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

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

Silicosis initially presenting with empyema.

The current global outbreak of artificial stone silicosis is a recrudescence of a major occupational disease in the context of a novel exposure source. Respirable crystalline silica exposure, even without frank pneumoconiosis, is associated with an increased risk of respiratory infection. Empyema is a well-recognized complication of bacterial pneumonia; pneumonia among working-age adults, in turn, has been epidemiologically linked to occupational exposure to fumes and dust, including silica. A connection between empyema and silica dust inhalation has not been reported, however, whether through antecedent pneumonia or another mechanism. We describe a case of silicosis initially presenting with empyema in a 31-year-old Computerized Numerical Control stone-cutting machine operator who had heavy exposure to artificial stone and other rock dust.

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

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

[Diffuse interstitial lung disease of possible occupational origin treated at the Navarra Health Service. Navarra, Spain, 2017-2022]. / Enfermedad pulmonar intersticial difusa de posible origen laboral atendida en el Servicio Navarro de Salud. Navarra, España, 2017-2022.

INTRODUCTION: Diffuse interstitial lung disease (ILD) describes a broad group of pulmonary inflammatory and fibrosis disorders. Asbestosis and silicosis are the main causes linked to occupational exposure. The aim of this study was to estimate the proportion of cases with possible occupational origin and describe their exposure, clinical, and occupational status. METHOD: We conducted a retrospective longitudinal study of ILD cases between 2017 - 2022 at the University Hospital of Navarra was conducted. Information was supplemented with interviews of cases with possible occupational origin. The occupational proportion was calculated, labor and clinical characteristics analyzed, by statistical comparison of percentages and means. RESULTS: Out of 1067 ILD cases, 56 had a possible occupational origin 5,2% (95% CI 3,9-6,6%). 36 (64,3%) corresponded to asbestosis, 15 (26,8%) to silicosis, and 5 (8,9%) to unspecified pneumoconiosis. The most frequent activities in silicosis were "stone cutting-carving" and in asbestosis "manufacture of iron products". The average age of asbestosis cases was higher than that of silicosis cases (78,2 vs. 67,3 years), as well as their clinical manifestation. Five cases (8,9%) had been recognized as occupational diseases. CONCLUSIONS: The implementation of a computer tool in medical records has made it possible to estimate the magnitude and assess the evolution of occupational ILD treated in the Public Health Service. Economic activities reflect the economic risk structure of the region. However, there is a lack of recognition of these diseases as occupational illnesses and they represent a preventable burden of respiratory disease.

Introducción: La enfermedad pulmonar intersticial difusa (EPID) describe un amplio grupo de trastornos con inflamación y fibrosis pulmonar. La asbestosis y la silicosis son las principales causas por exposición laboral. El objetivo de este trabajo fue estimar la proporción de casos de posible origen laboral y describir la exposición, situación clínica y laboral.  Método: Estudio longitudinal retrospectivo de los casos de EPID, en el período 2017-2022 en el Hospital Universitario de Navarra. Se completó la información con entrevista a los casos de posible origen laboral.  Resultados: De un total de 1067 casos de EPID, 56 tuvieron un posible origen laboral, 5,2% (3,9-6,6 IC 95%) 36 (64,3%) correspondieron a asbestosis, 15 (26,8%) a silicosis y 5 (8,9%) a neumoconiosis no especificada. Las actividades más frecuentes en silicosis fueron "corte-tallado de piedra" y para asbestosis "fabricación productos hierro". La media de edad de los casos de asbestosis fue superior a los de silicosis (78,2 vs. 67,3 años), así como su afectación clínica. Cinco casos (8,9%) habían sido reconocidos como enfermedad profesional  Conclusiones: La implementación de una herramienta informática en historia clínica ha hecho posible estimar la magnitud y valorar la evolución de las EPID laborales atendidas en el servicio nacional de salud. Las actividades económicas reflejan la estructura económica de riesgo de la región. Sin embargo, existe una falta de su reconocimiento como enfermedad profesional y suponen una carga de enfermedad respiratoria evitable.

FOXF1 reverses lung fibroblasts transdifferentiation via inhibiting TGF-ß/SMAD2/3 pathway in silica-induced pulmonary fibrosis.

Silicosis is one of the most common and severe types of pneumoconiosis and is characterized by lung dysfunction, persistent lung inflammation, pulmonary nodule formation, and irreversible pulmonary fibrosis. The transdifferentiation of fibroblasts into myofibroblasts is one of the main reasons for the exacerbation of silicosis. However, the underlying mechanism of transcription factors regulating silicosis fibrosis has not been clarified. The aim of this study was to investigate the potential mechanism of transcription factor FOXF1 in fibroblast transdifferentiation in silica-induced pulmonary fibrosis. Therefore, a silicosis mouse model was established, and we found that FOXF1 expression level was significantly down-regulated in the silicosis group, and after overexpression of FOXF1 by adeno-associated virus (AAV), FOXF1 expression level was up-regulated, and silicosis fibrosis was alleviated. In order to further explore the specific regulatory mechanism of FOXF1 in silicosis, we established a fibroblasts transdifferentiation model induced by TGF-ß in vitro. In the model, the expression levels of SMAD2/3 and P-SMAD2/3 were up-regulated, but the expression levels of SMAD2/3 and P-SMAD2/3 were down-regulated, inhibiting transdifferentiation and accumulation of extracellular matrix after the overexpressed FOXF1 plasmid was constructed. However, after silencing FOXF1, the expression levels of SMAD2/3 and P-SMAD2/3 were further up-regulated, aggravating transdifferentiation and accumulation of extracellular matrix. These results indicate that the activation of FOXF1 in fibroblasts can slow down the progression of silicosis fibrosis by inhibiting TGF-ß/SMAD2/3 classical pathway, which provides a new idea for further exploration of silicosis treatment.

[Clinical characteristics and follow-up analysis of 63 cases of silicosis complicated with cavity-pulmonary tuberculosis].

Objective: To investigate the clinical characteristics and prognosis of silicosis complicated with cavity-pulmonary tuberculosis. Methods: The clinical data of 63 patients with silicosis complicated with cavity-pulmonary tuberculosis (group A) and silicosis patients (group B) admitted to Yantaishan Hospital from July 2018 to July 2022 were collected and analyzed. Results: Patients in group A were all male, and the common symptoms were cough, expectoration, chest tightness, shortness of breath, and hemoptysis. CT cavity lesions involving the lung, often occurs in the lung after the tip section, after the back section and basal segment, thick-walled cavity, may be accompanied by satellite lesions, endobronchial spread focal, pneumothorax, pleural effusion, etc. 1225 cases of group B patients haemoptysis of 59 patients, cavity in 3 patients, haemoptysis and/or cavity rate was lower than that in group A, the difference was statistically significant (P<0.05) . In group A, CT reexamination 6-24 months after anti-tuberculosis treatment showed that 52 cases (82.5%) had cavity reduction/healing, 8 cases (12.7%) had recurrence, and 3 cases (4.8%) had damaged lung (2 died) . Conclusion: Silicosis patients with hemoptysis and/or CT in cavity should be more vigilant about combined tuberculosis, anti-tuberculosis treatment and/or dynamic CT follow-up helps laboratory diagnosis negative patients.

[5 cases of silicosis complicated with connective tissue diseases].

Long-term inhalation of silica dust can cause silicosis, but also may induce autoimmune diseases, such as systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, anti-histidyl tRNA synthetase antibody (JO-1 antibody) syndrome. These two diseases can be isolated or combined. In this paper, the clinical characteristics of 5 cases of silicosis complicated with connective tissue diseases were analyzed and summarized to strengthen the clinical understanding of silicosis complicated with connective tissue diseases, so as to reduce its misdiagnosis and missed diagnosis, and provide reference for clinicians in diagnosis and treatment.

[A case of silicosis complicated with non-tuberculous mycobacterium pulmonary disease].

Non-tuberculosis mycobacterium (NTM) refers to a general term for a large group of mycobacteria, excluding the mycobacterium tuberculosis and mycobacterium leprae, which is an opportunistic pathogen. NTM pulmonary disease and pulmonary tuberculosis have very similar clinical and imaging manifestations. Ordinary sputum tests can not distinguish between mycobacterium tuberculosis and NTM accurately, and it needs to be differentiated through detection methods such as mycobacterium culture medium, high-performance liquid chromatography, and molecular biology. During the diagnosis of occupational pneumoconiosis, a sandblasting and polishing worker's lung CT showed dynamic changes in infiltrating shadows and cavities in the right lung. A sputum drug sensitivity test showed NTM infection, but the patient refused treatment. After 20 months, the CT examination of the lung showed further enlargement of infiltrating shadows and cavities, and NTM bacterial identification showed intracellular mycobacterial infection. Amikacin, moxifloxacin, azithromycin, and ethambutol combined antibacterial treatment were given. Currently, the patient is still under treatment.

Clinical characteristics of systemic sclerosis patients with occupational silicosis.

To explore the clinical characteristics of systemic sclerosis complicated with silicosis. The systemic sclerosis patients treated in the Guangxi Workers' Hospital and the People's Hospital of Guangxi Zhuang Autonomous Region from January 2000 to December 2020 were divided into the systemic sclerosis with silicosis group and the systemic sclerosis without silicosis group. Survival analysis was performed using Kaplan-Meier estimates the Cox proportional hazards model. A propensity score matching was applied in order to avoid the selection bias.Over the past 20 years, 72 systemic sclerosis patients with silicosis and 238 systemic sclerosis patients without silicosis were treated in the two hospitals. The systemic sclerosis patients with silicosis group had more males (P < 0.000),lower mean age at onset of SSc (P < 0.000), more frequent occurrence of weight loss (P = 0.028), smoking (P < 0.000), tuberculosis (P < 0.000), cardiac involvement (P < 0.000), ILD (P = 0.017), pulmonary hypertension (P = 0.024), elevated BNP (P < 0.000). With regards to the multivariate Cox regression analysis, silicosis was related with a higher overall mortality before (HR = 3.666, 95% CI = 1.440-11.234, p = 0.025) and after the propensity score matching analysis (HR = 2.817, 95% CI = 1.196-10.764, p = 0.014). Independent risk factors for overall mortality were Gangrene (HR = 3.003, 95% CI = 1.343-9.431), Cardiac involved (HR = 5.370, 95% CI = 1.910-15.472), Scl-70 (HR = 3.569, 95% CI = 1.333-10.869), Elevated BNP (HR = 2.135, 95% CI = 1.293-9.564).Concomitant silicosis worsens systemic sclerosis patients' prognoses. Gangrene, Scl-70, elevated BNP and cardiac involvement are independent risk factors for overall mortality. Key Points •Concomitant silicosis worsens SSc patients' prognoses. •For individuals with occupational exposure, close observation of the symptoms of SSc, early diagnosis, and interruption of exposure may improve the prognosis. •Gangrene, Scl-70, elevated BNP and cardiac involvement are independent risk factors for overall mortality.

Exploring the Impact of Silicosis Incidence on Tuberculosis Mortality and Morbidity: A Multi-Country Study.

INTRODUCTION: There are several risk factors attributed to tuberculosis (TB) mortality and morbidity. There are few studies and systematic reviews showing the association of silicosis and tuberculosis at a country level. Very limited studies have been conducted using multi-country data in studying the association of incidence of silicosis with TB mortality and morbidity. Hence, the aim of this research was to explore the association of incidence of silicosis and other important risk factors with TB mortality and morbidity using multi-country data. METHODS: Data from 217 WHO region countries were utilized, sourcing TB-related statistics from the Institute of Health Metrics and Evaluation and additional risk factors from the Demographic and Health Survey, Global Burden of Disease, and World Bank for 2019. Regression analysis was conducted to examine the association between silicosis incidence and TB outcomes. RESULTS: The study found an average silicosis incidence of 121.92 per 100,000 population. Additionally, 62.69% of the sample population are exposed to air pollution from solid fuel cooking. Sanitation access stands at an average of 59.67%. Regression outcomes indicate that while alcohol consumption's influence on TB is not statistically significant, a unit increase in silicosis incidence significantly elevates TB deaths (235.9, p = 0.005), YLL (9399.3, p = 0.011), and YLD (910.8, p = 0.002). CONCLUSION: The burden of silicosis is found to be one of the important determinants of deaths, YLL, and YLD due to tuberculosis. Country-specific strategies to prevent and control silicosis is a need of the hour.

Association of family sequence similarity gene 13A gene polymorphism and interstitial lung disease susceptibility: A systematic review and meta-analysis.

BACKGROUND: Among present reports, the T/G allelic variation at the rs2609255 locus of the family sequence similarity gene 13A (FAM13A) was considerable associated with susceptibility to interstitial lung diseases (ILDs). In this study, we summarized relevant studies and applied a meta-analysis to explore whether the polymorphism of rs2609255 site of the FAM13A gene can be utilized to predict susceptibility to idiopathic pulmonary fibrosis (IPF) patients or rheumatoid arthritis-associated interstitial lung disease (RA-ILD) or silicosis patients in different populations for the first time. METHODS: We compared the frequency of G allele on rs2609255 site of FAM13A between the control subjects and IPF or RA-ILD or silicosis patients from different races by using meta-analysis. Nine studies were involved in this meta-analysis, including five IPF studies, two RA-ILD studies, and two silicosis studies, and containing 14 subgroups. We conducted separate meta-analyses for different races. RESULTS: In all individuals, a substantial link between the G allele of the FAM13A rs2609255 polymorphism and IPF (OR: 1.47, 95% CI: 1.33-1.63, p < 0.00001) was indicated. After dividing by ethnicity, the G allele was illustrated to be considerable correlation with IPF in Asian (OR: 2.63, 95% CI: 1.81-3.81, p < 0.00001) and with RA-ILD individuals (OR: 3.27, 95% CI: 1.26-8.49, p = 0.01). Conversely, there was no correlation with the G allele and IPF in European individuals (OR: 1.27, 95% CI: 0.89-1.83, p = 0.13) or silicosis in Chinese individuals (OR: 1.20, 95% CI: 0.99-1.46, p = 0.07). CONCLUSION: This is the first meta-analysis that provides evidence that the rs2609255 of FAM13A might increase susceptibility to RA-ILD, and IPF especially in Asian but not in European individuals, and not be correlated with silicosis in Chinese individuals, which indicated the differences in susceptibility to disease by race were noteworthy.

[Evaluation of right ventricular function using two-dimensional speckle tracking echocardiography and analysis of the risk factors for right ventricular dysfunction in patients with silicosis].

Objective: To evaluate the right ventricular function using two-dimensional speckle tracking echocardiography (2-D STE) and analyze the associated risk factors of right ventricular dysfunction in patients with silicosis. Methods: All 104 patients with silicosis treated in the Department of Occupational Medicine and Toxicology in Beijing Chao-Yang Hospital, Capital Medical University from May 2021 to September 2022 were enrolled in this study in October 2022. The clinical information of patients such as general data, arterial blood gas analysis and pulmonary function test were collected. The right ventricular function of patients was evaluated by 2-D STE-derived right ventricular free wall longitudinal strain (RVFWLS) and conventional echocardiographic-derived parameters, including right ventricular fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE) and doppler tissue imaging-derived tricuspid lateral annular systolic velocity (S'), respectively. Based on their RVFWLS, the patients were divided into right ventricular dysfunction group and normal right ventricular function group. Risk factors for right ventricular dysfunction in patients with silicosis were analyzed using binary logistic regression analysis. Results: A total of 104 silicosis patients were enrolled, with aneverage age (65.52±11.18) years old, among whom including 57 cases diagnosed with stage Ⅰ/Ⅱ silicosis and 47 cases diagnosed with stage Ⅲ silicosis. 26 (25.00%) patients concurrent right ventricular dysfunction. The abnormal rates of RVFAC, TAPSE and S' in patients were 16.35% (17 cases), 21.15% (22 cases) and 6.73% (7 cases), respectively. The RVFAC and TAPSE in right ventricular dysfunction group were lower than those in normal right ventricular function group, and the incidence of pulmonary arterial systolic pressure ≥36 mmHg was higher than that in normal right ventricular function group (P<0.05). Logistic regression analysis showed that arterial partial pressure of oxygen (OR=0.932, 95%CI: 0.885-0.981, P=0.007) was the protective factor, and the forced expiratory volume in 1 second (FEV(1)) /forced vital capacity (FVC) ratio<70% (OR=5.484, 95%CI: 1.049-28.662, P=0.044) and stage Ⅲ silicosis (OR=6.343, 95%CI: 1.698-23.697, P=0.007) were the risk factors for silicosis patients concurrent right ventricular dysfunction. Conclusion: The incidence of right ventricular dysfunction is higher in patients with stage Ⅲ silicosis than that in patients with stage Ⅰ/Ⅱ silicosis. Using 2-D STE can help the early detection of silicosis with right ventricular dysfunction. Hypoxemia, airflow limitation and the stage Ⅲ silicosis are the risk factors for silicosis patients concurrent right ventricular dysfunction.

[Silicosis]. / Silicose.

BACKGROUND: Silicosis is a potentially severe but preventable occupational lung disease caused by inhalation of silica particles. There is a wide application in the usage of silica especially in lesser known industries. This disease has yet not been eradicated due to insufficient application of protective measures. CASE DESCRIPTION: A 57-year-old patient presents to the pulmonary outpatient clinic with progressive dyspnea d'effort. The professional history states that he worked as a sandblaster 10 years ago. The accompanying protective measures were not properly followed by the patient at the time. The CT chest showed a nodular interstitial lung disease and silica particles were detected in the bronchial lavage conforming the diagnosis of silicosis. CONCLUSION: Early detection of silicosis is essential to prevent further lung damage and silicosis associated complications. The occupational history and radiological diagnostics are essential to confirm the diagnosis. There is no specific treatment for silicosis. Therefore prevention is better than cure.

Silicosis as an unusual cause of symptomatic cervical adenopathy.

A case of symptomatic cervical adenopathy is reported as a presentation of silicosis. Silicosis is one of the most important occupational health diseases worldwide caused by the inhalation of airborne silica particles. The presence of thoracic adenopathies is a common clinical feature of silicosis, cervical silicotic adenopathies on the other hand are rare and unknown to most clinicians and can therefore lead to a differential diagnostic problem. Awareness of the clinical, radiological, and histological features is key for the diagnosis.

[Analysis of serum CA125 and related influencing factors in silicosis patients with pulmonary heart disease].

Objective: To analyze the serum carbohydrate antigen 125 (CA125) level and its influencing factors in male silicosis patients with pulmonary heart disease. Methods: In October 2021, data of 38 male patients with simple silicosis (silicosis group), 28 cases of silicosis with pulmonary heart disease (pulmonary heart disease group), and 27 healthy controls (control group) in the same age group were collected in inpatient and outpatient of Nanjing Occupational Disease Prevention and Control Hospital from January 2017 to December 2020. The serum CA125 levels of the three groups were compared, and the correlation between disease-related indexes and serum CA125 in silicosis patients with pulmonary heart disease was analyzed, as well as the influencing factors of pulmonary heart disease and serum CA125 levels in silicosis patients. Results: The serum CA125 level[ (19.95±7.52) IU/ml] in pulmonary heart disease group was higher than that in silicosis group[ (12.98±6.35) IU/ml] and control group[ (9.17±5.32) IU/ml] (P<0.05). There was no significant difference in serum CA125 level between the silicosis group and the control group (P>0.05). Serum CA125 levels were positively correlated with blood uric acid and fasting blood glucose in silicosis patients with pulmonary heart disease (r=0.39, 0.46, P<0.05). Serum CA125 level was a risk factor for silicosis patients with pulmonary heart disease (OR=1.13, 95%CI: 1.02-1.24, P<0.05). Dust exposure time, lactate dehydrogenase and smoking history were positively correlated with serum CA125 level in silicosis patients (P<0.05) . Conclusion: The serum CA125 level of male silicosis patients with pulmonary heart disease is significantly increased, and the level of CA125 is correlated with the level of fasting blood glucose and blood uric acid.