RÉSUMÉ
Epithelial-mesenchymal transition (EMT) plays an irreplaceable role in the development of silicosis. However, molecular mechanisms of EMT induced by silica exposure still remain to be addressed. Herein, metabolic profiles of human alveolar type II epithelial cells (A549 cells) exposed directly to silica were characterized using non-targeted metabolomic approaches. A total of 84 differential metabolites (DMs) were identified in silica-treated A549 cells undergoing EMT, which were mainly enriched in metabolisms of amino acids (e.g., glutamate, alanine, aspartate), purine metabolism, glycolysis, etc. The number of DMs identified in the A549 cells obviously increased with the elevated exposure concentration of silica. Remarkably, glutamine catabolism was significantly promoted in the silica-treated A549 cells, and the levels of related metabolites (e.g., succinate) and enzymes (e.g., α-ketoglutarate (α-KG) dehydrogenase) were substantially up-regulated, with a preference to α-KG pathway. Supplementation of glutamine into the cell culture could substantially enhance the expression levels of both EMT-related markers and Snail (zinc finger transcription factor). Our results suggest that the EMT of human alveolar epithelial cells directly induced by silica can be essential to the development of silicosis.
Sujet(s)
Pneumocytes , Transition épithélio-mésenchymateuse , Silice , Humains , Transition épithélio-mésenchymateuse/effets des médicaments et des substances chimiques , Silice/toxicité , Pneumocytes/métabolisme , Pneumocytes/effets des médicaments et des substances chimiques , Cellules A549 , Silicose/métabolisme , Métabolome/effets des médicaments et des substances chimiquesRÉSUMÉ
Occupational crystalline silica (CS) particle exposure leads to silicosis. The burden of CS-associated disease remains high, and treatment options are limited due to vague mechanisms. Here we show that pulmonary CD4+ tissue-resident memory T cells (TRM) accumulate in response to CS particles, mediating the pathogenesis of silicosis. The TRM cells are derived from peripheral lymphocyte recruitment and in situ expansion. Specifically, CD69+CD103+ TRM-Tregs depend more on circulating T cell replenishment. CD69 and CD103 can divide the TRM cells into functionally distinct subsets, mirroring the immuno-balance within CD4+ TRM cells. However, targeting CD103+ TRM-Tregs do not mitigate disease phenotype since the TRM subsets exert immunosuppressive but not pro-fibrotic roles. After identifying pathogenic CD69+CD103- subsets, we highlight IL-7 for their maintenance and function, that present a promising avenue for mitigating silicosis. Together, our findings highlight the distinct role of CD4+ TRM cells in mediating CS-induced fibrosis and provide potential therapeutic strategies.
Sujet(s)
Lymphocytes T CD4+ , Cellules T mémoire , Silice , Silicose , Silicose/immunologie , Silicose/anatomopathologie , Silice/toxicité , Animaux , Cellules T mémoire/immunologie , Souris , Lymphocytes T CD4+/immunologie , Évolution de la maladie , Souris de lignée C57BL , Mâle , Poumon/immunologie , Poumon/anatomopathologie , Mémoire immunologiqueRÉSUMÉ
AIMS: Silicosis is the most common and severe type of pneumoconiosis, imposing a substantial disease burden and economic loss on patients and society. The pathogenesis and key targets of silicosis are not yet clear, and there are currently no effective treatments available. Therefore, we conducted research on mefunidone (MFD), a novel antifibrotic drug, to explore its efficacy and mechanism of action in murine silicosis. METHODS: Acute 7-day and chronic 28-day silicosis models were constructed in C57BL/6J mice by the intratracheal instillation of silica and subsequently treated with MFD to assess its therapeutic potential. The effects of MFD on silica-induced inflammation, pyroptosis, and fibrosis were further investigated using immortalized mouse bone marrow-derived macrophages (iBMDMs). RESULTS: In the 7-day silica-exposed mouse models, MFD treatment significantly alleviated pulmonary inflammation and notably reduced macrophage infiltration into the lung tissue. RNA-sequencing analysis of silica-induced iBMDMs followed by gene set enrichment analysis revealed that MFD profoundly influenced cytokine-cytokine receptor interactions, chemokine signaling, and the toll-like receptor signaling pathways. MFD treatment also markedly reduced the secretion of inflammatory cytokines and chemokines from silica-exposed iBMDMs. Moreover, MFD effectively downregulated the activation of the TLR4-NF-κB/MAPK signaling pathway induced by silica and mitigated the upregulation of pyroptosis markers. Additionally, MFD treatment significantly suppressed the activation of fibroblasts and alveolar epithelial cells co-cultured with silica-exposed mouse macrophages. Ultimately, in the 28-day silica-exposed mouse models, MFD administration led to a substantial reduction in the severity of pulmonary fibrosis. CONCLUSION: MFD mitigates silica-induced pulmonary inflammation and fibrosis in mice by suppressing the TLR4-NF-κB/MAPK signaling pathway and reducing pyroptotic responses in macrophages. MFD could potentially emerge as a novel therapeutic agent for the treatment of silicosis.
Sujet(s)
Macrophages , Souris de lignée C57BL , Facteur de transcription NF-kappa B , Pyroptose , Silice , Silicose , Récepteur de type Toll-4 , Animaux , Récepteur de type Toll-4/métabolisme , Silice/toxicité , Pyroptose/effets des médicaments et des substances chimiques , Facteur de transcription NF-kappa B/métabolisme , Souris , Macrophages/effets des médicaments et des substances chimiques , Macrophages/métabolisme , Silicose/traitement médicamenteux , Silicose/anatomopathologie , Silicose/métabolisme , Mâle , Transduction du signal/effets des médicaments et des substances chimiques , Inflammation/traitement médicamenteux , Inflammation/anatomopathologie , Inflammation/métabolisme , Pyridones/pharmacologie , Fibrose pulmonaire/induit chimiquement , Fibrose pulmonaire/traitement médicamenteux , Fibrose pulmonaire/anatomopathologie , Fibrose pulmonaire/métabolisme , Modèles animaux de maladie humaine , Système de signalisation des MAP kinases/effets des médicaments et des substances chimiquesRÉSUMÉ
Objective: To understand the health-related quality of life for patients of pneumoconiosis combined with tuberculosis and its main influencing factors. Methods: This was a cross-sectional study, and 951 patients of pneumoconiosis combined with tuberculosis from the pneumoconiosis survey in 27 provinces and autonomous regions in China from December 2017 to December 2021 were selected for the study. The nonparametric Mann-Whitney test and the Kruskal-Wallis H test were used to compare the health utility values, and multiple linear regression was used for multifactor analysis. AMOS 24.0 was used to establish a structural equation modeling. Results: The mean age of 951 patients of pneumoconiosis combined with tuberculosis was (59.3±12.4) years. The main types were silicosis combined with tuberculosis (62.2%, 591/951) and coal-worker's pneumoconiosis combined with tuberculosis (34.9%, 332/951), and other type pneumoconiosis-combined tuberculosis was 2.9% (28/951). The proportion of patients with stage â , â ¡, â ¢, and unstaged clinical diagnosis was 27.4% (261/951), 26.6% (253/951), 32.5% (309/951) and 13.5% (128/951), respectively. 63.3% (602/951) of study participants suffered from other chronic diseases, and the percentage of patients combined the number of chronic diseases with 1, 2, and more than 3 respectively were 24.1% (229/951), 16.3% (155/951) and 22.9% (218/951). The median and quartiles of health utility values and the mean±standard deviation of self-rating scores of patients of pneumoconiosis combined with tuberculosis were 0.562 (0.482, 0.766) and (53.7±18.4), respectively, which were lower than patients of pneumoconiosis without tuberculosis (Z=-11.29, P<0.001; t=8.97, P<0.01). The health utility values and self-rating scores for patients of pneumoconiosis combined with tuberculosis were significantly different between urban and rural areas (Z= -2.22, P=0.027; t=4.85, P<0.01). Pain/discomfort was the most frequently reported problem in the five-dimensional distribution of problems, followed by daily activities and anxiety/depression, and the difference in the percentage reported by anxiety/depression between urban and rural areas was significant (χ(2)=30.28, P<0.01). The results of multiple linear regression showed that the survey area, body mass index, education level, age, employment status, annual personal income, stage of pneumoconiosis, number of multi-morbidities, hemoptysis, acute exacerbation of symptoms in two-week, social support and minimum living standard were the main influences on the health utility values of the patients of pneumoconiosis combined with tuberculosis (P<0.05). The results of structural equation model showed that economic security and health status directly affected the health-related quality of life among patients of pneumoconiosis combined with tuberculosis and played a chain-mediating effect in the influence of socioeconomic status on the health-related quality of life among patients of pneumoconiosis combined with tuberculosis. Conclusion: Health-related quality of life was poorer in patients of pneumoconiosis with tuberculosis, with pain and discomfort and anxiety/depression problems being more pronounced, and economic status and health status played multiple mediating roles in the influence of general socio-demographic characteristics on quality of life in pneumoconiosis.
Sujet(s)
Pneumoconiose , Qualité de vie , Humains , Adulte d'âge moyen , Mâle , Pneumoconiose/épidémiologie , Chine/épidémiologie , Femelle , Silicose/épidémiologie , Enquêtes et questionnaires , Sujet âgé , Tuberculose/épidémiologieRÉSUMÉ
Objective: To understand the utilization and characteristics of outpatient services for pneumoconiosis patients within two weeks in Chongqing, and analyze the influencing factors, so as to provide reference for relevant policy making. Methods: From October 2020 to October 2022, 1771 pneumoconiosis patients who met the inclusion criteria were selected by multi-stage stratified random cluster sampling. A questionnaire survey was conducted on their basic situation, utilization of outpatient services within two weeks, treatment for pneumoconiosis-related symptoms, and selection of medical service institutions using χ(2)-test and logistic regression analysis. Results: All the 1771 pneumoconiosis patients were male, with the average age of (56.1±10.19) years old. In the pneumoconiosis patients were treated in outpatient department within 2 weeks.40.0% (204/510) of aged 41~50 years Rural patients accounted for 87.8% (448/510) ; 65.1% (332/510) of silicosis patients, 37.5% (191/510) of stage II patients, 75.1% (383/510) of patients did not continue to engage in dust work after diagnosis of pneumoconiosis, and 57.1% (291/510) of patients never had work-related injury insurance at work. The outpatient rate within two weeks of pneumoconiosis related assistance and subsistence allowance was 17.6% (90/510) and 12.5% (64/510), respectively. The average self-health score of the patients was (52.9±16.2). 28.2% of the patients had purchased work-related injury insurance; Among the 1204 patients who received the treatment within two weeks, 42.2% were in the outpatient department, 20.7% were in the inpatient department, and 36.9% were self-buyers. There was a significant difference between the different treatment methods of the patients (χ(2)=27.53, P<0.05). There was a significant difference in patients from different residence choosing to visit different medical institutions (χ(2)=13.97, P<0.05). The stage of pneumoconiosis, presence of complications, presence of work injury insurance, self-health score, and whether he/she has been hospitalized in the past year are the important factors affecting the outpatient treatment of pneumoconiosis patients. Conclusion: The utilization of outpatient service of pneumoconiosis patients is influenced by demographic sociology, social support and disease characteristics. The quality of occupational disease medical service in primary health institutions should be strengthened so that pneumoconiosis patients can get convenient and effective treatment. Establish a more perfect social security support system to reduce the disease burden of pneumoconiosis patients.
Sujet(s)
Soins ambulatoires , Patients en consultation externe , Pneumoconiose , Humains , Adulte d'âge moyen , Mâle , Pneumoconiose/thérapie , Pneumoconiose/épidémiologie , Enquêtes et questionnaires , Patients en consultation externe/statistiques et données numériques , Soins ambulatoires/statistiques et données numériques , Adulte , Sujet âgé , Chine/épidémiologie , Silicose/thérapie , Silicose/épidémiologieRÉSUMÉ
Objective: To study the prevalence of occupational pneumoconiosis in Qinhuangdao from 1961 to 2020 and offer a foundation for developing occupational pneumoconiosis prevention and control methods. Methods: In December 2020, the data of occupational pneumoconiosis cases diagnosed by medical institutions with occupational disease diagnosis qualifications in Qinhuangdao City from 1961 to 2020 were collected Anova or kruskal-Walls tests and chi-square tests were used for inter-group comparisons of continuous and categorical variables, and LSD tests or Tamhane T2 tests were used for multiple comparisons. Results: Between 1961 and 2020, 384 cases of pneumoconiosis were documented in Qinhuangdao, of which 382 (99.5%) patients were men and 2 (0.5%) were women. The average dust service duration is 15 (9, 25) years, with a minimum duration of 0.5 years and a maximum duration of 49 years; Cases were primarily distributed in Qinglong Manchu Autonomous County (187 cases, 48.7%) and the Haigang district (160 cases, 41.7%) ; Type of pneumoconiosis was silicosis (340 cases, 88.5%), mainly 273 cases (71.1%) of stage I, 88 cases (22.9%) of stage II, and 23 cases (6.0% of stage III) ; Cases of Phase II and III and with short lengths of service are mainly concentrated in medium-sized, small, private limited liability companies and collective enterprises. Rrock work (166 cases, 43.2%), and loading kiln workers (42 cases, 10.9%) were the main types. Conclusion: Because the distribution of pneumoconiosis cases in Qinhuangdao city is concentrated and the length of service is decreasing, it is important to enhance the oversight of important area, businesses, industries, and job categories in line with the growth of the region's mineral resources.
Sujet(s)
Pneumoconiose , Humains , Mâle , Pneumoconiose/épidémiologie , Femelle , Maladies professionnelles/épidémiologie , Chine/épidémiologie , Prévalence , Exposition professionnelle/statistiques et données numériques , Adulte d'âge moyen , Poussière , Adulte , Silicose/épidémiologieRÉSUMÉ
Objective: To explore the active ingredients of shengxian and jinshuiliujun decoction with the method of network pharmacology, and to verify the experimental mechanism of its treatment of silicosis. Methods: In May 2023, the active ingredients and targets of drugs in shengxian and jinshuiliujun decoction were obtained through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database. The target of silicosis disease was screened by databases such as Genecards, Disease Gene Network (DisGeNET), Comparative Toxicogenomics Database (CTD), etc. The screened drug targets and disease targets were intersected to obtain the target set of shengxian and jinshuiliujun decoction for the treatment of silicosis. Protein-protein interaction (PPI) network analysis was performed on the target set through STRING database, and core target genes were screened. GO enrichment analysis and KEGG pathway analysis of intersection genes were performed based on Metascape database, and molecular docking verification of key components and targets of shengxian and jinshuiliujun decoction was carried out. Twenty-four adult male SD rats with SPF grade were randomly divided into control group, model group and TCM intervention group, with 8 rats in each group. The dust-stained rat model was prepared by non-tracheal exposure of 1 ml silica suspension (50 mg/ml) in one go, and TCM intervention group was given shengxian and jinshuiliujun decoction[6 g/ (kg·d) ] on the second day. The CT of the lungs of each group was observed 28 days after the dust-stained rat model. Paraffin sections of rat lung tissues were prepared and stained with Hematoxylin-Eosin (HE) and Masson. Western blot was used to verify the expression of core target-related proteins in rat lung tissues after the intervention of shengxian and jinshuiliujun decoction for 28 days, and the differences in protein expression between groups were compared by one-way analysis of variance. Results: A total of 205 active ingredients and 3345 active compounds were selected from shengxian and jinshuiliujun decoction, corresponding to 281 targets, among which 240 targets were related to silicosis. Serine/threonine kinase 1 (AKT1), tumor protein p53 (TP53), tumor necrosis factor (TNF) and interleukin (IL) 6 may be the key targets of shengxian and jinshuiliujun decoction in the treatment of silicosis. Through enrichment analysis, 30 GO entries and 20 potential signaling pathways were screened according to P-value, including nuclear factor κB (NF-κB), mitogen-activated protein kinase (MAPK) and cancer signaling pathways. Molecular docking showed that the active compounds of shengxian and jinshuiliujun decoction had good binding with the core target proteins, and the strongest binding properties were beta-sitosterol and TNF-α (-10.45 kcal/mol). In animal experiments, the inflammatory infiltration and fibrosis of lung tissue of rats in TCM intervention group were significantly improved. Compared with control group, the levels of TNF-α, IL-1ß, IL-6 and NF-κB in lung tissue of model group were significantly increased (P<0.05). Compared with model group, the lung injury of rats in TCM intervention group was significantly improved, and the expressions of TNF-α, IL-1ß, IL-6 and NF-κB were significantly decreased (P<0.05) . Conclusion: Shengxian and jinshuiliujun decoction in the treatment of silicosis may play an anti-fibrosis role by inhibiting the NF-κB signal transduction pathway mediated by inflammatory factors such as TNF-α and IL-1ß, which provides a reference for further exploring the material basis and mechanism of its action.
Sujet(s)
Médicaments issus de plantes chinoises , Simulation de docking moléculaire , Rat Sprague-Dawley , Silicose , Silicose/traitement médicamenteux , Silicose/métabolisme , Médicaments issus de plantes chinoises/pharmacologie , Médicaments issus de plantes chinoises/usage thérapeutique , Animaux , Rats , Mâle , Pharmacologie des réseaux , Médecine traditionnelle chinoise , Humains , Cartes d'interactions protéiquesRÉSUMÉ
Objective: The aim of this study was to explore the role and mechanism of ferroptosis in SiO 2-induced cardiac injury using a mouse model. Methods: Male C57BL/6 mice were intratracheally instilled with SiO 2 to create a silicosis model. Ferrostatin-1 (Fer-1) and deferoxamine (DFO) were used to suppress ferroptosis. Serum biomarkers, oxidative stress markers, histopathology, iron content, and the expression of ferroptosis-related proteins were assessed. Results: SiO 2 altered serum cardiac injury biomarkers, oxidative stress, iron accumulation, and ferroptosis markers in myocardial tissue. Fer-1 and DFO reduced lipid peroxidation and iron overload, and alleviated SiO 2-induced mitochondrial damage and myocardial injury. SiO 2 inhibited Nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant genes, while Fer-1 more potently reactivated Nrf2 compared to DFO. Conclusion: Iron overload-induced ferroptosis contributes to SiO 2-induced cardiac injury. Targeting ferroptosis by reducing iron accumulation or inhibiting lipid peroxidation protects against SiO 2 cardiotoxicity, potentially via modulation of the Nrf2 pathway.
Sujet(s)
Modèles animaux de maladie humaine , Ferroptose , Surcharge en fer , Souris de lignée C57BL , Myocytes cardiaques , Silice , Silicose , Animaux , Ferroptose/effets des médicaments et des substances chimiques , Mâle , Souris , Surcharge en fer/métabolisme , Silice/toxicité , Silicose/métabolisme , Silicose/traitement médicamenteux , Silicose/anatomopathologie , Myocytes cardiaques/effets des médicaments et des substances chimiques , Myocytes cardiaques/métabolisme , Déferoxamine/pharmacologie , Phénylènediamines/pharmacologie , Facteur-2 apparenté à NF-E2/métabolisme , Facteur-2 apparenté à NF-E2/génétique , Stress oxydatif/effets des médicaments et des substances chimiques , Fer/métabolisme , Cyclohexylamines/pharmacologieRÉSUMÉ
Silicosis, caused by silica exposure, is the most widespread and deadliest occupational disease. However, effective treatments are lacking. Therefore, it is crucial to elucidate the mechanisms and targets involved in the development of silicosis. We investigated the basic processes of silicosis development and onset at different exposure durations (2 or 4 weeks) using various techniques such as histopathology, immunohistochemistry, Enzyme linked immunosorbent assay(ELISA),16â¯S rRNA, and untargeted metabolomics.These results indicate that exposure to silica leads to progressive damage to lung tissue with significant deterioration observed over time. Time-dependent cytokines such as the IL-4, IL-13, and IL-6 are detected in lung lavage fluid, the model group consistently exhibited elevated levels of these cytokines, indicating a persistent and worsening inflammatory response in the lungs. Meanwhile, HE and Masson results show that 4-week exposure to silica causes more obvious lung injury and pulmonary fibrosis. Besides, the model group consistently exhibited a distinct lung bacterial population, known as the Lachnospiraceae_NK4A136_group, regardless of exposure duration. However, with increasing exposure duration, specific temporal changes were observed in lung bacterial populations, including Haliangium, Allobaculum, and Sandaracinus (at 4 weeks; p < 0.05). Furthermore, our study revealed a strong correlation between the mechanism of silica-induced lung injury and three factors: oxidative stress, impaired lipid metabolism, and imbalanced amino acid metabolism. We observed a close correlation between cytokine levels, changes in lung microbiota, and metabolic disturbances during various exposure periods. These findings propose that a possible mechanism of silica-induced lung injury involves the interplay of cytokines, lung microbiota, and metabolites.
Sujet(s)
Cytokines , Lésion pulmonaire , Poumon , Microbiote , Silice , Silice/toxicité , Animaux , Poumon/microbiologie , Poumon/effets des médicaments et des substances chimiques , Poumon/anatomopathologie , Microbiote/effets des médicaments et des substances chimiques , Lésion pulmonaire/induit chimiquement , Lésion pulmonaire/microbiologie , Lésion pulmonaire/anatomopathologie , Cytokines/métabolisme , Mâle , Silicose/métabolisme , Liquide de lavage bronchoalvéolaire/composition chimiqueRÉSUMÉ
Environmental exposure to crystalline silica (CS) particles is common and occurs during natural, industrial, and agricultural activities. Prolonged inhalation of CS particles can cause silicosis, a serious and incurable pulmonary fibrosis disease. However, the underlying mechanisms remain veiled. Herein, we aim to elucidate the novel mechanisms of interleukin-11 (IL-11) driving fibroblast metabolic reprogramming during the development of silicosis. We observed that CS exposure induced lung fibrosis in mice and activated fibroblasts, accompanied by increased IL-11 expression and metabolic reprogramming switched from mitochondrial respiration to glycolysis. Besides, we innovatively uncovered that elevated IL-11 promoted the glycolysis process, thereby facilitating the fibroblast-myofibroblast transition (FMT). Mechanistically, CS-stimulated IL-11 activated the extracellular signal-regulated kinase (ERK) pathway and the latter increased the expression of hypoxia inducible factor-1α (HIF-1α) via promoting the translation and delaying the degradation of the protein. HIF-1α further facilitated glycolysis, driving the FMT process and ultimately the formation of silicosis. Moreover, either silence or neutralization of IL-11 inhibited glycolysis augmentation and attenuated CS-induced lung myofibroblast generation and fibrosis. Overall, our findings elucidate the role of IL-11 in promoting fibroblast metabolic reprogramming through the ERK-HIF-1α axis during CS-induced lung fibrosis, providing novel insights into the molecular mechanisms and potential therapeutic targets of silicosis.
Sujet(s)
Fibroblastes , Interleukine-11 , , Fibrose pulmonaire , Silice , Animaux , Souris , Fibroblastes/effets des médicaments et des substances chimiques , Glycolyse , Interleukine-11/métabolisme , /effets des médicaments et des substances chimiques , Fibrose pulmonaire/induit chimiquement , Fibrose pulmonaire/métabolisme , Silice/toxicité , Silicose/métabolismeRÉSUMÉ
Silicosis is a systemic disease with predominantly diffuse fibrosis of the lungs due to prolonged inhalation of free SiO2 dust during the manufacturing process, for which there is no effective treatment. In this study, we used a combined epigenetic and transcriptomic approach to reveal the chromatin-opening features of silicosis and identify the key transcription factor activator protein 1 (AP-1) that responds to silicosis fibrosis. Therapeutic administration of an AP-1 inhibitor inhibits the PI3K/AKT signaling pathway, reduces fibrosis marker proteins, and significantly ameliorates lung fibrosis in a mouse model of silicosis. In addition, it was observed that the expression of Jun and JunB was significantly up-regulated in a TGF-ß1-induced in vitro transdifferentiation model of NIH/3T3 cells, and Co-IP confirmed that a protein complex could be formed between Jun and JunB. Mechanistically, silencing of Jun and JunB expression reversed the activation of the PI3K/AKT signaling pathway and the upregulation of fibrosis marker proteins in NIH/3 T3 cells after TGF-ß1 stimulation. Taken together, Jun/JunB is expected to be a potential therapeutic target for silicosis fibrosis.
Sujet(s)
Protéines proto-oncogènes c-jun , Transduction du signal , Silicose , Facteur de transcription AP-1 , Silicose/métabolisme , Silicose/traitement médicamenteux , Silicose/anatomopathologie , Animaux , Souris , Facteur de transcription AP-1/métabolisme , Cellules NIH 3T3 , Transduction du signal/effets des médicaments et des substances chimiques , Protéines proto-oncogènes c-jun/métabolisme , Facteur de croissance transformant bêta-1/métabolisme , Humains , Mâle , Phosphatidylinositol 3-kinases/métabolisme , Protéines proto-oncogènes c-akt/métabolisme , Modèles animaux de maladie humaine , Facteurs de transcription/métabolisme , Facteurs de transcription/génétique , Fibrose pulmonaire/traitement médicamenteux , Fibrose pulmonaire/métabolisme , Fibrose pulmonaire/induit chimiquement , Fibrose pulmonaire/anatomopathologie , Souris de lignée C57BLRÉSUMÉ
OBJECTIVE: To explore the mechanisms of Yangqing Chenfei formula (, YCF) in the treatment of silicosis through a comprehensive strategy consisting of serum pharmacochemistry, network pharmacology analysis, and in vitro validation. METHODS: An ultrahigh-performance liquid chroma-tography-tandem mass spectrometry method was used to confirm the active components in YCF-medicated serum. Then, we obtained targets for active components and genes for silicosis from multiple databases. Furthermore, a protein-protein interaction network was constructed, and Kyoto Encyclopedia of Genes and Genomes pathway and biological process analyses were conducted to elucidate the mechanisms of YCF for the treatment of silicosis. Finally, we validated the important components and mechanisms in vitro. RESULTS: Altogether, 19 active components were identified from rat serum after YCF administration. We identified 724 targets for 19 components, which were mainly related to inflammation [phosphatidy linositol 3 kinase/protein kinase B, forkhead box O, hypoxia inducible factor, and T-cell receptor signaling pathway, nitric oxide biosynthetic process], fibrotic processes [vascular endothelial growth factor signaling pathway, extracellular signal regulated kinase (ERK) 1 and ERK2 cascade, smooth muscle cell proliferation], and apoptosis (negative regulation of apoptotic process). In addition, 218 genes for silicosis were identified and were mainly associated with the inflammatory response and immune process [cytokine?cytokine receptor interaction, tumor necrosis factor alpha (TNF-α), toll-like receptor, and nucleotide binding oligomerization domain-like receptor signaling pathway]. Taking an intersection of active component targets and silicosis genes, we obtained 61 common genes that were mainly related to the inflammatory response and apoptosis, such as the phosphatidylinositol-3-kinase/protein kinase B signaling pathway, mitogen activated protein kinases signaling pathway, TNF signaling pathway, toll-like receptor signaling pathway, biosynthesis of nitric oxide, and apoptotic process. In the herb-component-gene-pathway network, paeoniflorin, rutin and nobiletin targeted the most genes. In vitro, paeoniflorin, rutin and nobiletin decreased the mRNA levels of inflammatory factors [interleukin (IL)-6, TNF-α, and IL-1ß], suppressed p-AKT and cleaved caspase-3, and increased B cell lymphoma (Bcl)-2 protein expression in silica-induced macrophages in a concentration-dependent manner. CONCLUSION: YCF could significantly relieve the inflammatory response of silicosis via suppression of the AKT/Bcl-2/Caspase-3 pathway.
Sujet(s)
Médicaments issus de plantes chinoises , Pharmacologie des réseaux , Silicose , Silicose/traitement médicamenteux , Silicose/métabolisme , Silicose/génétique , Médicaments issus de plantes chinoises/pharmacologie , Animaux , Rats , Mâle , Humains , Transduction du signal/effets des médicaments et des substances chimiques , Cartes d'interactions protéiques/effets des médicaments et des substances chimiques , Rat Sprague-Dawley , Apoptose/effets des médicaments et des substances chimiquesRÉSUMÉ
OBJECTIVES: Brick kiln workers in Nepal are a neglected population who are exposed to high respirable silica concentrations, and few use interventions to reduce exposure. We aimed to characterise the prevalence of respiratory personal protective equipment (PPE) use, understand knowledge and attitudes towards kiln dust and respiratory PPE and identify factors associated with respiratory PPE use. METHODS: We conducted a cross-sectional study in Bhaktapur, Nepal. We used simple random selection to identify 10 out of 64 total kilns and stratified random sampling of 30 households to enrol workers aged ≥14 years within selected kilns. Field workers surveyed participants using structured questionnaires. Our primary outcome was to characterise the prevalence of current respiratory PPE use and secondary outcomes were summaries of knowledge, attitudes and practice of PPE use. RESULTS: We surveyed 83 workers (mean age 30.8 years, 77.1% male). Of these, 28.9% reported current respiratory PPE use at work, 3.6% heard of silicosis prior to the survey and 24.1% correctly identified the best respiratory PPE (N95, compared with surgical masks and barrier face coverings) for reducing dust exposure. Respiratory PPE users had higher income (mean monthly household income US$206 vs US$145; p=0.04) and education levels (25% vs 5.1% completed more than primary school; p=0.02) compared with non-users. CONCLUSIONS: Respiratory PPE use was low. Workers had poor knowledge of kiln dust health effects and proper respiratory PPE. We highlight important barriers to PPE use, particularly knowledge gaps, which can guide future investigations to reduce the silicosis burden among brick kiln workers.
Sujet(s)
Poussière , Connaissances, attitudes et pratiques en santé , Exposition professionnelle , Équipement de protection individuelle , Silice , Humains , Népal/épidémiologie , Mâle , Adulte , Femelle , Études transversales , Exposition professionnelle/prévention et contrôle , Équipement de protection individuelle/statistiques et données numériques , Enquêtes et questionnaires , Silicose/épidémiologie , Silicose/prévention et contrôle , Respirateurs purificateurs d'air/statistiques et données numériques , Adulte d'âge moyen , Jeune adulte , Matériaux de constructionRÉSUMÉ
The pathophysiology of silicosis is poorly understood, limiting development of therapies for those who have been exposed to the respirable particle. We explored mechanisms of silica-induced pulmonary fibrosis in human lung samples collected from patients with occupational exposure to silica and in a longitudinal mouse model of silicosis using multiple modalities including whole-lung single-cell RNA sequencing and histological, biochemical, and physiologic assessments. In addition to pulmonary inflammation and fibrosis, intratracheal silica challenge induced osteoclast-like differentiation of alveolar macrophages and recruited monocytes, driven by induction of the osteoclastogenic cytokine, receptor activator of nuclear factor κΒ ligand (RANKL) in pulmonary lymphocytes, and alveolar type II cells. Anti-RANKL monoclonal antibody treatment suppressed silica-induced osteoclast-like differentiation in the lung and attenuated pulmonary fibrosis. We conclude that silica induces differentiation of pulmonary osteoclast-like cells leading to progressive lung injury, likely due to sustained elaboration of bone-resorbing proteases and hydrochloric acid. Interrupting osteoclast-like differentiation may therefore constitute a promising avenue for moderating lung damage in silicosis.
Sujet(s)
Différenciation cellulaire , Ostéoclastes , Fibrose pulmonaire , Silice , Silicose , Silice/toxicité , Animaux , Humains , Ostéoclastes/métabolisme , Ostéoclastes/effets des médicaments et des substances chimiques , Ostéoclastes/anatomopathologie , Fibrose pulmonaire/induit chimiquement , Fibrose pulmonaire/anatomopathologie , Fibrose pulmonaire/métabolisme , Souris , Silicose/anatomopathologie , Silicose/métabolisme , Silicose/étiologie , Différenciation cellulaire/effets des médicaments et des substances chimiques , Ligand de RANK/métabolisme , Modèles animaux de maladie humaine , Mâle , Poumon/anatomopathologie , Poumon/métabolisme , Poumon/effets des médicaments et des substances chimiques , Macrophages alvéolaires/métabolisme , Macrophages alvéolaires/anatomopathologie , Macrophages alvéolaires/effets des médicaments et des substances chimiques , FemelleRÉSUMÉ
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.
Sujet(s)
Fibrose pulmonaire , Transduction du signal , Silicose , Facteur de croissance transformant bêta-1 , Animaux , Silicose/traitement médicamenteux , Silicose/anatomopathologie , Silicose/métabolisme , Silicose/complications , Fibrose pulmonaire/traitement médicamenteux , Fibrose pulmonaire/anatomopathologie , Fibrose pulmonaire/complications , Souris , Transduction du signal/effets des médicaments et des substances chimiques , Cellules RAW 264.7 , Mâle , Facteur de croissance transformant bêta-1/métabolisme , Cellules NIH 3T3 , Rats , Transition épithélio-mésenchymateuse/effets des médicaments et des substances chimiques , Poumon/anatomopathologie , Poumon/effets des médicaments et des substances chimiques , Cytokines/métabolisme , Macrophages/métabolisme , Macrophages/effets des médicaments et des substances chimiques , Inflammation/anatomopathologie , Rat Sprague-Dawley , Modèles animaux de maladie humaine , Fibroblastes/métabolisme , Fibroblastes/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des médicaments et des substances chimiques , Dérivés du biphényleRÉSUMÉ
Engineered stone (ES) is a popular building product, due to its architectural versatility and generally lower cost. However, the fabrication of organic resin-based ES kitchen benchtops from slabs has been associated with alarming rates of silicosis among workers. In 2024, fifteen years after the first reported ES-related cases in the world, Australia became the first country to ban the use and importation of ES. A range of interacting factors are relevant for ES-associated silicosis, including ES material composition, characteristics of dust exposure and lung cell-particle response. In turn, these are influenced by consumer demand, work practices, particle size and chemistry, dust control measures, industry regulation and worker-related characteristics. This literature review provides an evidence synthesis using a narrative approach, with the themes of product, exposure and host. Exposure pathways and pathogenesis are explored. Apart from crystalline silica content, consideration is given to non-siliceous ES components such as resins and metals that may modify chemical interactions and disease risk. Preventive effort can be aligned with each theme and associated evidence.
Sujet(s)
Matériaux de construction , Exposition professionnelle , Silicose , Silicose/étiologie , Humains , PoussièreRÉSUMÉ
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 ß1/ILK/PI3K signaling pathway may be associated with the pathogenesis of silicosis fibrosis. In this study, we investigated the effects of Echistatin (Integrin ß1 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 ß1/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 ß-catenin in the downstream Integrin ß1/ILK/PI3K pathway was inhibited. These results indicate that Echistatin and BYL 719 can inhibit EMT and pulmonary fibrosis by blocking different stages of Integrinß1 /ILK/PI3K signaling pathway. This indicates that the Integrin ß1/ILK/PI3K signaling pathway is associated with silica-induced EMT and may serve as a potential therapeutic target for silicosis.
Sujet(s)
Transition épithélio-mésenchymateuse , Antigènes CD29 , Phosphatidylinositol 3-kinases , Protein-Serine-Threonine Kinases , Fibrose pulmonaire , Transduction du signal , Silice , Silicose , Animaux , Transition épithélio-mésenchymateuse/effets des médicaments et des substances chimiques , Transduction du signal/effets des médicaments et des substances chimiques , Antigènes CD29/métabolisme , Antigènes CD29/génétique , Fibrose pulmonaire/induit chimiquement , Fibrose pulmonaire/métabolisme , Fibrose pulmonaire/traitement médicamenteux , Fibrose pulmonaire/anatomopathologie , Mâle , Silice/toxicité , Silicose/métabolisme , Silicose/anatomopathologie , Silicose/traitement médicamenteux , Phosphatidylinositol 3-kinases/métabolisme , Protein-Serine-Threonine Kinases/métabolisme , Rats , Poumon/anatomopathologie , Poumon/effets des médicaments et des substances chimiques , Rat Sprague-DawleyRÉSUMÉ
Silicosis, recognized as a severe global public health issue, is an irreversible pulmonary fibrosis caused by the long-term inhalation of silica particles. Given the intricate pathogenesis of silicosis, there is no effective intervention measure, which poses a severe threat to public health. Our previous study reported that dysbiosis of lung microbiota is associated with the development of pulmonary fibrosis, potentially involving the lipopolysaccharides/toll-like receptor 4 pathway. Similarly, the process of pulmonary fibrosis is accompanied by alterations in metabolic pathways. This study employed a combined approach of 16S rDNA sequencing and metabolomic analysis to investigate further the role of lung microbiota in silicosis delving deeper into the potential pathogenesis of silicosis. Silica exposure can lead to dysbiosis of the lung microbiota and the occurrence of pulmonary fibrosis, which was alleviated by a combination antibiotic intervention. Additionally, significant metabolic disturbances were found in silicosis, involving 85 differential metabolites among the three groups, which are mainly focused on amino acid metabolic pathways. The changed lung metabolites showed a substantial correlation with lung microbiota. The relative abundance of Pseudomonas negatively correlated with L-Aspartic acid, L-Glutamic acid, and L-Threonine levels. These results indicate that dysbiosis in pulmonary microbiota exacerbates silica-induced fibrosis through impacts on amino acid metabolism, providing new insights into the potential mechanisms and interventions of silicosis.
Sujet(s)
Acides aminés , Poumon , Microbiote , Fibrose pulmonaire , Silice , Silicose , Microbiote/effets des médicaments et des substances chimiques , Poumon/microbiologie , Animaux , Fibrose pulmonaire/induit chimiquement , Fibrose pulmonaire/microbiologie , Fibrose pulmonaire/métabolisme , Acides aminés/métabolisme , Silicose/métabolisme , Dysbiose/induit chimiquement , MâleRÉSUMÉ
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.