compared with healthy controls ( p < 0.05). Each 1 ng/mL increase in plasma HMGB-1 was positively associated with increased odds of silicosis, and the odds ratio (OR) (95% confidence interval) was 1.86 (1.52, 2.27). Additionally, compared with subjects with lower HMGB-1 concentrations, increased odds of silicosis were observed in those with higher HMGB-1 concentrations, and the OR was 15.33 (6.70, 35.10). Nonlinear models including a natural cubic spline function of continuous HMGB-1 yielded similar results. In ROC analyses, we found that plasma HMGB-1 >7.419 ng/mL had 81.6% sensitivity and 80.4% specificity for silicosis, and the area under the curve (AUC) was 0.84. Our results demonstrated that elevated plasma HMGB-1 was positivity associated with increased OR of silicosis.

Workers involved in mining activities are exposed to crystalline silica, which leads to constant pulmonary inflammatory reactions and severe oxidative damage, resulting in silicosis. In this work, we aimed to evaluate inflammatory and oxidative stress parameters as potential early biomarkers of effect to assess crystalline silica toxicity in workers who had occupational exposure during mining. We enrolled 38 workers exposed to crystalline silica (WECS), 24 individuals with silicosis (IWS), and 30 occupationally unexposed workers (OUW), a total of 92 participants. The WECS were divided into 2 groups, according to the time of exposure: 19 workers with 1-15 years of occupational exposure (WECS I) and 19 workers with >16 years of occupational exposure (WECS II). The inflammatory parameters assessed were L-selectin, β-2 integrin, and intercellular adhesion molecule-1 (ICAM-1) surface protein expression in lymphocytes and monocytes, complement C3 and C4, high sensitivity C-reactive protein (hsCRP), and adenosine deaminase (ADA) in serum. Plasma levels of malondialdehyde (MDA) and serum levels of vitamin C were determined as biomarkers of oxidative stress. Biochemical and hematological parameters were also investigated. L-selectin surface protein expression was significantly decreased in the WECS II group (p < 0.05), indicating the importance of this immune system component as a potential marker of crystalline-silica-induced toxicity. The MDA levels were significantly increased in the WECS I, WECS II, and IWS groups compared to the OUW group (p < 0.05). Vitamin C levels were decreased, while C3, hsCRP, ADA, and aspartate aminotransferase (AST) levels were increased in the IWS group compared to the OUW group (p < 0.05). Glucose and urea levels were significantly higher in the WECS I, II, and IWS groups compared to the OUW group (p < 0.05). Negative partial association was found between L-selectin and time of exposure (p < 0.001), supporting the relevance of this biomarker evaluation in long-term exposure to crystalline silica. Significant associations were also observed among inflammatory and oxidative stress biomarkers. Therefore, our results demonstrated the relevance of L-selectin as a potential peripheral biomarker for monitoring crystalline silica-induced toxicity in miners after chronic exposure, before silicosis has developed. However, more studies are necessary for better understanding of the use L-selectin as an early biomarker in exposed workers., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Epidemiological studies have confidently linked occupational crystalline silica exposure to autoimmunity, but pathogenic mechanisms and role of genetic predisposition remain poorly defined. Although studies of single inbred strains have yielded insights, understanding the relationships between lung pathology, silica-induced autoimmunity, and genetic predisposition will require examination of a broad spectrum of responses and susceptibilities. We defined the characteristics of silicosis and autoimmunity and their relationships using the genetically heterogeneous diversity outbred (DO) mouse population and determined the suitability of this model for investigating silica-induced autoimmunity. Clinically relevant lung and autoimmune phenotypes were assessed 12 weeks after a transoral dose of 0, 5, or 10 mg crystalline silica in large cohorts of DO mice. Data were further analyzed for correlations, hierarchical clustering, and sex effects. DO mice exhibited a wide range of responses to silica, including mild to severe silicosis and importantly silica-induced systemic autoimmunity. Strikingly, about half of PBS controls were anti-nuclear antibodies (ANA) positive, however, few had disease-associated specificities, whereas most ANAs in silica-exposed mice showed anti-ENA5 reactivity. Correlation and hierarchical clustering showed close association of silicosis, lung biomarkers, and anti-ENA5, while other autoimmune characteristics, such as ANA and glomerulonephritis, clustered separately. Silica-exposed males had more lung inflammation, bronchoalveolar lavage fluid cells, IL-6, and autoantibodies. DO mice are susceptible to both silicosis and silica-induced autoimmunity and show substantial individual variations reflecting their genetic diverseness and the importance of predisposition particularly for autoimmunity. This model provides a new tool for deciphering the relationship between silica exposure, genes, and disease.

Rationale: Phagocytosis of silicon dioxide (SiO 2 ) into lung cells causes an inflammatory cascade that results in fibroblast proliferation and migration, followed by fibrosis. Circular RNAs (circRNAs) are a subclass of non-coding RNAs detected within mammalian cells; however, researchers have not determined whether circRNAs are involved in the pathophysiological process of silicosis. The upstream molecular mechanisms and functional effects on cell apoptosis, proliferation and migration were investigated to elucidate the role of circRNAs in SiO 2 -induced inflammation in pulmonary macrophages. Methods: Primary cultures of alveolar macrophages from healthy donors and patients as well as the RAW264.7 macrophage cell line were used to explore the functions of circHECTD1 (HECT domain E3 ubiquitin protein ligase 1) in macrophage activation. Results: The results of the experiments indicated that 1) SiO 2 concomitantly decreased circHECTD1 levels and increased HECTD1 protein expression; 2) circHECTD1 and HECTD1 were involved in SiO 2 -induced macrophage activation via ubiquitination; and 3) SiO 2 -activated macrophages promoted fibroblast proliferation and migration via the circHECTD1/HECTD1 pathway. Tissue samples from silicosis patients confirmed the upregulation of HECTD1. Conclusions: Our study elucidated a link between SiO 2 -induced macrophage activation and the circHECTD1/HECTD1 pathway, thereby providing new insight into the potential use of HECTD1 in the development of novel therapeutic strategies for treating silicosis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Background: Asbestosis and silicosis are progressive pneumoconioses characterized by interstitial fibrosis following exposure to asbestos or silica dust. We evaluated the potential diagnostic biomarkers for these diseases., Methods: The serum concentrations of Krebs von den Lungen-6 (KL-6), surfactant protein D (SP-D), and matrix metalloproteinase-2 (MMP-2), MMP-7, and MMP-9 were measured in 43 patients with asbestosis, 45 patients with silicosis, 40 dust-exposed workers (DEWs) without pneumoconiosis, and 45 healthy controls (HCs). Chest high-resolution computed tomography (HRCT) images were reviewed by experts blinded to the clinical data. According to the receiver operating characteristic (ROC) curve, the ideal level of each biomarker and its diagnostic sensitivity were obtained., Results: The serum KL-6 and MMP-2 concentrations were highest in patients with asbestosis, particularly in comparison with those in DEWs and HCs (P<0.05). The serum SP-D concentration was significantly higher in patients with asbestosis than in patients with silicosis, DEWs, and HCs (P<0.01), whereas no significant difference was noted among patients with silicosis, DEWs, and HCs. No significant difference in the serum MMP-7 or -9 concentration was found among patients with asbestosis, patients with silicosis, DEWs, or HCs. Among patients with asbestosis, the serum KL-6 concentration was significantly correlated with the lung fibrosis scores on HRCT and negatively correlated with the forced vital capacity (FVC) % predicted and diffusing capacity of the lung for carbon monoxide (DL CO ) % predicted. The serum SP-D and MMP-2 concentrations were negatively correlated with the DL CO % predicted (all P<0.05). The order of diagnostic accuracy according to the ROC curve was KL-6, SP-D, and MMP-2 in patients with asbestosis alone and in the combination of both patients with asbestosis and those with silicosis. The combination of all three biomarkers may increase the possibility of diagnosing asbestosis (sensitivity, 93%; specificity, 57%) and both asbestosis and silicosis (sensitivity, 83%; specificity, 62%)., Conclusions: KL-6, SP-D, and MMP-2 are available biomarkers for the adjuvant diagnosis of asbestosis and silicosis. The combination of all three biomarkers may improve the diagnostic sensitivity for asbestosis and silicosis.

Crystalline silica (SiO 2 ) is an important material for industry but is considered potentially carcinogenic. Inhalation of a crystalline SiO 2 aerosol may contribute to serious lung diseases. Crystalline SiO 2 particles are commonly used as a positive control in toxicity assays of particulate materials (e.g. nanoparticles). Crystalline SiO 2 induces oxidative stress resulting in lipid peroxidation, but the acute oxidative stress response in the lung is not well understood. Lipid peroxidation during the acute stage of oxidative stress after instillation of crystalline SiO 2 into rats was examined by bronchoalveolar lavage fluid (BALF) analysis. The levels of 8-iso-prostaglandin F 2α and hydroxyoctadecadienoic acid (HODE) in the BALF were measured using liquid chromatography coupled to quadrupole mass spectrometry. The concentration of the antioxidant protein heme oxygenase-1 (HO-1) in the BALF was determined using enzyme-linked immunosorbent assay. Intratracheal instillation of crystalline SiO 2 increased the level of HODE and HO-1 in BALF at 24 h after administration. The levels of HODE and HO-1 returned to baseline at 72 h after instillation. Lactate dehydrogenase leakage was observed only after 1 h instillation. These results suggest that the contribution of oxidative stress to the pulmonary toxicity of crystalline SiO 2 is minimal in the early acute stage after exposure., (© The Author(s) 2014.)

Context: Silicosis is a devastating, irreversible lung fibrosis condition exposed to crystalline silica. The mononuclear phagocyte system plays an important role in the pathogenesis of silicosis., Objective: The present study was aimed to explore the dynamic changes of mononuclear phagocytes in circulating, pulmonary alveolar and interstitial compartments in experimental silicosis model., Materials and Methods: A mouse model of lung fibrosis was developed with crystalline silica particles (2 mg/40 μL via oropharyngeal instillation) using male C57BL/6 mice, and were killed on days 1, 3, 7, 14, and 28. The lung inflammation and fibrosis was investigated using hematoxylin-eosin staining and bronchoalveolar lavage fluid (BALF) analysis, Masson's trichrome staining, and immunofluorescence. Circulating monocyte subsets (Ly6C(hi) and Ly6C(lo)), polarization state of BALF-derived alveolar macrophages (AMϕ) and lung interstitial macrophages (IMϕ, derived from enzymatically digested lung tissue) were analyzed by flow cytometry., Results: The percentage of Ly6C(hi) monocytes significantly increased on day 1 after silica exposure, which reached the peak level from day 7 till day 28. Moreover, M2 (alternative activation) AMϕ (PI - CD64 + CD206+) was dramatically and progressively increased from day 1 to day 28. A parallel increase in IMϕ with M2 polarization (PI-CD64 + CD11b + CD206+) was also observed from day 1 to day 28., Conclusion: Our data demonstrate a dynamic view of mononuclear phagocyte change in three compartments after silica challenge, which highlights the remodeling of mononuclear phagocyte system as a potential therapeutic target for silicosis.

Objective: To investigate the plasma level of extracellular histones in patients with silicosis, and to explore the role of extracellular histones in the pathogenesis of pulmonary fibrosis in silicosis., Methods: Sixty-two patients with silicosis were enrolled as the silicosis group, consisting of 23 patients with stage I silicosis, 25 with stage II silicosis, and 14 with stage III silicosis; sixty workers who had a history of occupational exposure to silica dust for more than 2 years and had not been diagnosed with silicosis were enrolled as the silica dust exposure group; sixty-five healthy workers without a history of occupational exposure to dust were enrolled as healthy controls. Enzyme-linked immunosorbent assay was applied to measure the plasma levels of plasma extracellular histone (H4) and transforming growth factor-β(TGF-β)., Results: Compared with healthy controls [(0.82±0.67) μg/ml], the silica dust exposure group[(4.14±2.85) μg/ml] and silicosis group[(9.50±5.04) μg/ml] had significant increases in plasma level of H4 (P<0.01). The plasma level of H4 was significantly correlated with the stage of silicosis(r=0.8955, P=0.0388). The silicosis group had a significantly higher plasma level of TGF-β than the silica dust exposure group and healthy controls(P <0.05). In the patients with silicosis, the plasma level of H4 was significantly correlated with that of TGF-β(r=0.5375, P<0.01)., Conclusion: The plasma level of extracellular histones increases significantly in the pathogenesis of silicosis, and extracellular histones may play an important role in the progression of fibrosis in silicosis.

Pulmonary silicosis is an irreversible and untreatable disease that is characterized by interstitial lesions and perpetual fibrosis in the lungs. This study was performed to determine whether mesenchymal stem cells (MSCs) and hepatocyte growth factor (HGF) could exhibit therapeutic effects on human silicosis. This non-randomized uncontrolled trial comprised four patients with pulmonary silicosis who had developed lung fibrosis and received autologous bone marrow MSCs previously transfected by a vector containing human HGF cDNA (MSCs/HGF). MSCs/HGF were intravenously administered weekly for three consecutive weeks at a dose of 2 x 10(6) cells/kg. Pulmonary function, high kilo-voltage chest X-ray radiography, computed tomography (CT) scan, and peripheral blood lymphocyte subset and serum IgG concentrations were evaluated after cell therapy. The treatment was found to be generally safe. Symptoms such as cough and chest distress gradually ameliorated at six months post-therapy, accompanied by the significant improvement of pulmonary function. The ratios of the peripheral CD4- and CD8- positive cell concentrations were increased (P < 0.05). Furthermore, the serum IgG levels in these patients were decreased and reached the normal range (P < 0.05). CT scans showed partial absorption of the nodular and reticulonodular lesions in the lungs during follow-up of at least 12 months. The effectiveness of this novel regimen observed in these patients suggests that a placebo-controlled clinical trial needs to be developed. This study carries trial registration No. NCT01977131 (ClinicalTrials.gov).

Background: Silica has been associated with end stage kidney disease and kidney dysfunction., Methods: Calculated glomerular filtration rate, history of kidney disease or chronic dialysis, elevated serum creatinine, and stages of chronic kidney disease among silicotics identified in Michigan's Silicosis Surveillance System from 1987 to 2009 were reviewed to determine the prevalence of kidney disease in confirmed cases of silicosis., Results: Twenty-four percent of 1,072 silicotics had a measure of kidney dysfunction (32.3% if diabetes or hypertension present vs. 20.2% if not). Sixty-nine percent of silicotics had Stage I or greater chronic kidney dysfunction versus 38.8% of the U.S. general population ≥60 years. No association was found between kidney function and measures of silica exposure., Conclusions: Individuals with silicosis have an increased prevalence of kidney disease. More work to define the pathological changes associated with silica exposure is needed to understand the cause of silica's adverse effect on the kidney., (© 2015 Wiley Periodicals, Inc.)

Aim: To study serum autoantibodies and immunoglobulin levels in cement workers., Methods: Blood samples for numerous antibodies were collected from 30 silicosis and 42 non-silicosis cement workers. Spirometry of the silicosis workers was also studied., Results: Serum IgA mean level showed a significant increase in the silicosis group compared to the non-silicosis group. Elevated titers of serum anti-smooth muscle antibodies (ASMA) and anti-glomerular basement membrane (anti-GBM) were detected only in the silicosis group. The duration of exposure showed a significant positive correlation with serum IgA, ASMA and anti-GBM, and a significant negative correlation with serum IgG. Serum anti-GBM showed a significant positive correlation with IgG while the inverse titer (1/titer) of anti-GBM showed highly significant positive correlations with serum IgA and ASMA. The percent predicted FVC was the ventilatory function most closely associated with immunological parameters in silicosis group., Conclusion: Serum IgA, ASMA, and anti-GBM are the principal immunologic parameters associated with silicosis., (© 2014 Wiley Periodicals, Inc.)

Objective: Silicosis is usually recognized at later stages of the disease, and early biomarkers for silicosis will be useful for timely diagnosis. We aimed at examining plasma levels of TNF-α and MMP-9, and correlation between these, in patients with different stages of silicosis in order to test suitability of these inflammatory factors as early biomarkers for silicosis., Patients and Methods: TNF-α and MMP-9 were quantified by ELISA in plasma specimens from 30 healthy individuals (control group), 28 individuals exposed to silica dust but without clinical disease, and 30 patients with silicosis., Results: Plasma levels of TNF-α and MMP-9 were increased in individuals exposed to silica dust (p < 0.05 vs. control individuals) and were further elevated in patients with silicosis (p < 0.05 vs. control individuals and individuals exposed to silica dust). There was a significant correlation between plasma levels of TNF-α and MMP-9 both in individuals exposed to silica dust (r = 0.696, p < 0.01) and patients with silicosis (r = 0.768, p < 0.01)., Conclusions: Plasma levels of TNF-α and MMP-9 are increased prior to development of clinically recognized silicosis, suggesting that these biomarkers are involved in the onset and development of silicosis. Combined detection of TNF-α and MMP-9 may be useful for early diagnosis of silicosis.

Silica particles and asbestos fibers, which are known as typical causatives of pneumoconiosis, induce lung fibrosis. Moreover, silicosis patients often complicate with autoimmune diseases, and asbestos-exposed patients suffer from malignant diseases such as pleural mesothelioma and lung cancer. We have been conducting experimental studies to investigate altered regulation of self-tolerance caused by silica exposure, including analyses using specimens such as plasma and immunocompetent cells obtained from silicosis patients, as a means of examining the supposition that silica exposure induces molecular and cellular biological alterations of immune cells. These approaches have resulted in the detection of several specific autoantibodies, alterations of CD95/Fas and its related molecules, and evidence of chronic activation of responder T cells and regulatory T cells following silica exposure. In this review, we present details of our investigations as an introduction to scientific approaches examining the immunological effects of environmental and occupational substances.

Objectives: Agate workers are chronically exposed to silica dust generated from agate grinding, which makes them susceptible to silicosis. In the absence of diagnosis at an early stage, the workers continue to be exposed to silica dust until the development of silicosis. The present study was undertaken to investigate total lactate dehydrogenase (LDH) activity in blood samples of silica-exposed agate workers as a non-invasive way to measure silica-induced toxicity., Methods: Blood samples were collected from agate workers and control subjects. Total LDH activity was measured in the blood plasma and blood cells of agate workers and non-exposed (control) subjects using sodium pyruvate as a substrate. The reduction of pyruvate to L-lactate with the concurrent oxidation of nicotinamide adenine dinucleotide (NADH) during the assay was monitored by change in absorbance (or optical density (OD)) at 340 nm at the fixed interval of 10 min. The ratio of LDH activity (blood plasma/blood cells) in the blood samples was calculated as a measure to detect cytotoxicity in exposed workers., Results: The LDH activity in blood plasma samples of exposed workers was found to increase about 25 times, while the activity in the blood cells of silica-exposed agate workers was reduced to 10% of control subjects. The ratio of LDH activity (blood plasma/cells) was found to be 6.6 in the silica-exposed agate workers, while it was 0.02 in control (non-exposed) subjects., Conclusions: This study proposes that total LDH activity and the LDH ratio (plasma/cells), along with occupational exposure history, are markers for silica exposure-induced toxicity in agate workers., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: We investigated the clinical significance of tumor markers in patients with silicosis., Methods: Eighty silicosis patients without malignancy and 50 healthy volunteers were compared for serum tumor marker concentrations. Pulmonary function and several routine laboratory tests were performed. Correlation between serum tumor marker concentrations and severity markers for silicosis was analyzed. Tumor marker concentrations were detected in both blood and BALF samples in silicosis patients. The pre- and post-lavage differences in the serum tumor marker concentrations were also investigated. Immunohistochemical staining for tumor markers was performed in a lung biopsy specimen from a silicosis patient., Results: Both serum NSE and CA125 concentrations were significantly higher in cases compared with controls. Significant positive correlations were found between values of NSE and CA125 and LDH concentration. Significant negative correlations were also observed between values of NSE and CA125 and spirometric parameters. Patients with silicosis had higher concentrations of NSE in BALF than that in serum. 11 of 14 patients experienced a decrease in NSE concentrations following whole lung lavage. Immunohistochemical studies showed positive NSE staining in lung biopsy specimen., Conclusions: Serum NSE and CA125 concentrations would provide valuable clinical information to assess disease severity in silicosis., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: To investigate the serum myeloperoxidase (MPO) activity and serum paraoxonase-1 (PON-1) activity in patients with silicosis and observation subjects and their clinical significance., Methods: Seventy-two patients with silicosis (stage I: 30 cases, stage II: 22 cases, stage III: 20 cases) and 37 observation subjects were selected as a case group, and 110 healthy men were selected as a control group. Serum MPO activity was measured by double-antibody sandwich enzyme-linked immunosorbent assay, and serum PON-1 activity was measured by chemical spectrophotometry., Results: Serum MPO activity was significantly higher in the case group than in the control group [(102.1 ± 15.7) U/L vs. (62.4 ± 11.4) U/L, P < 0.01], but serum PON-1 activity was significantly lower in the case group than in the control group [(85.4 ± 15.7) U/ml vs. (125.4 ± 13.7) U/ml, P < 0.01]. Serum MPO activity was significantly lower in patients with stages I, II, and III silicosis than in the observation subjects [(91.3 ± 13.5) U/L, (85.7 ± 14.4) U/L, and (88.6 ± 14.5) U/L vs. (128.4 ± 16.4) U/L, P < 0.01]. Serum PON-1 activity declined as the stage of silicosis increased; serum PON-1 activity was significantly lower in the patients with stages II and III silicosis than in the observation subjects and the patients with stage I silicosis [(70.4 ± 11.4) U/ml and (67.6 ± 13.7) U/ml vs. (101.5 ± 14.0) U/ml and (89.1 ± 10.1) U/ml, P < 0.01]., Conclusion: Serum MPO activity and serum PON-1 activity are valuable for early diagnosis of silicosis and evaluation of patient's condition.

Objectives: Selenoprotein P (SeP) is a selenium (Se) supply protein, which is an antioxidant micronutrient considered to be vital for human health. The aim of this study was to assess the serum selenium status in patients with silicosis., Methods: We conducted a retrospective case-control study where serum samples from a total of 78 patients (males with a median age of 73.5 years old) with silicosis and 20 healthy controls (males with a median age of 72.5 years old) were assayed for Se and SeP. They underwent medical and job history taking, lung function testing, and chest radiography examinations. Levels of serum Se were measured using electrothermal atomic absorption spectrophotomerty, while levels of SeP were assessed with sandwich Enzyme Immunoassay. Spearman's rank correlation test was carried out to evaluate the relationship between Se and SeP. The Mann-Whitney test was used to evaluate differences in serum Se and SeP between study groups., Results: The median serum Se and SeP concentrations were significantly lower in cases (74.0 μg/l and 4.2mg/l, respectively) compared with controls (116.0 μg/l and 5.8 mg/l, respectively). In both cases and controls, serum Se was positively correlated with serum SeP (rho=0.781, p<0.001 and rho=0.768, p<0.001, respectively). Serum Se and SeP levels were significantly lower in patients classified in category four compared with those who were classified in category two or three., Conclusions: Serum Se and SeP concentrations were found to be at inadequate levels in patients with silicosis, and decreased significantly with the severity of the disease., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

The role of angiogenesis in the pathogenesis of interstitial lung diseases (ILD) is unknown. Angiotensin-converting enzyme (ACE) is a marker of sarcoidosis activity and may modulate angiogenesis. The aim of this study was to examine the relationship between ACE activity in ILD patients' sera and their effect on microvessels formation in an in vivo model of leukocyte-induced angiogenesis. The study population consisted of 77 sarcoidosis patients, 22 idiopathic pulmonary fibrosis patients, 16 bird fanciers lung patients, eight silicosis patients and 14 healthy donors. Serum ACE activity was assayed by spectrophotometric method. As an angiogenic test, a leukocyte-induced angiogenesis assay in an animal model was used. Sera from interstitial lung disease patients significantly stimulated angiogenic activity of mononuclear cells compared with healthy donors (p < 0.001). The highest ACE serum activity was measured in sera from the silicosis patients, and lowest in sera from the sarcoidosis and IPF patients. A significantly lower serum ACE activity was detected in the bird fanciers lung patients. Serum angiogenic activity of ILD patients measured by angiogenesis index negatively correlated with ACE serum activity (r = ;-0.52; p < 0.01). This correlation was highest in the sarcoidosis group (r = -0.6; p < ). Sera from ILD patient constitute the source of factors modulating angiogenesis.

Objective: To identify predictive factors of excess decline in forced expiratory volume in one second (FEV1) in patients with chronic silicosis., Methods: Forty-six male patients enrolled in 2004 were screened and received pulmonary function tests., Results: Among the 33 included patients, 12 were categorized as rapid decliners (reduction in FEV1 > 60 mL/yr). The mean level of serum heme oxygenase-1 (HO-1), a marker of oxidative stress, was significantly lower in rapid decliners than in normal decliners (P = 0.002). Logistic regression analysis revealed that serum HO-1 was a factor affecting clinically important decline in FEV1 (odds ratio = 0.52; 95% confidence interval, 0.31 to 0.88) independent of the effects of age, height, weight, smoking, exposure status, and C-reactive protein., Conclusions: Serum HO-1 may be a predictor of lung function decline in silicosis patients.

Objective: To explore the correlation between the exposure levels and serum protein fingerprints in population exposed to silica., Methods: Liquid chip time-of-flight mass spectrometry technology was used to investigate the serum profiles in control group (30 cases), group exposed to silica (30 cases), silicosis group (I stage, 25 cases) and suspected silicosis group (30 cases), and screen the differential expression proteins. The correlation between the levels of the differential expression proteins and the exposure levels was performed., Results: Five differential expression proteins were found among 4 groups, the expression of 5081 and 5066 proteins was upregulated, and the expression of 3954, 2021 and 1777 proteins was downregulated. There was no the correlation between the exposure levels and the peak with M/Z among those proteins., Conclusion: the results of present investigation indicated there was no correlation between the exposure levels and protein/peptide peak.

Background: The aim of the present study was to investigate serum lactate dehydrogenase (LD) levels in patients with silicosis due to denim sandblasting (SDDS) and also to investigate possible correlations between serum LD levels and the degree of radiological extent of disease (RED) and pulmonary function tests., Methods: Forty-four males with SDDS and 32 healthy male subjects were included in the study. Patients and healthy controls were compared for serum LD levels. Correlations between serum LD levels, RED and spirometric values were investigated., Results: Patients with SDDS had significantly higher serum LD levels than healthy controls. Patients with complicated SDDS had significantly higher serum LD levels than patients with simple SDDS. Significant correlations were found between serum LD levels and RED values. Significant correlations were found between serum LD levels and spirometric parameters., Conclusions: High serum LD levels might be considered as a marker of pulmonary parenchymal involvement in patients with SDDS. This study also suggests that the increase in serum LD levels might be closely related to the degree of pulmonary involvement in SDDS patients.

Objective: To study the roles of macrophage apoptosis, IL-1, and IL-8 in the pathogenesis of rat pulmonary fibrosis induced by silica., Methods: Forty eight male Wistar rats were divided into the 4 control groups (24 rats) and 4 experimental groups (24 rats). Rats in the control groups were treated with 1 ml normal saline by trachea instillation, whereas the rats in experimental groups were exposed 1 ml silica suspension (100 mg/ml) by trachea instillation for 1, 7, 14 and 28 days, respectively. Six rats of each group were sacrificed, then the bronchoalveolar lavage fluid and lung tissues were collected, respectively. Pulmonary inflammation, fibrosis and other pathological changes were detected with H.E. staining. Morphological changes of the early stage apoptosis in macrophages were detected with transmission electron microscope (TEM). The early apoptosis rates of macrophages in BALF were also assessed using Annexin V-FITC/PI kit. The IL-1 and IL-8 levels of serum were measured with the ELISA., Results: The apoptotic rates (11.48% +/- 0.24%, 16.03% +/- 0.68%, 15.53% +/- 1.07%, 18.92% +/- 2.70%, respectively) of macrophage in the experimental groups increased obviously with time, as compared to the controls (5.47% +/- 2.06%, 6.39% +/- 0.215, 9.07% +/- 0.61% and 8.54% +/- 0.16%, Respectively) (P < 0.05). The IL-1 levels of serum in the experimental groups were 23.64 +/- 0.84, 23.38 +/- 1.10, 22.21 +/- 0.86 and 24.29 +/- 1.31 pg/ml, respectively, which were significantly higher than those (18.52 +/- 1.23, 18.40 +/- 1.6, 17.92 +/- 2.21 and 18.53 +/- 2.64 pg/ml, respectively) in the control groups (P < 0.05) without time-effect relationship. The serum IL-8 levels on the 1st, 7th and 14th days in the experimental groups were 21.32 +/- 1.44, 21.90 +/- 2.08 and 22.00 +/- 2.80 pg/ml, respectively, which were significantly higher than those (17.69 +/- 1.09, 16.98 +/- 2.09 and 17.54 +/- 1.62 pg/ml, respectively) in the control groups (P < 0.05)., Conclusion: The early macrophage apoptosis and changes of IL-1 and IL-8 may in lungs may play an important role in the development of pulmonary fibrosis induced by silica.

Objective: To observe serum TGF-beta1 and TNF-alpha in silicosis patients and workers exposed to silica dust to study the role of TGF-beta1 and TNF-alpha in the development of silicosis., Methods: One hundred non-exposed workers were selected as control group, 200 workers exposed to silica dust for more than 1 year as exposed group, 32 suspected silicosis patients (originally diagnosed as 0+) as observing group, 130 silicosis patients were as silicosis group. Serum TGF-beta1 and TNF-alpha in each group were determined with ELISA., Results: Serum TNF-alpha in exposed group [(47.86 +/- 16.52) pg/ml], observing group [(109.11 +/- 31.08) pg/ml], silicosis group [(216.35 +/- 51.03) pg/ml] were significantly higher than that in control group [(6.90 +/- 2.24) pg/ml] (P < 0.01); Silicosis group and observing group were also higher than exposed group (P < 0.01, P < 0.05). Compared with control group [(23.28 +/- 12.24) pg/ml] and exposed group [(29.31 +/- 14.52) pg/ml], serum TGF-beta1 in silicosis group was much higher (P < 0.01)., Conclusion: TGF-beta1, and TNF-alpha were essential in the development of silicosis, so the detection of TGF-beta1 and TNF-alpha in peripheral blood was very useful for occupational health surveillance and early diagnosis of silicosis.

Objective: To investigate the change of indicators of oxidative stress in serum and NF-kappaB in peripheral blood mononuclear cells of patients with silicosis, and explore the mechanism of the development of silicosis., Methods: The subjects were divided into (1) 200 workers exposed to SiO2 for at least 1 years in a foundry served as the dust-exposure group; (2) 130 cases with silicosis (I phase silicosis 64 cases, II phase 46 cases III phase 20 cases) served as the silicosis group; (3) 32 cases with 0+ phase silicosis in the foundry served as the observed group,(4)100 subjects from a hotel served as the control group. The serum including superoxide dismutase (SOD), nitric oxide (NO), serum glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC), nitric oxide synthase (NOS), lipid malondialdehyde (MDA) and NF-kappaB protein levels in peripheral blood mononuclear cells were determined, respectively., Results: Compared with the control group, NO levels in dust-exposed group and silicosis group significantly increased, and SOD decreased significantly (P < 0.05 or P < 0.01). Compared with the control group and dust-exposed group, T-AOC, NOS, MDA levels in silicosis group significantly increased (P < 0.05 or P < 0.01). GSH-Px in dust-exposed group and silicosis group were (231.164 +/- 36.484) and (270.469 +/- 39.228)U/ml, respectively which were significantly than that [(223.360 +/- 46.838) U/ml] in control group (P < 0.05 or P < 0.01), and there was significant difference of GSHPx between the silicosis group and the dust-exposed group significantly (P < 0.01) . GSH-Px level [(290.750 +/- 39.129) U/ml] in III phase silicosis group were significantly higher than those [(256.906 +/- 21.41) and (259.594 +/- 34.79) U/ml] in observation group and I phase silicosis group (P < 0.05). NF-kappaB levels [(72.06 +/- 9.12) and (85.25 +/- 11.64) ng/L] in dust-exposed group and silicosis group were significantly higher than that [(59.71 +/- 9.27) ng/L] in control group (P < 0.01), and there was significant difference of between the silicosis group and the dust-exposed group (P < 0.01). There was a positive correlation between serum GSH-Px level and the silicosis stages (r = 0.507, P < 0.01). Also there was a positive correlation between NF-kappaB level and silicosis stages, age, GSH-Px or NO levels (r = 0.376, 0.243, 0.233, 0.221, P < 0.01)., Conclusion: The imbalance of oxidative and anti-oxidation system and the activation of NF-kappaB are related with the occurrence and development of silicosis. The monitoring of oxidative stress indicators and NF-kappaB is beneficial to the prediction and prognosis assessment of silicosis.

Serum of 79 workers exposed to silica and 25 healthy controls cases were determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). 7 protein peaks were selected and used by artificial neural network (ANN) to establish a diagnostic model. A blinded test showed that accuracy, sensitivity and specificity were 91.35%, 93.69%, and 84.52%, respectively. The diagnostic pattern was also established to distinguish each stage of silica-exposed population. The diagnostic pattern worked excellently with 89.23%, 94.20% and 92.37% of accurate rate for classifying phase 0, phase 0+, and phase I of silicosis, respectively.

The aim of this study was to evaluate the prevalence of autoantibodies in silica-exposed patients with and without silicosis and without any known rheumatic disease. We studied 61 males exposed to silica for a mean time of 12.2 +/- 10.2 years of exposure. A total of 72.1% (44/61) of them presented with pulmonary silicosis. As control group we included 62 healthy males. In all samples we screened for rheumatoid factor (latex agglutination), antinuclear antibodies (indirect immunofluorescence), anti Scl-70 (ELISA) and ANCA (indirect immunofluorescence technique). One patient (1.6%) of the silica group had weakly positive ANA (titer 1:80, centromeric pattern); one (1.6%) had atypical ANCA and seven patients (11.4%) presented positive rheumatoid factor (values range from 8 to 32 UI/ml). One control patient had a positive RF and none of them had positive ANA or ANCA. All patients and controls were negative for anti-Scl-70. The finding of positive RF was higher in the silica-exposed patients (p = 0.032; Fisher). All patients with positive RF had pulmonary silicosis. In the silica-exposed group we could not find a relationship between the presence of RF and age (p = 0.21; Mann-Whitney), smoking habits (p = 0.25; Fisher) but a positive relationship was found with exposure time to silica dust (p = 0.005; Mann-Whitney). We conclude that there was 11.4% prevalence of low titer RF in the silica-exposed patients without known rheumatic disease. RF was more common in patients with longer exposure to silica dust and appeared only in those with silicosis. The presence of ANA, Scl-70 and ANCA was the same as in the control population.

Prolonged exposure to silica dust causes an imbalance in the generation of free radicals and in the antioxidant system, thereby inducing oxidative stress. The antioxidant status of 113 silicosis patients and 116 control subjects without silicosis was examined. Serum superoxide dismutase (SOD) activity and serum levels of malondialdehyde (MDA) and glutathione (GSH) were significantly higher in silicosis patients than in controls. The GSH level in patients with stage I silicosis was higher than that in patients with other stages, but there was no difference in serum MDA level and SOD activity between disease stages. The GSH level of patients who worked with air drills was significantly lower than that of patients in other occupations, whereas the MDA level was significantly elevated in patients who used air drills. Serum SOD activity did not differ significantly according to the occupational group. It is concluded that the measurement of serum SOD, GSH and MDA levels could be beneficial in the clinical evaluation of serum antioxidant status in silicosis patients.