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Redox Biology Aug 2024Silicosis, characterized by interstitial lung inflammation and fibrosis, poses a significant health threat. ATII cells play a crucial role in alveolar epithelial repair...
BACKGROUND
Silicosis, characterized by interstitial lung inflammation and fibrosis, poses a significant health threat. ATII cells play a crucial role in alveolar epithelial repair and structural integrity maintenance. Inhibiting ATII cell senescence has shown promise in silicosis treatment. However, the mechanism behind silica-induced senescence remains elusive.
METHODS
The study employed male C57BL/6 N mice and A549 human alveolar epithelial cells to investigate silicosis and its potential treatment. Silicosis was induced in mice via intratracheal instillation of crystalline silica particles, with honokiol administered intraperitoneally for 14 days. Silica-induced senescence in A549 cells was confirmed, and SIRT3 knockout and overexpression cell lines were generated. Various analyses were conducted, including immunoblotting, qRT-PCR, histology, and transmission electron microscopy. Statistical significance was determined using one-way ANOVA with Tukey's post-hoc test.
RESULTS
This study elucidates how silica induces ATII cell senescence, emphasizing mtDNA damage. Notably, honokiol (HKL) emerges as a promising anti-senescence and anti-fibrosis agent, acting through sirt3. honokiol effectively attenuated senescence in ATII cells, dependent on sirt3 expression, while mitigating mtDNA damage. Sirt3, a class III histone deacetylase, regulates senescence and mitochondrial stress. HKL activates sirt3, protecting against pulmonary fibrosis and mitochondrial damage. Additionally, HKL downregulated cGAS expression in senescent ATII cells induced by silica, suggesting sirt3's role as an upstream regulator of the cGAS/STING signaling pathway. Moreover, honokiol treatment inhibited the activation of the NF-κB signaling pathway, associated with reduced oxidative stress and mtDNA damage. Notably, HKL enhanced the activity of SOD2, crucial for mitochondrial function, through sirt3-mediated deacetylation. Additionally, HKL promoted the deacetylation activity of sirt3, further safeguarding mtDNA integrity.
CONCLUSIONS
This study uncovers a natural compound, HKL, with significant anti-fibrotic properties through activating sirt3, shedding light on silicosis pathogenesis and treatment avenues.
Topics: Animals; Silicosis; Sirtuin 3; Cellular Senescence; Mice; Alveolar Epithelial Cells; Biphenyl Compounds; Humans; Lignans; Signal Transduction; Male; A549 Cells; Nucleotidyltransferases; Disease Models, Animal; Membrane Proteins; Mice, Inbred C57BL; DNA Damage; Allyl Compounds; Phenols
PubMed: 38865904
DOI: 10.1016/j.redox.2024.103224 -
Occupational Medicine (Oxford, England) Jun 2024The current global outbreak of artificial stone silicosis is a recrudescence of a major occupational disease in the context of a novel exposure source. Respirable...
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.
PubMed: 38856490
DOI: 10.1093/occmed/kqae047 -
Trends in Molecular Medicine Jun 2024Crystalline material can cause a multitude of acute and chronic inflammatory diseases, such as gouty arthritis, silicosis, kidney disease, and atherosclerosis. Crystals... (Review)
Review
Crystalline material can cause a multitude of acute and chronic inflammatory diseases, such as gouty arthritis, silicosis, kidney disease, and atherosclerosis. Crystals of various types are thought to cause similar inflammatory responses, including the release of proinflammatory mediators and formation of neutrophil extracellular traps (NETs), processes that further promote necroinflammation and tissue damage. It has become apparent that the intensity of inflammation and the related mechanisms of NET formation and neutrophil death in crystal-associated diseases can vary depending on the crystal type, amount, and site of deposition. This review details new mechanistic insights into crystal biology, highlights the differential effects of various crystals on neutrophils and extracellular trap (ET) formation, and discusses treatment strategies and potential future approaches for crystal-associated disorders.
PubMed: 38853086
DOI: 10.1016/j.molmed.2024.05.010 -
Environmental Pollution (Barking, Essex... Jun 2024Prolonged exposure to free silica leads to the development of silicosis, wherein activated fibroblasts play a pivotal role in its pathogenesis and progression....
Prolonged exposure to free silica leads to the development of silicosis, wherein activated fibroblasts play a pivotal role in its pathogenesis and progression. Fibroblast Activation Protein (FAP), as a biomarker for activated fibroblasts, its expression pattern and role in key aspects of silicosis pathogenesis remain unclear. This study elucidated the expression pattern and function of FAP through population-based epidemiological investigations, establishment of mouse models of silicosis, and in vitro cellular models. Results indicated a significant elevation of FAP in plasma from silicosis patients and lung tissues from mouse models of silicosis. In the cellular model, we observed a sharp increase in FAP expression early in the differentiation process, which remained high expression. Inhibition of FAP suppressed fibroblast differentiation, while overexpression of FAP produced the opposite effect. Moreover, fibroblast-derived FAP can alter the phenotype and function of neighboring macrophages. In summary, we revealed a high expression pattern of FAP in silicosis and its potential mechanistic role in fibrosis, suggesting FAP as a potential therapeutic target for silicosis.
PubMed: 38838811
DOI: 10.1016/j.envpol.2024.124311 -
Journal of Applied Toxicology : JAT Jun 2024Engineered stone-associated silicosis is characterised by a rapid progression of fibrosis linked to a shorter duration of exposure. To date, there is lack of information...
Engineered stone-associated silicosis is characterised by a rapid progression of fibrosis linked to a shorter duration of exposure. To date, there is lack of information about molecular pathways that regulates disease development and the aggressiveness of this form of silicosis. Therefore, we compared transcriptome responses to different engineered stone samples and standard silica. We then identified and further tested a stone dust specific pathway (aryl hydrocarbon receptor [AhR]) in relation to mitigation of adverse lung cell responses. Cells (epithelial cells, A549; macrophages, THP-1) were exposed to two different benchtop stone samples, standard silica and vehicle control, followed by RNA sequencing analysis. Bioinformatics analyses were conducted, and the expression of dysregulated AhR pathway genes resulting from engineered stone exposure was then correlated with cytokine responses. Finally, we inhibited AhR pathway in cells pretreated with AhR antagonist and observed how this impacted cell cytotoxicity and inflammation. Through transcriptome analysis, we identified the AhR pathway genes (CYP1A1, CYP1B1 and TIPARP) that showed differential expression that was unique to engineered stones and common between both cell types. The expression of these genes was positively correlated with interleukin-8 production in A549 and THP-1 cells. However, we only observed a mild effect of AhR pathway inhibition on engineered stone dust induced cytokine responses. Given the dual roles of AhR pathway in physiological and pathological processes, our data showed that expression of AhR target genes could be markers for assessing toxicity of engineered stones; however, AhR pathway might not play a significant pathologic role in engineered stone-associated silicosis.
PubMed: 38837244
DOI: 10.1002/jat.4653 -
Journal of Global Antimicrobial... May 2024India's projected silica-dust-exposed workers will be 52 million at the end of 2025. Elimination of tuberculosis is also targeted in India by 2025. Scientists in India...
India's projected silica-dust-exposed workers will be 52 million at the end of 2025. Elimination of tuberculosis is also targeted in India by 2025. Scientists in India have already pointed out that unless silicosis is controlled, the said elimination is difficult to achieve. This study evidences an increasing incidence of tuberculosis and multidrug resistant tuberculosis (MDR-TB) with five deaths due to treatment failure among the silica dust-exposed workers compared to their unexposed counterparts. It was also observed that both tuberculosis as well as MDR-TB were directly proportional to the dose and/or duration of silica dust exposure. This means the incidence of MDR-TB is lowest in the unexposed group, moderate in the radiologically negative but silica dust exposed group (subradiological silicosis due to moderate exposure), and highest in the radiologically confirmed silicotic workers (maximally exposed group. Since India has a huge burden of silicosis, they are vulnerable to tuberculosis including multidrug-resistant tuberculosis resulting in the emergence of MDR-TB among the silica dust-exposed workers. This will also lead to a silent epidemic of silicotuberculosis in India shortly. Therefore, it would be important to have tools to quickly detect silicosis cases at an early stage to identify a vulnerable population and adopt an effective intervention measure.
PubMed: 38825150
DOI: 10.1016/j.jgar.2024.05.012 -
International Immunopharmacology Jul 2024Silicosis is a chronic fibroproliferative lung disease caused by long-term inhalation of crystalline silica dust, characterized by the proliferation of fibroblasts and...
Silicosis is a chronic fibroproliferative lung disease caused by long-term inhalation of crystalline silica dust, characterized by the proliferation of fibroblasts and pulmonary interstitial fibrosis. Currently, there are no effective treatments available. Recent research suggests that the Integrin β1/ILK/PI3K signaling pathway may be associated with the pathogenesis of silicosis fibrosis. In this study, we investigated the effects of Echistatin (Integrin β1 inhibitor) and BYL-719 (PI3K inhibitor) on silicosis rats at 28 and 56 days after silica exposure. Histopathological analysis of rat lung tissue was performed using H&E staining and Masson staining. Immunohistochemistry, Western blotting, and qRT-PCR were employed to assess the expression of markers associated with epithelial-mesenchymal transition (EMT), fibrosis, and the Integrin β1/ILK/PI3K pathway in lung tissue. The results showed that Echistatin, BYL 719 or their combination up-regulated the expression of E-cadherin and down-regulated the expression of Vimentin and extracellular matrix (ECM) components, including type I and type III collagen. The increase of Snail, AKT and β-catenin in the downstream Integrin β1/ILK/PI3K pathway was inhibited. These results indicate that Echistatin and BYL 719 can inhibit EMT and pulmonary fibrosis by blocking different stages of Integrinβ1 /ILK/PI3K signaling pathway. This indicates that the Integrin β1/ILK/PI3K signaling pathway is associated with silica-induced EMT and may serve as a potential therapeutic target for silicosis.
Topics: Animals; Epithelial-Mesenchymal Transition; Signal Transduction; Integrin beta1; Pulmonary Fibrosis; Male; Silicon Dioxide; Silicosis; Phosphatidylinositol 3-Kinases; Protein Serine-Threonine Kinases; Rats; Lung; Rats, Sprague-Dawley
PubMed: 38823175
DOI: 10.1016/j.intimp.2024.112368 -
BMC Public Health May 2024Pneumoconiosis, a chronic disease stemming from prolonged inhalation of dust particles, stands as a significant global burden of occupational diseases. This study aims...
BACKGROUND
Pneumoconiosis, a chronic disease stemming from prolonged inhalation of dust particles, stands as a significant global burden of occupational diseases. This study aims to investigate the survival outcomes of pneumoconiosis patients in Huangshi city, China, while also evaluating the disease burden on afflicted patients.
METHODS
Data for this study were sourced from the Huangshi Center for Disease Control and Prevention. Survival analyses of pneumoconiosis patients were conducted employing life tables and the Kaplan-Meier method. The Cox proportional hazards models were deployed to identify factors influencing pneumoconiosis patients' survival duration. Competing risks models were employed to confirm the validity of the model outcomes. Additionally, in the disease burden assessment, disability-adjusted life years (DALYs) were computed for various demographic groups and time frames.
RESULTS
A total of 5,641 pneumoconiosis cases, diagnosed in Huangshi City, Hubei Province between 1958 and 2021, were incorporated into the cohort analysis. The probability of mortality and the risk ratio increased with advancing age. Notably, the median survival time of stage III pneumoconiosis patients was significantly shorter compared with those in stages I and II. The Cox proportional hazards model and competing risks analyses underscored several significant factors influencing survival time, including dust exposure duration (HR = 1.197, 95% CI: 1.104-1.298), age at first diagnosis (HR = 3.149, 95% CI: 2.961-3.349), presence of silicosis (HR = 1.378, 95% CI: 1.254-1.515), and stage II-III pneumoconiosis (HR = 1.456, 95% CI: 1.148-1.848). Cumulatively, DALYs amounted to 7,974.35 person-years, with an average of 1.41 person-years. The period between 2000 and 2019 witnessed the highest disease burden.
CONCLUSION
Our findings highlight the urgent need for improved prevention, earlier detection, and more effective management strategies for the occupational pneumoconiosis population. This study not only underscores the persistent issue of pneumoconiosis in industrial environments but also serves as a crucial call to action for policymakers and healthcare providers.
Topics: Humans; China; Male; Middle Aged; Pneumoconiosis; Retrospective Studies; Female; Aged; Occupational Diseases; Adult; Cost of Illness; Survival Analysis; Disability-Adjusted Life Years; Proportional Hazards Models; Occupational Exposure
PubMed: 38811934
DOI: 10.1186/s12889-024-18847-6 -
Archives of Toxicology May 2024Assessing the association between candidate single-nucleotide polymorphisms (SNPs) identified by multi-omics approaches and susceptibility to silicosis. RNA-seq analysis...
Assessing the association between candidate single-nucleotide polymorphisms (SNPs) identified by multi-omics approaches and susceptibility to silicosis. RNA-seq analysis was performed to screen the differentially expressed mRNAs in the fibrotic lung tissues of mice exposed to silica particles. Following this, we integrated the SNPs located in the above human homologenes with the silicosis-related genome-wide association study (GWAS) data to select the candidate SNPs. Then, expression quantitative trait locus (eQTL)-SNPs were identified by the GTEx database. Next, we validated the associations between the functional eQTL-SNPs and silicosis susceptibility by additional case-control study. And the contribution of the identified SNP and its host gene in the fibrosis process was further validated by functional experiments. A total of 12 eQTL-SNPs were identified in the screening stage. The results of the validation stage suggested that the variant T allele of rs419540 located in IL12RB1 significantly increased the risk of developing silicosis [additive model: odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.11-2.85, P = 0.017]. Furthermore, the combination of GWAS and the results of validation stage also indicated that the variant T allele of rs419540 in IL12RB1 was associated with increased silicosis risk (additive model: OR = 2.07, 95% CI 1.38-3.12, P < 0.001). Additionally, after knockdown or overexpression of IL12RB1, the levels of pro-inflammatory factors, such as IL-12, IFN-γ, and other pro-inflammatory factors, were correspondingly decreased or increased. The novel eQTL-SNP, rs419540, might increase the risk of silicosis by modulating the expression levels of IL12RB1.
PubMed: 38811393
DOI: 10.1007/s00204-024-03795-2 -
Cureus Apr 2024Primary biliary cholangitis (PBC) is common in females during middle age, presenting with fatigue and itching. In our case, an African-American male patient presented...
Primary biliary cholangitis (PBC) is common in females during middle age, presenting with fatigue and itching. In our case, an African-American male patient presented with abdominal pain, vomiting, fatigue, and lung manifestations such as interstitial lung disease, granulomatous lung disease, and pulmonary hypertension. In our case, the patient reported abdominal pain and fatigue with abnormal chest X-ray findings (bilateral pulmonic nodular lesion with calcifications), which mimicked silicosis/sarcoidosis lung findings such as bronchiectasis and parenchymal nodules. We diagnosed PBC as there was an absence of extrahepatic biliary obstruction and the presence of antimitochondrial antibodies (AMA) at a titer of 1:40 or higher. Bronchoalveolar lavage was performed due to the suspicion of interstitial lung disease and sarcoidosis, which was inconclusive but revealed enterococcus faecalis organisms. Initial antibiotic response heightens suspicion of infection, not colonization, leading to the diagnosis of enterococcal pneumonia. In our case, the diagnosis was made using clinical and laboratory criteria, and treatment with Ursodeoxycholic acid was opted for without resorting to more expensive and invasive tests like magnetic resonance cholangiopancreatography (MRCP) and endoscopic retrograde cholangiopancreatography (ERCP). In summary, this case report presented the unique diagnostic challenges that will aid clinicians in considering a broad range of differential diagnoses and management plans.
PubMed: 38803766
DOI: 10.7759/cureus.59160