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Canadian Respiratory Journal 2022Silicosis is a global problem, and it has brought about great burdens to society and patients' families. The etiology of silicosis is clear, preventable, and... (Review)
Review
Silicosis is a global problem, and it has brought about great burdens to society and patients' families. The etiology of silicosis is clear, preventable, and controllable, but the onset is hidden and the duration is long. Thus, it is difficult to diagnose it early and treat it effectively, leaving workers unaware of the consequences of dust exposure. As such, a lack of details in the work history and a slow progression of lung disease contribute to the deterioration of patients until silicosis has advanced to fibrosis. These issues are the key factors impeding the diagnosis and the treatment of silicosis. This article reviews the literature on the early identification, diagnosis, and treatment of silicosis as well as analyzes the difficulties in the diagnosis and the treatment of silicosis and discusses its direction of future development.
Topics: Dust; Humans; Occupational Exposure; Silicon Dioxide; Silicosis
PubMed: 35509892
DOI: 10.1155/2022/3769134 -
Journal of Physiology and Biochemistry Nov 2022Pyroptosis is commonly induced by the gasdermin (GSDM) family and is accompanied by the release of inflammatory cytokines such as IL-1β and IL-18. Recently, increasing... (Review)
Review
Pyroptosis is commonly induced by the gasdermin (GSDM) family and is accompanied by the release of inflammatory cytokines such as IL-1β and IL-18. Recently, increasing evidence suggests that pyroptosis plays a role in respiratory diseases. This review aimed to summarize the roles and mechanisms of pyroptosis in inflammation-related respiratory diseases. There are several pathways involved in pyroptosis, such as the canonical inflammasome-induced pathway, non-canonical inflammasome-induced pathway, caspase-1/3/6/7/GSDMB pathway, caspase-8/GSDMC pathway, caspase-8/GSDMD pathway, and caspase-3/GSEME pathway. Pyroptosis may be involved in asthma, chronic obstructive pulmonary disease (COPD), lung cancer, acute lung injury (ALI), silicosis, pulmonary hypertension (PH), and tuberculosis (TB), in which the NLRP3 inflammasome-induced pathway is mostly highlighted. Pyroptosis contributes to the deterioration of asthma, COPD, ALI, silicosis, and PH. In addition, pyroptosis has dual effects on lung cancer and TB. Additionally, whether pyroptosis participates in cystic fibrosis (CF) and sarcoidosis or not is largely unknown, though the activation of NLRP3 inflammasome is found in CF and sarcoidosis. In conclusion, pyroptosis may play a role in inflammation-related respiratory diseases, providing new therapeutic targets.
Topics: Humans; Pyroptosis; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Caspase 8; Acute Lung Injury; Inflammation; Lung Neoplasms; Silicosis; Pulmonary Disease, Chronic Obstructive; Asthma; Sarcoidosis; DNA-Binding Proteins; Biomarkers, Tumor
PubMed: 35819638
DOI: 10.1007/s13105-022-00909-1 -
Signal Transduction and Targeted Therapy May 2022Silicosis is the most prevalent and fatal occupational disease with no effective therapeutics, and currently used drugs cannot reverse the disease progress. Worse still,...
Silicosis is the most prevalent and fatal occupational disease with no effective therapeutics, and currently used drugs cannot reverse the disease progress. Worse still, there are still challenges to be addressed to fully decipher the intricated pathogenesis. Thus, specifying the essential mechanisms and targets in silicosis progression then exploring anti-silicosis pharmacuticals are desperately needed. In this work, multi-omics atlas was constructed to depict the pivotal abnormalities of silicosis and develop targeted agents. By utilizing an unbiased and time-resolved analysis of the transcriptome, proteome and phosphoproteome of a silicosis mouse model, we have verified the significant differences in transcript, protein, kinase activity and signaling pathway level during silicosis progression, in which the importance of essential biological processes such as macrophage activation, chemotaxis, immune cell recruitment and chronic inflammation were emphasized. Notably, the phosphorylation of EGFR (p-EGFR) and SYK (p-SYK) were identified as potential therapeutic targets in the progression of silicosis. To inhibit and validate these targets, we tested fostamatinib (targeting SYK) and Gefitinib (targeting EGFR), and both drugs effectively ameliorated pulmonary dysfunction and inhibited the progression of inflammation and fibrosis. Overall, our drug discovery with multi-omics approach provides novel and viable therapeutic strategies for the treatment of silicosis.
Topics: Aminopyridines; Animals; ErbB Receptors; Gefitinib; Inflammation; Mice; Morpholines; Pulmonary Fibrosis; Pyridines; Pyrimidines; Silicosis
PubMed: 35551173
DOI: 10.1038/s41392-022-00959-3 -
International Journal of Molecular... Apr 2021Inhalation of silica particles is an environmental and occupational cause of silicosis, a type of pneumoconiosis. Development of the lung silicosis is a unique process... (Review)
Review
Inhalation of silica particles is an environmental and occupational cause of silicosis, a type of pneumoconiosis. Development of the lung silicosis is a unique process in which the vicious cycle of ingestion of inhaled silica particles by alveolar macrophages and their release triggers inflammation, generation of nodular lesions, and irreversible fibrosis. The pathophysiology of silicosis is complex, and interactions between the pathomechanisms have not been completely understood. However, elucidation of silica-induced inflammation cascades and inflammation-fibrosis relations has uncovered several novel possibilities of therapeutic targeting. This article reviews new information on the pathophysiology of silicosis and points out several promising treatment approaches targeting silicosis-related pathways.
Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cytokines; Humans; Inflammasomes; Macrophages; Silicosis
PubMed: 33920534
DOI: 10.3390/ijms22084162 -
International Journal of Molecular... Jul 2021Silicosis remains one of the most severe pulmonary fibrotic diseases worldwide, caused by chronic exposure to silica dust. In this review, we have proposed that... (Review)
Review
Silicosis remains one of the most severe pulmonary fibrotic diseases worldwide, caused by chronic exposure to silica dust. In this review, we have proposed that programmed cell death (PCD), including autophagy, apoptosis, and pyroptosis, is closely associated with silicosis progression. Furthermore, some autophagy, apoptosis, or pyroptosis-related signaling pathways or regulatory proteins have also been summarized to contribute greatly to the formation and development of silicosis. In addition, silicosis pathogenesis depends on the crosstalk among these three ways of PCD to a certain extent. In summary, more profound research on these mechanisms and effects may be expected to become promising targets for intervention or therapeutic methods of silicosis in the future.
Topics: Disease Progression; Humans; Regulated Cell Death; Signal Transduction; Silicosis
PubMed: 34360876
DOI: 10.3390/ijms22158110 -
Respirology (Carlton, Vic.) Dec 2019Despite silica dust exposure being one of the earliest recognized causes of lung disease, Australia, USA, Israel, Turkey and other countries around the world have... (Review)
Review
Despite silica dust exposure being one of the earliest recognized causes of lung disease, Australia, USA, Israel, Turkey and other countries around the world have recently experienced significant outbreaks of silicosis. These outbreaks have occurred in modern industries such as denim jean production, domestic benchtop fabrication and jewellery polishing, where silica has been introduced without recognition and control of the hazard. Much of our understanding of silica-related lung disease is derived from traditional occupations such as mining, whereby workers may develop slowly progressive chronic silicosis. However, workers in modern industries are developing acute and accelerated silicosis over a short period of time, due to high-intensity silica concentrations, oxidative stress from freshly fractured silica and a rapid pro-inflammatory and pro-fibrotic response. Appropriate methods of screening and diagnosis remain unclear in these workers, and a significant proportion may go on to develop respiratory failure and death. There are no current effective treatments for silicosis. For those with near fatal respiratory failure, lung transplantation remains the only option. Strategies to reduce high-intensity silica dust exposure, enforced screening programmes and the identification of new treatments are urgently required.
Topics: Disease Management; Dust; Global Health; Humans; Occupational Exposure; Occupational Health; Silicon Dioxide; Silicosis
PubMed: 31517432
DOI: 10.1111/resp.13695 -
Frontiers in Bioscience (Landmark... May 2023Silicosis, an occupational lung disease that can be prevented, is still a significant public health concern in many countries, despite its considerably decreased... (Review)
Review
Silicosis, an occupational lung disease that can be prevented, is still a significant public health concern in many countries, despite its considerably decreased incidence over the years. The latency period for silicosis ranges from a few years to several decades, depending on the duration and intensity of exposure to silica dust. The complex pathogenic mechanisms of the disease are not fully understood, but it is known to be characterized by inflammation, the formation of silicotic nodules, and progressive and irreversible fibrosis. The aim of this paper was to present the current sources of exposure to silica dust and summarize the updates on risk factors (e.g., socioeconomic status, genetic susceptibility) and sex differences, silico-tuberculosis, prognostic markers including 16-kDa Clara cell secretory protein, antifibrotic treatment, and other therapeutic possibilities with promising results. There are no effective treatment options for silicosis, and prevention remains the primary tool to significantly reduce the risk of disease. There are promising new treatments under investigation including antifibrotic, cellular, and immunomodulatory therapies, but further research is needed to demonstrate the efficacy and safety of these therapies in adequately powered clinical trials.
Topics: Female; Humans; Male; Silicon Dioxide; Silicosis; Fibrosis; Inflammation; Dust
PubMed: 37258484
DOI: 10.31083/j.fbl2805096 -
Acta Pharmacologica Sinica May 2022Silicosis caused by inhalation of silica particles leads to more than ten thousand new occupational exposure-related deaths yearly. Exacerbating this issue, there are...
Silicosis caused by inhalation of silica particles leads to more than ten thousand new occupational exposure-related deaths yearly. Exacerbating this issue, there are currently few drugs reported to effectively treat silicosis. Tetrandrine is the only drug approved for silicosis treatment in China, and despite more than decades of use, its efficacy and mechanisms of action remain largely unknown. Here, in this study, we established silicosis mouse models to investigate the effectiveness of tetrandrine of early and late therapeutic administration. To this end, we used multiple cardiopulmonary function test, as well as markers for inflammation and fibrosis. Moreover, using single cell RNA sequencing and transcriptomics of lung tissue and quantitative microarray analysis of serum from silicosis and control mice, our results provide a novel description of the target pathways for tetrandrine. Specifically, we found that tetrandrine attenuated silicosis by inhibiting both the canonical and non-canonical NLRP3 inflammasome pathways in lung macrophages. Taken together, our work showed that tetrandrine yielded promising results against silicosis-associated inflammation and fibrosis and further lied the groundwork for understanding its molecular targets. Our results also facilitated the wider adoption and development of tetrandirne, potentially accelerating a globally accepted therapeutic strategy for silicosis.
Topics: Animals; Benzylisoquinolines; Fibrosis; Inflammasomes; Inflammation; Lung; Macrophages; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Silicosis
PubMed: 34417574
DOI: 10.1038/s41401-021-00693-6 -
Nature Communications Dec 2018Silica particles induce lung inflammation and fibrosis. Here we show that stimulator of interferon genes (STING) is essential for silica-induced lung inflammation. In...
Silica particles induce lung inflammation and fibrosis. Here we show that stimulator of interferon genes (STING) is essential for silica-induced lung inflammation. In mice, silica induces lung cell death and self-dsDNA release in the bronchoalveolar space that activates STING pathway. Degradation of extracellular self-dsDNA by DNase I inhibits silica-induced STING activation and the downstream type I IFN response. Patients with silicosis have increased circulating dsDNA and CXCL10 in sputum, and patients with fibrotic interstitial lung disease display STING activation and CXCL10 in the lung. In vitro, while mitochondrial dsDNA is sensed by cGAS-STING in dendritic cells, in macrophages extracellular dsDNA activates STING independent of cGAS after silica exposure. These results reveal an essential function of STING-mediated self-dsDNA sensing after silica exposure, and identify DNase I as a potential therapy for silica-induced lung inflammation.
Topics: Animals; Cells, Cultured; Chemokine CXCL10; DNA; Dendritic Cells; Humans; Macrophages; Membrane Proteins; Mice, Inbred C57BL; Mice, Knockout; Pneumonia; Silicon Dioxide; Silicosis; Sputum
PubMed: 30523277
DOI: 10.1038/s41467-018-07425-1 -
Theranostics 2021: Silicosis is a severe occupational lung disease. Current treatments for silicosis have highly limited availability ( lung transplantation) or, do not effectively...
: Silicosis is a severe occupational lung disease. Current treatments for silicosis have highly limited availability ( lung transplantation) or, do not effectively prolong patient survival time ( lung lavage). There is thus an urgent clinical need for effective drugs to retard the progression of silicosis. : To systematically characterize the molecular changes associated with silicosis and to discover potential therapeutic targets, we conducted a transcriptomics analysis of human lung tissues acquired during transplantation, which was integrated with transcriptomics and metabolomics analyses of silicosis mouse lungs. The results from the multi-omics analyses were then verified by qPCR, western blot, and immunohistochemistry. The effect of Ramatroban on the progression of silicosis was evaluated in a silica-induced mouse model. : Wide metabolic alterations were found in lungs from both human patients and mice with silicosis. Targeted metabolite quantification and validation of expression of their synthases revealed that arachidonic acid (AA) pathway metabolites, prostaglandin D (PGD) and thromboxane A (TXA), were significantly up-regulated in silicosis lungs. We further examined the effect of Ramatroban, a clinical antagonist of both PGD and TXA receptors, on treating silicosis using a mouse model. The results showed that Ramatroban significantly alleviated silica-induced pulmonary inflammation, fibrosis, and cardiopulmonary dysfunction compared with the control group. : Our results revealed the importance of AA metabolic reprogramming, especially PGD and TXA in the progression of silicosis. By blocking the receptors of these two prostanoids, Ramatroban may be a novel potential therapeutic drug to inhibit the progression of silicosis.
Topics: Animals; Biomarkers; Case-Control Studies; Female; Humans; Lung; Male; Metabolome; Mice; Prostaglandin D2; Silicosis; Thromboxane A2; Transcriptome
PubMed: 33500731
DOI: 10.7150/thno.47627