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There has been significant global interest in respiratory health driven by the coronavirus disease (COVID-19) and severe environmental pollution. This study explored the potential of schisantherin A (SchA), a compound derived from Schisandra chinensis, to protect against acute pneumoconiosis. We assessed the effects of SchA on phorbol 12-myristate 13-acetate (PMA)-stimulated A549 alveolar epithelial cells and SiO 2 /TiO 2 -induced pulmonary injury in mice. In A549 cells, SchA significantly decreased pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and interleukin (IL)-8 levels. SchA-mediated reduction in inflammatory mediators was associated with the downregulation of PMA-stimulated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling activation. In SiO 2/ TiO 2 -induced lung-injured mice, SchA administration significantly reduced MUC5AC production in lung tissue. SchA administration significantly downregulated the overexpression of NK-κB and the subsequent production of COX-2, iNOS, and NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasomes. It significantly suppressed expected increases in total cell numbers and pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and IL-1β in the bronchoalveolar lavage fluid (BALF) in SiO 2 /TiO 2 -stimulated mice. In contrast, the SiO 2 /TiO 2 -mediated decrease in IL-10 levels was significantly improved by SchA treatment. These fundamental results can be used to develop potential treatments involving SchA for acute pneumoconiosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Macrophage polarization facilitates the inflammatory response and intensified fibrosis in the silicosis microenvironment by a mechanism related to macrophage pyroptosis, although the upstream target remains poorly defined. Currently, there are few reports on the development of drugs that alleviate macrophage polarization by dampening pyroptosis. The present study aims to explore the mechanics of silica mediating macrophage polarization and to investigate whether quercetin (Que) can depolarize macrophages with this mechanism. Silica processing led to prominent M1 polarization of macrophages. Additionally, significant macrophage polarization could be detected in the lung tissue of mice with airway-perfused silica. Further investigation turned out that pronounced mitochondria damage, mtDNA cytoplasmic ectomy, and pyroptosis occurred in response to silica. Nevertheless, Que treatment could effectively attenuate silica-induced mitochondria damage and pyroptosis as demonstrated in vitro and in vivo. Further exploration presented Que could bind to TOM70 and restore silica-induced mitochondrial damage. More importantly, the M1 polarization of macrophage was depressed with the co-treatment of Que and silica, wherein the inflammatory response and pulmonary fibrosis were also mitigated without obvious damage to vital organs. In conclusion, these findings proved that silica leads to mitochondrial damage, thereby evoking pyroptosis and promoting macrophage M1 polarization. Que could bind to TOM70 and restore its function, suppressing mitochondrial damage and pyroptosis, and depolarizing macrophages to reduce fibrosis, which provides a promising strategy for silicosis treatment in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: India, with the highest global burden of tuberculosis (TB) and drug-resistant TB, aims to eliminate TB by 2025. Yet, limited evidence exists on drug resistance patterns and retreatment among patients with silico-tuberculosis. This study explores these patterns and assesses the impact of silicosis on TB retreatment in India., Methods: This secondary data analysis stems from a larger retrospective cohort study conducted in Khambhat, Gujarat, between January 2006 and February 2022. It included 138 patients with silico-tuberculosis and 2,610 TB patients without silicosis. Data from the Nikshay TB information portal were linked with silicosis diagnosis reports from the Pneumoconiosis Board using the unique Nikshay ID as the linking variable. Drug-resistant TB was defined as resistance to any anti-TB drug recorded in Nikshay. Retreatment refers to TB patients who have previously undergone anti-TB treatment for one month or more and need further treatment. Recurrent TB denotes patients who were previously declared cured or had completed treatment but later tested positive for microbiologically confirmed TB. Multivariable logistic regression was used to determine the impact of co-prevalent silicosis on drug resistance and retreatment., Results: Patients with silico-tuberculosis showed a higher proportion of retreatment compared to those without silicosis (55% vs. 23%, p < 0.001). Notably, 28% of patients with silico-tuberculosis were recurrent TB cases, compared to 11% among those without silicosis. Regarding drug resistance, the silico-tuberculosis group exhibited a higher rate (6% vs. 3%), largely due to rifampicin resistance (5% vs. 2%, p = 0.022). Co-prevalent silicosis was associated with a 2.5 times greater risk of drug-resistant TB (adjusted OR 2.5, 95% CI, 1.1-5.3; p = 0.021). Additionally, patients with silico-tuberculosis had a fourfold increased risk of retreatment for TB (adjusted OR 4, 95% CI, 3-6; p < 0.001)., Conclusions: Co-prevalent silicosis significantly elevates the risk of drug resistance, recurrence, and retreatment among TB patients in India. This study indicates a need for improved treatment protocols and suggests that future research should focus on randomized controlled trials to evaluate appropriate anti-TB regimen and duration of therapy for this high-risk group. Given India's goal to eliminate TB by 2025, addressing the challenges posed by silico-tuberculosis is critical., (© 2024. The Author(s).)

Silicosis is an occupational disease caused by exposure to silica characterized by pulmonary inflammation and fibrosis, for which there is a lack of effective drugs. Glycyrrhetinic acid 3-O-β-D-glucuronide (GAMG) can treat silicosis due to its anti-inflammatory and anti-fibrotic properties. Here, the effect of therapeutic interventions of GAMG was evaluated in early-stage and advanced silicosis mouse models. GAMG significantly improved fibrotic pathological changes and collagen deposition in the lungs, alleviated lung inflammation in the BALF, reduced the expression of TNF-α, IL-6, NLRP3, TGF-β1, vimentin, Col-Ⅰ, N-cadherin, and inhibited epithelial-mesenchymal transition (EMT), thereby ameliorating pulmonary fibrosis. Moreover, the dose of 100 mg/kg GAMG can effectively prevent early-stage silicosis, while that of 200 mg/kg was recommended for advanced silicosis. In vitro and in vivo study verified that GAMG can suppress EMT through the NLRP3/TGF-β1/Smad2/3 signaling pathway. Therefore, GAMG could be a promising preventive (early-stage silicosis) and therapeutic (advanced silicosis) strategy, which provides a new idea for formulating prevention and treatment strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Silicosis is one of the most severe occupational diseases characterized by inflammatory cell infiltration, fibroblasts activation, and fibrosis in the lung. However, specific drug treatments are lacking. Cardamonin (CDM) has been reported to possess antitumor, anti-inflammatory/fibrotic effects. While, the effect of CDM on the progression of silicosis remains unknown. In this study, we established a SiO 2 -M stimulated fibroblast cell model, and explored the antifibrotic effect of CDM and the related molecular mechanism using WB, RT-qPCR, and immunofluorescence. The results indicate that CDM inhibits SiO 2 -M-induced fibroblast activation, proliferation, and migration. Furthermore, a silicosis mouse model was established through injecting silica suspension intratracheally. The results revealed that CDM retards the progression of pulmonary fibrosis. The RNA sequencing results suggest that the antifibrotic effect of CDM may be mediated by the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. In conclusion, the results of this study demonstrate that CDM inhibits the development of silicosis via the PI3K-AKT signaling pathway, which could provide guidance for the development of drugs for silicosis treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Silicosis is a systemic disease with predominantly diffuse fibrosis of the lungs due to prolonged inhalation of free SiO 2 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-β1-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-β1 stimulation. Taken together, Jun/JunB is expected to be a potential therapeutic target for silicosis fibrosis., Competing Interests: Declaration of competing interest The authors report no conflicts of interest in this work. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: A mouse silicosis model was constructed by injecting silicon dioxide (SiO(2)) particles into the trachea to explore the effect and mechanism of Cordyceps cicadae polysaccharides (CCP) on ameliorating pulmonary fibrosis in silicosis mice. Methods: In May 2023, CCP were extracted and isolated, the monosaccharide composition and functional group composition were analyzed by high performance liquid chromatography and Fourier transform infrared spectroscopy. C57BL/6J mice were injected with 50 μl 50 mg/ml SiO(2) suspension to construct silicosis mouse model, which were then randomly divided into model group, CCP intervention groups [low dose group (LCCP group), medium dose group (MCCP group) and high dose group (HCCP group) ], the control group was administered by physiological saline, 8 mice in each group. Mice in the CCP intervention groups received oral gavage administration once daily with CCP solution (100, 200 and 400 mg/kg), while control group and model group received physiological saline, lasted for 30 days. The body weight of mice was recorded and the lung coefficient was calculated. The pathomorphological changes of mouse lung tissue were determined by HE and Masson staining. The contents of fibrosis indexes [hydroxyproline acid (HYP), connective tissue growth factor (CTGF) and matrix metallopeptidase 2 (MMP-2) ] of lung tissue and the pro-inflammatory factors[tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) ] of lung tissue and alveolar lavage fluid were determined by ELISA. The expression level of Collagen Ⅰ was determined by immunohistochemistry. The relative protein expression levels of transforming growth factor-β1 (TGF-β1), P-Smad2, α-smooth muscle actin (α-SMA), Toll-like receptor 4 (TLR4), nuclear factor kappa-B p65 (NF-κBp65) and myeloid differentiation primary response gene 88 (MyD88) in lung tissue were determined by Western blot. Results: The total sugar content of the CCP was 86.78%, composed of D-mannose, D-rhamnose, D-glucose and D-galactose, with a molar ratio of 12.71∶1.53∶1.00∶12.64. The infrared spectrum indicated the characteristic groups of its polysaccharides. Compared with the control group, the body weight of mice in the model group was decreased, lung coefficient was increased, the contents of HYP, CTGF and MMP-2 in lung tissue were increased, and the contents of TNF-α, IL-1β and IL-6 in lung tissue and alveolar lavage fluid were increased ( P <0.05). The mice lung showed massive inflammatory cell infiltration and collagen fiber deposition, and the silicosis fibrosis was severe. The expression of CollagenⅠin lung tissue of model group was increased, and the proteins expression levels of TGF-β1, P-Smad2/Smad2, α-SMA, TLR4, NF-κBp65 and MyD88 were increased in mouse lung tissue ( P <0.05). Compared with the model group, the body weights of mice in the MCCP and HCCP groups were increased, the lung coefficients were decreased, the contents of HYP, CTGF and MMP-2 in lung tissue were decreased, and the contents of TNF-α, IL-1β and IL-6 in lung tissue and alveolar lavage fluid were decreased ( P <0.05). The inflammatory cell infiltration in the lung was reduced, and the degree of fibrosis was improved to varying degrees. The expression level of CollagenⅠwas down-regulated in the lung tissue of MCCP and HCCP groups, and the protein expression levels of TGF-β1, P-Smad2/Smad2, α-SMA, TLR4, NF-κBp65 and MyD88 were decreased in lung tissue ( P <0.05) . Conclusion: The CCP could reduce the levels of fibrosis-related indicators and pro-inflammatory factors in lung tissue, ameliorating mouse lung inflammation and silicosis fibrosis caused by SiO(2) particles by inhibiting the activation of TGF-β1/Smad pathway and TLR4/nuclear factor kappa-B (NF-κB) pathway.

Silicosis is a progressive disease characterized by interstitial fibrosis resulting from inhalation of silica particles, and currently lacks specific treatment. Hydrogen (H 2 ) has demonstrated antioxidative, anti-inflammatory, and anti-fibrotic properties, yet its efficacy in treating silicosis remains unexplored. In this study, rats exposed to silica were administered interventions of H 2 combined with tetrandrine, and euthanized at 14, 28, and 56 days post-intervention. Lung tissues and serum samples were collected for analysis. Histological examination, MDA assay, enzyme-linked immunosorbent assay, hydroxyproline assay, and Western blotting were employed to assess the impact of H 2 combined with tetrandrine on pulmonary fibrosis. The results revealed that this combination significantly alleviated inflammation in silicosis-afflicted rats, effectively suppressed levels of MDA, TNF-α, and IL-1β expression, and inhibited epithelial-mesenchymal transition (EMT), thereby ameliorating pulmonary fibrosis. Notably, protein expression level of E-cadherin was increased，however protein expression levels of vimentin and α-SMA were reduced, and TGF-β were reduced, alongside a significant decrease in hydroxyproline content. Furthermore, H 2 combined with tetrandrine downregulated protein expression of NF-κB p65, NF-κB p-p65, Caspase-1, ASC, and NLRP3. These findings substantiate the hypothesis that H 2 combined with tetrandrine mitigates inflammation associated with silicosis and suppresses the EMT process to ameliorate fibrosis via the NF-κB/NLRP3 signaling pathway. However, the pressure of airway opening was not assessed in this study and dynamic readings of lung physiological function were not obtained, which is a major limitation of this study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Silicosis is an occupational disease of the lungs brought in by repeated silica dust exposures. Inhalation of crystalline silica leads to persistent lung inflammation characterized by lung lesions due to granuloma formation. The specific molecular mechanism has not yet been identified, though. The Present study investigated the impact of silica-exposed lung fibrosis and probable molecular mechanisms. Here, Curcumin, derived from Curcuma longa shown to be an effective anti-inflammatory and anti-fibrotic molecule has been taken to investigate its therapeutic efficacy in silica-induced lung fibrosis. An experimental model of silicosis was established in mice where curcumin was administered an hour before intranasal silica exposure every alternate day for 35 days. Intranasal Curcumin treatment reduced silica-induced oxidative stress, inflammation marked by inflammatory cell recruitment, and prominent granuloma nodules along with aberrant collagen repair. Its protective benefits were confirmed by reduced MMP9 activities along with EMT markers (Vimentin and α-SMA). It has restored autophagy and suppressed the deposition of damaged mitochondria after silica exposure. Intranasal Curcumin also inhibited oxidative stress by boosting antioxidant enzyme activities and enhanced Nrf2-Keap1 expressions. Higher levels of PINK1, PARKIN, Cyt-c, P62/SQSTM, and damaged mitochondria in the silicosis group were significantly lowered after curcumin and dexamethasone treatments. Curcumin-induced autophagy resulted in reduced silica-induced mitochondria-dependent apoptosis. We report that intranasal curcumin treatment showed protective properties on pathological features prompted by silica particles, suggesting that the compound may constitute a promising strategy for the treatment of silicosis in the near future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

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., Competing Interests: Declaration of Competing Interest The authors confirm that there are no conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Silicosis is the most common type of pneumoconiosis, having a high incidence in workers chronically exposed to crystalline silica (CS). No specific medication exists for this condition. GHK, a tripeptide naturally occurring in human blood and urine, has antioxidant effects. We aimed to investigate the therapeutic effect of GHK-Cu on silicosis and its potential underlying molecular mechanism. An experimental silicosis mouse model was established to observe the effects of GHK-Cu on lung inflammation and fibrosis. Moreover, the effects of GHK-Cu on the alveolar macrophages (AM) were examined using the RAW264.7 cell line. Its molecular target, peroxiredoxin 6 (PRDX6), has been identified, and GHK-Cu can bind to PRDX6, thus attenuating lung inflammation and fibrosis in silicosis mice without significant systemic toxicity. These effects were partly related to the inhibition of the CS-induced oxidative stress in AM induced by GHK-Cu. Thus, our results suggest that GHK-Cu acts as a potential drug by attenuating alveolar macrophage oxidative stress. This, in turn, attenuates the progression of pulmonary inflammation and fibrosis, which provides a reference for the treatment of silicosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Silicosis is a systemic disease characterized by extensive fibrosis due to prolonged exposure to silica dust, with rising incidence rates significantly impacting global public health. ShengXian and JinShuiLiuJun Decoction (SXD) is a Chinese medicinal preparation containing a variety of medicinal plants. It has shown notable clinical efficacy in treating silicotic fibrosis in China. However, the precise mechanisms underlying its therapeutic effects remain unclear. This study integrates network pharmacology, multi-omics analysis, and experimental validation to investigate the potential mechanisms by which SXD treats silicotic fibrosis., Objective: The study aims to investigate the therapeutic efficacy of SXD in treating silicotic fibrosis and to elucidate its underlying molecular mechanisms., Methods: HPLC-Q-TOF-MS was used to identify the active components of SXD, and combined with network pharmacology, metabolomics, and transcriptomics, the mechanism of SXD in treating silicotic fibrosis was explored from multiple perspectives. The therapeutic effect of SXD was assessed through HE staining, Masson staining, Micro CT imaging, pulmonary function tests, and hydroxyproline content in lung tissue. Finally, network pharmacology and multi-omics findings were validated using molecular docking. CETSA, immunofluorescence, SPR, and Western blotting were used to analyze key factors in the NF-κB pathway at the animal, cellular, and molecular levels., Results: SXD treatment improved lung function in silicosis rats, reduced inflammatory cell infiltration, collagen deposition, fibrosis and other pathological changes, and inhibited the protein expression of TNF-α, IL-17A, and IL-1β, and NF-κB in lung tissue. HPLC-Q-TOF-MS combined with network pharmacology identified key compounds such as Liquiritigenin, 3-Methoxynobiletin, Isomangiferin, Hesperidin, shogaol, and Ligustroflavone, which likely exert therapeutic effects through the TNF, IL-17, NF-κB, and TGF-β signaling pathways. Transcriptomics and metabolomics results revealed that SXD up-regulated the expression of NF-κB pathway-related genes (NFKBIA, NFKBIZ) and key regulators of the retinol metabolism pathway, while down-regulating pro-inflammatory genes (IL1B, IL17A, IL6). Experimental findings confirmed that SXD suppressed the expression of NF-κB pathway-related proteins and upstream activators TNF-α, IL-17A, and IL-1β, as well as their receptors, in both lung tissue and cellular models. Additionally, SXD-containing serum had a direct, non-toxic effect on MRC-5 cells, effectively inhibiting collagen expression and TGF-β secretion. SXD also had a positive effect on collagen production and extracellular matrix (ECM) aggregation in fibroblasts. Molecular dynamics studies showed that SXD directly binds to NF-κB and IκB., Conclusion: SXD exerts therapeutic effects on silicotic fibrosis by inhibiting NF-κB signaling transduction mediated by TNF-α, IL-17A, and IL-1β, and suppressing fibroblast activation., Competing Interests: Declaration of competing interest All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Silicosis is an occupational disease caused by long-term inhalation of free silica, resulting in a significant global health burden. Its pathogenesis remains unclear, and there is no effective treatment. Proliferative and activated myofibroblasts play a key role in the development of silicosis. Traditional studies have focused on fibroblast proliferation and collagen secretion, neglecting their functional heterogeneity. With the advancement of omics research, more pathogenic fibroblast subgroups and their functions have been identified. In this study, we applied transcriptomics to analyze gene changes in primary lung fibroblasts during silicosis development using a mouse model. Our results indicate that DEGs are enriched in collagen secretion, ECM synthesis, leukocyte migration, and chemotaxis functions. Altered core genes are associated with immune cell recruitment and cell migration. Nrf2 agonists, known for anti-inflammatory and antioxidant properties, have shown potential therapeutic effects in fibrotic diseases. However, their effects on fibroblasts in silicosis are not fully understood. We used four common Nrf2 agonists to study gene expression changes in lung fibroblasts at the transcriptome level, combined with histopathological and biochemical methods, to investigate their effects on silicosis in mice. Results show that Nrf2 agonists can exert anti-silicosis fibrosis functions by downregulating genes like Fos and Egr1, involved in cell differentiation, proliferation, and inflammation. In conclusion, this study suggests that inflammation-related co-functions of fibroblasts may be a potential mechanism in silicosis pathogenesis. Targeting Nrf2 may be a promising strategy to alleviate oxidative stress and inflammation in silicosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Silica-induced pulmonary fibrosis is an irreversible and progressive lung disease with limited treatments available. In this work, FDA-approved cannabidiol (CBD) was studied for its potential medical use in silicosis. In silicosis female C57BL/6 mice model, oral CBD or pirfenidone (PFD) on day 1 after intratracheal drip silica (150 mg/mL) and continued for 42 days. Lung inflammatory and fibrotic changes were studied using ELISA kits, H&E staining and Masson staining. Osteopontion (OPN) and α-smooth muscle actin (α-SMA) expression in lung tissues was determined using immunohistochemical staining. The results indicated that CBD attenuated silica-induced pulmonary inflammation and fibrosis. Human myeloid leukemia mononuclear cells (THP-1) were treated with silica (200 μg/mL) to induce cell damage, then CBD (10 μM, 20 μM) and PFD (100 μM) were incubated. In vitro experiments showed that CBD can effectively reduce the expression of NLRP3 inflammasome in THP-1 cells and subsequently block silica-stimulated transformation of fibromuscular-myofibroblast transition (FMT) by culturing human embryonic lung fibroblasts (MRC-5) in conditioned medium of THP-1 cells. Therefore, CBD exhibited the potential therapy for silicosis through inhibiting the silica-induced pulmonary inflammation and fibrosis via the NLRP3/TGF-β1/Smad2/3 signaling pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Tetrandrine (TET) is a bisbenzylisoquinoline alkaloid derived from Stephania tetrandra S. Moor, known for its potential use in attenuating the progression of silicosis. However, the precise effects and underlying mechanisms of TET remain controversial. In this study, we aimed to elucidate the pharmacological mechanism of TET using a network pharmacology approach, while also evaluating its effect on silica-induced lung fibrosis in mice and TGF-β1-stimulated pulmonary fibroblasts in vitro. We employed network pharmacology to unravel the biological mechanisms through which TET may exert its therapeutic effects on pulmonary fibrosis and silicosis. In a silica-induced mouse model of lung fibrosis, TET was administered orally either during the early or late stage of fibrotic progression. Additionally, we examined the effects of TET on fibroblasts stimulated by TGF-β1 in vitro. Through the analysis, we identified a total of 101 targets of TET, 7,851 genes associated with pulmonary fibrosis, and 80 overlapping genes. These genes were primarily associated with key pathways such as epidermal growth factor receptor tyrosine kinase inhibitor resistance, the vascular endothelial growth factor signaling pathway, and the phosphatidylinositol 3 kinase (PI3K)-protein kinase B (PKB or AKT) signaling pathway. Furthermore, molecular docking analysis revealed the binding of TET to AKT1, the catalytic subunit of phosphatidylinositol-3 kinase, and KDR. In vivo experiments demonstrated that TET significantly alleviated silica-induced pulmonary fibrosis and reduced the expression of fibrotic markers. Moreover, TET exhibited inhibitory effects on the migration, proliferation, and differentiation of TGF-β1-induced lung fibroblasts in vitro. Notably, TET mitigated silica-induced pulmonary fibrosis by suppressing the PI3K/AKT pathway. In conclusion, our findings suggest that TET possesses the ability to suppress silica-induced pulmonary fibrosis by targeting the PI3K/AKT signaling pathway. These results provide valuable insights into the therapeutic potential of TET in the treatment of pulmonary fibrosis and silicosis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study examines the involvement of TRIM59 in silica-induced pulmonary fibrosis and explores the therapeutic efficacy of Tanshinone IIA (Tan IIA). In vivo experiments conducted on rats with silica-induced pulmonary fibrosis unveiled an increase in TRIM59 levels and a decrease in PPM1A levels. Subsequent investigations using in vitro silicosis cell models demonstrated that modulation of TRIM59 expression significantly impacts silicosis fibrosis, influencing the levels of PPM1A and activation of the Smad2/3 signaling pathway. Immunofluorescence and co-immunoprecipitation assays confirmed the interaction between TRIM59 and PPM1A in fibroblasts, wherein TRIM59 facilitated the degradation of PPM1A protein via proteasomal and ubiquitin-mediated pathways. Furthermore, employing a rat model of silica-induced pulmonary fibrosis, Tan IIA exhibited efficacy in mitigating lung tissue damage and fibrosis. Immunohistochemical analysis validated the upregulation of TRIM59 and downregulation of PPM1A in silica-induced pulmonary fibrosis, which Tan IIA alleviated. In vitro studies elucidated the mechanism by which Tan IIA regulates the Smad2/3 signaling pathway through TRIM59-mediated modulation of PPM1A. Treatment with Tan IIA in silica-induced fibrosis cell models resulted in concentration-dependent reductions in fibrotic markers and attenuation of relevant protein expressions. Tan IIA intervention in silica-induced fibrosis cell models mitigated the TRIM59-induced upregulation of fibrotic markers and enhanced PPM1A expression, thereby partially reversing Smad2/3 activation. Overall, the findings indicate that while overexpression of TRIM59 may activate the Smads pathway by suppressing PPM1A expression, treatment with Tan IIA holds promise in counteracting these effects by inhibiting TRIM59 expression., Competing Interests: Declaration of Competing Interest The authors declared that they have no conflicts of interest to this work. We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

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-1β], 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.

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Sanqiao Yao is the author who funded this research., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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 SiO 2 . Additionally, BIC inhibited SiO 2 -mediated secretion of the inflammatory cytokines IL-1β, IL-6, TNF-α, and TGF-β1 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-β1. 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-β1, and consequently inhibits FMT and EMT via TGF-β1 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., (© 2024. The Author(s).)

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-1β, 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-1β, 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-1β, which provides a reference for further exploring the material basis and mechanism of its action.

Background: Silicosis presents a significant clinical challenges and economic burdens, with Traditional Chinese Medicine (TCM) emerging as a potential therapeutic avenue. However, the precise effects and mechanisms of TCM in treating silicosis remain uncertain and subject to debate., Objective: The study aims to elucidate the therapeutic role and mechanisms of the Yang-Yin-Qing-Fei Decoction (YYQFD) and its key component, paeoniflorin, in silicosis using a murine model., Methods: Silicotic mice were treated with YYQFD, pirfenidone (PFD), or paeoniflorin. RAW264.7 cells and mouse lung fibroblasts (MLF) were stimulated with silica, matrix metalloproteinase-12 (MMP-12), or TGF-β1, followed by treatment with paeoniflorin, PFD, or relevant inhibitors. YYQFD constituents were characterized using High-Performance Liquid Chromatography (HPLC). Lung fibrosis severity was assessed via histopathological examination, micro-CT imaging, lung functions, and Western blot analysis. Transcriptome sequencing and bioinformatics analysis were employed to delineate the gene expression profile and target genes modulated by YYQFD in silicosis., Results: Treatment with YYQFD ameliorated silica-induced lung fibrosis. Transcriptome sequencing identified MMP-12 as a potential common target of YYQFD and PFD. Additionally, a potential pro-inflammatory role of MMP-12, regulated by silica-induced TLR4 signaling pathways, was revealed. Paeoniflorin, one of the most distinctive compounds in YYQFD, attenuated silica-induced MMP-12 increase and its derived inflammatory factors in macrophages through a direct binding effect. Notably, paeoniflorin treatment exerted anti-fibrotic effects by inhibiting MMP-12-derived inflammatory factors and TGF-β1-induced myofibroblast differentiation in silica-exposed mice., Conclusions: This study underscores paeoniflorin as one of the most principal bioactive compounds in YYQFD, highlighting its capacity to attenuate lung inflammation driven by macrophage-derived MMP-12 and reduce lung fibrosis both in vivo and in vitro., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Silicon dioxide (SiO 2 )-induced pulmonary fibrosis is potentially associated with the impairment of mitochondrial function. Previous research found that inhibition of macrophage receptor with collagenous structure (MARCO) could alleviate particle-induced lung injury by regulating phagocytosis and mitigating mitochondrial damage. The present study aims to explore the underlying anti-fibrosis mechanism of polyguanylic acid (PolyG, MARCO inhibitor) in a silicotic rat model. Hematoxylin and eosin and Masson staining were performed to visualize lung tissue pathological changes. Confocal microscopy, transmission electron microscope, western blot analysis, quantitative real-time PCR (qPCR), and adenosine triphosphate (ATP) content assay were performed to evaluate collagen content, mitochondrial function, and morphology changes in SiO 2 -induced rat pulmonary fibrosis. The results suggested that SiO 2 exposure contributed to reactive oxygen species aggregation and the reduction of respiratory complexes and ATP synthesis. PolyG treatment could effectively reduce MARCO expression and ameliorate lung injury and fibrosis by rectifying the imbalance of mitochondrial respiration and energy synthesis. Furthermore, PolyG could maintain mitochondrial homeostasis by promoting peroxisome proliferator-activated receptor-coactivator 1 α (PGC1α)-mediated mitochondrial biogenesis and regulating fusion and fission. Together, PolyG could ameliorate SiO 2 -induced pulmonary fibrosis via inhibiting MARCO to protect mitochondrial function., (© 2024 Wiley Periodicals LLC.)

Oxidative stress and inflammation play a fundamental role in the beginning and advancement of silicosis. Hence, questing active phytocompounds (APCs) with anti-oxidative and anti-inflammatory properties such as diosgenin (DG) and emodin (ED) can be a therapeutic intervention targeting silica-induced pulmonary inflammation and fibrosis. Hydrophobicity and low bioavailability are the barriers that restrict the therapeutic efficacy of DG and ED against pulmonary defects. Encapsulating these APCs in polymeric nanoparticles can overcome this limitation. The present study has thus explored the anti-inflammatory and anti-fibrotic effects of polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) individually loaded with DG (DGn) or ED (EDn) and in combine DG+ED [(DG+ED)n] in respirable silica dust (RSD)-induced pulmonary fibrosis silicosis rat model. Our study found that individual and combined NPs revealed physiochemical characteristics appropriate for IV administration with sustained-drug release purposes. Physiological evaluations of RSD-induced silicosis rats suggested that no treatment could improve the body weight. Still, they reduced the lung coefficient by maintaining lung moisture. Only (DG+ED)n significantly cleared free lung silica. All interventions were found to attribute the increased per cent cell viability in BALF, reduce cytotoxicity via minimizing LDH levels, and balance the oxidant-antioxidant status in silicotic rats. The expression of inflammatory cytokines (TNF-α, IL-1β, IL-6, MCP-1, and TGF-β1) were efficiently down-regulated with NPs interventions compared to pure (DG+ED) treatment. All drug treatments significantly declined, the 8-HdG and HYP productions indicate that RSD-induced oxidative DNA damage and collagen deposition were successfully repaired. Moreover, histopathological investigations proposed that individual or combined drugs NPs interventions could decrease the fibrosis and alveolitis grades in RSD-induced silicosis rats. However, (DG+ED)n intervention significantly inhibited pulmonary fibrosis and alveolitis compared to pure (DG+ED) treatment. In conclusion, the RSD can induce oxidative stress and inflammation in rats, producing reactive oxygen species (ROS)-mediated cytotoxicity to pulmonary cells and leading to silicosis development. The IV administration of combined NP suppressed lung inflammation and collagen formation by maintaining oxidant-antioxidant status and effectively interrupting the fibrosis-silicosis progression. These results may be attributed to the improved bioavailability of DG and ED through their combined nano-encapsulation-mediated targeted drug delivery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

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., (Copyright © 2024 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Background: Silicosis represents a paramount occupational health hazard globally, with its incidence, morbidity, and mortality on an upward trajectory, posing substantial clinical dilemmas due to limited effective treatment options available. Trigonelline (Trig), a plant alkaloid extracted mainly from coffee and fenugreek, have diverse biological properties such as protecting dermal fibroblasts against ultraviolet radiation and has the potential to inhibit collagen synthesis. However, it's unclear whether Trig inhibits fibroblast activation to attenuate silicosis-induced pulmonary fibrosis is unclear., Methods: To evaluate the therapeutic efficacy of Trig in the context of silicosis-related pulmonary fibrosis, a mouse model of silicosis was utilized. The investigation seeks to elucidated Trig's impact on the progression of silica-induced pulmonary fibrosis by evaluating protein expression, mRNA levels and employing Hematoxylin and Eosin (H&E), Masson's trichrome, and Sirius Red staining. Subsequently, we explored the mechanism underlying of its functions., Results: In vivo experiment, Trig has been demonstrated the significant efficacy in mitigating SiO 2 -induced silicosis and BLM-induced pulmonary fibrosis, as evidenced by improved histochemical staining and reduced fibrotic marker expressions. Additionally, we showed that the differentiation of fibroblast to myofibroblast was imped in Trig + SiO 2 group. In terms of mechanism, we obtained in vitro evidence that Trig inhibited fibroblast-to-myofibroblast differentiation by repressing TGF-β/Smad signaling according to the in vitro evidence. Notably, our finding indicated that Trig seemed to be safe in mice and fibroblasts., Conclusion: In summary, Trig attenuated the severity of silicosis-related pulmonary fibrosis by alleviating the differentiation of myofibroblasts, indicating the development of novel therapeutic approaches for silicosis fibrosis., (© 2024. The Author(s).)

Inhalation of crystalline silica dust induces incurable lung damage, silicosis, and pulmonary fibrosis. However, the mechanisms of the lung injury remain poorly understood, with limited therapeutic options aside from lung transplantation. Posttranslational modifications can regulate the function of proteins and play an important role in studying disease mechanisms. To investigate changes in posttranslational modifications of proteins in silicosis, combined quantitative proteome, acetylome, and succinylome analyses were performed with lung tissues from silica-injured and healthy mice using liquid chromatography-mass spectrometry. Combined analysis was applied to the three omics datasets to construct a protein landscape. The acetylation and succinylation of the key transcription factor STAT1 were found to play important roles in the silica-induced pathophysiological changes. Modulating the acetylation level of STAT1 with geranylgeranylacetone effectively inhibited the progression of silicosis. This report revealed a comprehensive landscape of posttranslational modifications in silica-injured mouse and presented a novel therapeutic strategy targeting the posttranslational level for silica-induced lung diseases., Competing Interests: Conflicts of interest All authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Silicosis is a hazardous occupational disease caused by inhalation of silica, characterized by persistent lung inflammation that leads to fibrosis and subsequent lung dysfunction. Moreover, the complex pathophysiology of silicosis, the challenges associated with early detection, and the unfavorable prognosis contribute to the limited availability of treatment options. Daphnetin (DAP), a natural lactone, has demonstrated various pharmacological properties, including anti-inflammatory, anti-fibrotic, and pulmonary protective effects. However, the effects of DAP on silicosis and its molecular mechanisms remain uncover. This study aimed to evaluate the therapeutic effects of DAP against pulmonary inflammation and fibrosis using a silica-induced silicosis mouse model, and investigate the potential mechanisms and targets through network pharmacology, proteomics, molecular docking, and cellular thermal shift assay (CETSA). Here, we found that DAP significantly alleviated silica-induced lung injury in mice with silicosis. The results of H&E staining, Masson staining, and Sirius red staining indicated that DAP effectively reduced the inflammatory response and collagen deposition over a 28-day period following lung exposure to silica. Furthermore, DAP reduced the number of TUNEL-positive cells, increased the expression levels of Bcl-2, and decreased the expression of Bax and cleaved caspase-3 in the mice with silicosis. More importantly, DAP suppressed the expression levels of NLRP3 signaling pathway-related proteins, including NLRP3, ASC, and cleaved caspase-1, thereby inhibiting silica-induced lung inflammation. Further studies demonstrated that DAP possesses the ability to inhibit the epithelial mesenchymal transition (EMT) induced by silica through the inhibition of the TGF-β1/Smad2/3 signaling pathway. The experimental results of proteomic analysis found that the PI3K/AKT1 signaling pathway was the key targets of DAP to alleviate lung injury induced by silica. DAP significantly inhibited the activation of the PI3K/AKT1 signaling pathway induced by silica in lung tissues. The conclusion was also verified by the results of molecular and CETSA. To further verify this conclusion, the activity of PI3K/AKT1 signaling pathway was inhibited in A549 cells using LY294002. When the A549 cells were pretreated with LY294002, the protective effect of DAP on silica-induced injury was lost. In conclusion, the results of this study suggest that DAP alleviates pulmonary inflammation and fibrosis induced by silica by modulating the PI3K/AKT1 signaling pathway, and holds promise as a potentially effective treatment for silicosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Simvastatin (Sim), a hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been widely used in prevention and treatment of cardiovascular diseases. Studies have suggested that Sim exerts anti-fibrotic effects by interfering fibroblast proliferation and collagen synthesis. This study was to determine whether Sim could alleviate silica-induced pulmonary fibrosis and explore the underlying mechanisms., Methods: The rat model of silicosis was established by the tracheal perfusion method and treated with Sim (5 or 10 mg/kg), AICAR (an AMPK agonist), and apocynin (a NOX inhibitor) for 28 days. Lung tissues were collected for further analyses including pathological histology, inflammatory response, oxidative stress, epithelial mesenchymal transformation (EMT), and the AMPK-NOX pathway., Results: Sim significantly reduced silica-induced pulmonary inflammation and fibrosis at 28 days after administration. Sim could reduce the levels of interleukin (IL)-1β, IL-6, tumor necrosis factor-α and transforming growth factor-β1 in lung tissues. The expressions of hydroxyproline, α-SMA and vimentin were down-regulated, while E-cad was increased in Sim-treated rats. In addition, NOX4, p22pox, p40phox, p-p47phox/p47phox expressions and ROS levels were all increased, whereas p-AMPK/AMPK was decreased in silica-induced rats. Sim or AICAR treatment could notably reverse the decrease of AMPK activity and increase of NOX activity induced by silica. Apocynin treatment exhibited similar protective effects to Sim, including down-regulating of oxidative stress and inhibition of the EMT process and inflammatory reactions., Conclusions: Sim attenuates silica-induced pulmonary inflammation and fibrosis by downregulating EMT and oxidative stress through the AMPK-NOX pathway., (© 2024. The Author(s).)

Long term exposure to silica particles leads to various diseases, among which silicosis is of great concern. Silicosis is an interstitial lung disease caused by inhalation of silica particles in production environments. However, the mechanisms underlying silicosis remains unclear. Our previous studies revealed that progranulin (Pgrn) promoted the expression of pro-inflammatory factors in alveolar macrophages treated with silica particles and the secretion of extracellular matrix of pulmonary fibroblasts. Nevertheless, the role of Pgrn in silica particles-induced silicosis in vivo was unknown. This study found that silica particles increased Pgrn expression in silicosis patients. Pgrn deficiency reduced lung inflammation and fibrosis in silica particles-induced silicosis mouse models. Subsequently, based on transcriptional sequencing and interleukin (Il) -6 knockout mouse models, results demonstrated that Pgrn deficiency might decrease silicosis inflammation by reducing the production of Il-6, thereby modulating pulmonary fibrosis in the early stage of silicosis mouse models. Furthermore, another mechanism through which Pgrn deficiency reduced fibrosis in silicosis mouse models was the regulation of the transforming growth factor (Tgf) -β1/Smad signaling pathway. Conclusively, Pgrn contributed to silicosis inflammation and fibrosis induced by silica particles, indicating that Pgrn could be a promising therapeutic target., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Silicosis is a complex occupational disease without recognized effective treatment. Celastrol, a natural product, has shown antioxidant, anti-inflammatory, and anti-fibrotic activities, but the narrow therapeutic window and high toxicity severely limit its clinical application. Through structural optimization, we have identified a highly efficient and low-toxicity celastrol derivative, CEL-07 . In this study, we systematically investigated the therapeutic potential and underlying mechanisms of CEL-07 in silicosis fibrosis. By constructing a silicosis mouse model and analyzing with HE, Masson, Sirius Red, and immunohistochemical staining, CEL-07 significantly prevented the progress of inflammation and fibrosis, and it effectively improved the lung respiratory function of silicosis mice. Additionally, CEL-07 markedly suppressed the expression of inflammatory factors (IL-6, IL-1α, TNF-α, and TNF-β) and fibrotic factors (α-SMA, collagen I, and collagen III), and promoted apoptosis of fibroblasts by increasing ROS accumulation. Moreover, bioinformatics analysis combined with experimental validation revealed that CEL-07 inhibited the pathways associated with inflammation (PI3K-AKT and JAK2-STAT3) and the expression of apoptosis-related proteins. Overall, these results suggest that CEL-07 may serve as a potential candidate for the treatment of silicosis.

Inhaling silica causes the occupational illness silicosis, which mostly results in the gradual fibrosis of lung tissue. Previous research has demonstrated that hypoxia-inducible factor-1α (HIF-1α) and glycolysis-related genes are up-regulated in silicosis. The role of 2-deoxy-D-glucose (2-DG) as an inhibitor of glycolysis in silicosis mouse models and its molecular mechanisms remain unclear. Therefore, we used 2-DG to observe its effect on pulmonary inflammation and fibrosis in a silicosis mouse model. Furthermore, in vitro cell experiments were conducted to explore the specific mechanisms of HIF-1α. Our study found that 2-DG down-regulated HIF-1α levels in alveolar macrophages induced by silica exposure and reduced the interleukin-1β (IL-1β) level in pulmonary inflammation. Additionally, 2-DG reduced silica-induced pulmonary fibrosis. From these findings, we hypothesize that 2-DG reduced glucose transporter 1 (GLUT1) expression by inhibiting glycolysis, which inhibits the expression of HIF-1α and ultimately reduces transcription of the inflammatory cytokine, IL-1β, thus alleviating lung damage. Therefore, we elucidated the important regulatory role of HIF-1α in an experimental silicosis model and the potential defense mechanisms of 2-DG. These results provide a possible effective strategy for 2-DG in the treatment of silicosis., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Silicosis, a highly lethal occupational respiratory disease characterized by irreversible pulmonary fibrosis, remains challenging to treat due to its unclear pathogenesis. In this study, bioinformatics, network pharmacology, and experimental validation were combined to explore potential mechanisms and therapeutic drugs for silicosis. First, the differentially expressed genes（DEGs）and pathway enrichment in pulmonary fibrosis were identified by GO and KEGG analysis. Next, the differential genes were submitted to cMap database for drug prediction and celastrol stood out as the most promising candidate drug. Then, network pharmacology analysis identified pharmacological targets of celastrol and demonstrated that celastrol could regulate JAK-STAT, MAPK, and Toll-like receptor signaling pathways. Finally, we verified the therapeutic role and mechanism of celastrol on silicosis. In vivo, celastrol significantly ameliorated CS-induced inflammation and fibrosis in silicosis mice, including inflammatory cell infiltration, collagen fiber and extracellular matrix deposition, fibroblast activation and related factor expression. Moreover, it dramatically improved lung respiratory function of silicosis mice. In vitro, celastrol suppressed CS-induced cytokine expression, apoptosis of macrophages and activation of Stat3 and Erk1/2 signals. Overall, our research identified and verified celastrol as a novel and promising candidate drug for silicosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Silicosis is a serious silica-induced respiratory disease for which there is currently no effective treatment. Irreversible pulmonary fibrosis caused by persistent inflammation is the main feature of silicosis. As an underlying mechanism, acetylation regulated by histone deacetylases (HDACs) are believed to be closely associated with persistent inflammation and pulmonary fibrosis. However, details of the mechanisms associated with the regulation of acetylated modification in silicosis have yet to be sufficiently established. Furthermore, studies on the efficient delivery of DNA to lung tissues by nebulized inhalation for the treatment of silicosis are limited. In this study, we established a mouse model of silicosis successfully. Differentially expressed genes (DEGs) between the lung tissues of silicosis and control mice were identified based on transcriptomic analysis, and HDAC10 was the only DEG among the HDACs. Acetylomic and combined acetylomic/proteomic analysis were performed and found that the differentially expressed acetylated proteins have diverse biological functions, among which 12 proteins were identified as the main targets of HDAC10. Subsequently, HDAC10 expression levels were confirmed to increase following nebulized inhalation of linear poly(β-amino ester) (LPAE)-HDAC10 nanocomplexes. The levels of oxidative stress, the phosphorylation of IKKβ, IκBα and p65, as well as inflammation were inhibited by HDAC10. Pulmonary fibrosis, and lung function in silicosis showed significant improvements in response to the upregulation of HDAC10. Similar results were obtained for the silica-treated macrophages in vitro. In conclusion, HDAC10 was identified as the main mediator of acetylation in silicosis. Nebulized inhalation of LPAE-HDAC10 nanocomplexes was confirmed to be a promising treatment option for silicosis. The ROS/NF-κB pathway was identified as an essential signaling pathway through which HDAC10 attenuates oxidative stress, inflammation, and pulmonary fibrosis in silicosis. This study provides a new theoretical basis for the treatment of silicosis., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this study., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the intervention effect and its mechanism of apocynin, an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) on silicosis induced by silica (SiO(2)) in rats. Methods: In October 2021, 24 SPF SD male rats were divided into control group, silicosis model group and apocynin intervention group according to random number table method, with 8 rats in each group. SiO(2) was exposed by one-time intratracheal instillation. The rats in the apocynin intervention group were intraperitoneally injected with apocynin 50 mg/kg, 3 times a week, on the second day after treatment. The rats were sacrificed 28 days later, and lung coefficients were calculated after lung tissues were weighed. Hematoxylin-eosin staining and Masson staining were used to observe the lung histopathological changes in each group, respectively. The levels of NOX, reactive oxygen species (ROS), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in lung tissue were detected. The expressions of interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were determined by Enzyme-Linked Immunosorbent Assay (ELISA). The level of hydroxyproline (HYP) was detected by alkaline hydrolysate. The expressions of transforming growth factor beta 1 (TGF-β1), E-cadherin (E-cad) and α-smooth muscle actin (α-SMA) in lung tissue were detected by Western blotting. Results: Compared with the control group, the body weight of silicosis model group was decreased, the lung tissue showed obvious inflammatory infiltration and fibrosis, and the levels of lung coefficient, IL-1β, IL-6, TNF-α and TGF-β1 were significantly increased ( P <0.05). Compared with the silicosis model group, the lung tissue injury in the apocynin intervention group was significantly improved, the lung coefficient, NOX, ROS, MDA, IL-1β, IL-6, TNF-α and TGF-β1 levels were decreased, and the activity of GSH-Px was increased ( P <0.05). Compared with the silicosis model group, the expressions of HYP and α-SMA were decreased and the level of E-cad was increased in the apocynin intervention group ( P <0.05) . Conclusion: Apocynin may alleviate SiO(2)-induced fibrosis in silicosis rats by reducing oxidative stress, the release of inflammatory factors and inhibiting the process of epithelial-mesenchymal transition.

Silicosis is an incurable chronic disease characterized by lung fibrosis and inflammation. The combination of tetrandrine and Buyang Huanwu Decoction (BYHWD) has a curative effect on silicosis. However, the mechanism of action and the key active constituent in BYHWD are still unclear. The present study employed network pharmacology and molecular docking to determine the mechanism of action and the key active components of BYHWD of Tetrandrine in combination with BYHWD for silicosis. The primary elements and targets of BYHWD were obtained from the Traditional Chinese Medicine Systems Pharmacology and analysis platform. The targets associated with tetrandrine and silicosis were identified and extracted from the Comparative Toxicogenomics Database and GeneCards database. The potential targets for the treatment of silicosis using a combination of Tetrandrine and BYHWD were identified by considering the overlapping targets between compound drugs and silicosis. These targets were then utilized to construct protein-protein interaction networks, compound drug-ingredient-target networks, and perform enrichment analyses. The top 5 active ingredients present in the compound drug-ingredient-target network are tetrandrine, quercetin, luteolin, kaempferol, and beta-carotene. Similarly, the top 6 hub genes in the protein-protein interaction network are FGF2, MMP-9, MMP-1, IL-10, IL-17A, and IL-6. The molecular docking suggested that the active components may easily access the active pocket of the hub gene. The in-silico investigation suggested that quercetin might be the active component in BYHWD responsible for therapeutic effectiveness against silicosis. This study identified the active compound and potential molecular mechanism underlying the therapeutic effects of BYHWD in combination with tetrandrine for treating silicosis. Notably, we found that quercetin may serve as the key compound in BYHWD for the treatment of silicosis., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Silicosis as an occupational lung disease has been present in our lives for centuries. Research studies have already developed and implemented many animal models to study the pathogenesis and molecular basis of the disease and enabled the search for treatments. As all experimental animal models used to date have their advantages and disadvantages, there is a continuous search for a better model, which will not only accelerate basic research, but also contribute to clinical aspects and drug development. We review here, for the first time, the main animal models developed to date to study silicosis and the unique advantages of the zebrafish model that make it an optimal complement to other models. Among the main advantages of zebrafish for modelling human diseases are its ease of husbandry, low maintenance cost, external fertilisation and development, its transparency from early life, and its amenability to chemical and genetic screening. We discuss the use of zebrafish as a model of silicosis, its similarities to other animal models and the characteristics of patients at molecular and clinical levels, and show the current state of the art of inflammatory and fibrotic zebrafish models that could be used in silicosis research., Competing Interests: Conflict of interest: All authors have nothing to disclose., (Copyright ©The authors 2023.)

Silicosis is a common and ultimately fatal occupational disease, yet the limited therapeutic option remains the major clinical challenge. Apelin, an endogenous ligand of the G-protein-coupled receptor (APJ), is abundantly expressed in diverse organs. The apelin-APJ axis helps to control pathological and physiological processes in lung. The role of apelin in the pathological process and its possible therapeutic effects on silicosis have not been elucidated. In this study, we found that lung expression and circulating levels of apelin were markedly decreased in silicosis patients and silica-induced fibrotic mice and associated with the severity. Furthermore, in vivo data demonstrated that pre-treatment from day 3 and post-treatment from day 15 with apelin could both alleviate silica-induced pulmonary fibrosis in mice. Besides, apelin inhibited pulmonary fibroblast activation via transforming growth factor beta 1 (TGF-β1) signaling. Our study suggested that apelin could prevent and reverse silica-induced pulmonary fibrosis by inhibiting the fibroblast activation through TGF-β1 signaling pathway, thus providing a new potential therapeutic strategy for silicosis and other pulmonary fibrosis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Environmental exposure to crystalline silica (CS) can lead to silicosis. Alveolar macrophages (AMs) play a crucial role in the pathogenesis of silicosis. Previously, we demonstrated that enhancing AMs mitophagy exerted protective effects on silicosis with a restrained inflammatory response. However, the exact molecular mechanisms are elusive. Pyroptosis and mitophagy are two different biological processes that determine cell fate. Exploring whether there were interactions or balances between these two processes in AMs would provide new insight into treating silicosis. Here we reported that crystalline silica induced pyroptosis in silicotic lungs and AMs with apparent mitochondria injury. Notably, we identified a reciprocal inhibitory effect between mitophagy and pyroptosis cascades in AMs. By enhancing or diminishing mitophagy, we demonstrated that PINK1-mediated mitophagy helped clear damaged mitochondria to negatively regulate CS-induced pyroptosis. While constraining pyroptosis cascades by NLRP3, Caspase1, and GSDMD inhibitors, respectively, displayed enhanced PINK1-dependent mitophagy with lessened CS-injured mitochondria. These observed effects were echoed in the mice with enhanced mitophagy. Therapeutically, we demonstrated abolishing GSDMD-dependent pyroptosis by disulfiram attenuated CS-induced silicosis. Collectively, our data demonstrated that macrophage pyroptosis interacting with mitophagy contributes to pulmonary fibrosis via modulating mitochondria homeostasis, which may provide potential therapeutic targets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Silicosis is a life-threatening lung fibrotic disease caused by excessive inhalation of environmental exposure to crystalline silica-containing dust, whereas achieving therapeutic cures are constrained. Antioxidation and anti-inflammation are currently recognized as effective strategies to counteract organ fibrosis. Using naturally occurring phytomedicines quercetin (Qu) has emerged in antagonizing fibrotic disorders involving oxidative stress and inflammation, but unfortunately the hydrophilicity deficiency. Herein, chitosan-assisted encapsulation of Qu in nanoparticles (Qu/CS-NPs) was first fabricated for silicosis-associated fibrosis treatment by pulmonary delivery. Qu/CS-NPs with spherical diameters of ~160 nm, demonstrated a high Qu encapsulated capability, excellent hydrophilic stability, fantastic oxidation radical scavenging action, and outstanding controlled as well as slow release Qu action. A silicosis rat model induced by intratracheal instillation silica was established to estimate the anti-fibrosis effect of Qu/CS-NPs. After intratracheal administration, CS-NPs markedly enhanced Qu anti-fibrotic therapy efficacy, accompanying the evident changes in reducing ROS and MDA production to mitigate oxidative stress, inhibiting IL-1β and TNF-α release, improving lung histological architecture, down-regulating α-SAM levels and suppressing ECM deposition, and thereby ameliorating silica-induced pulmonary fibrosis. Results manifested that the augmented antioxidant and anti-inflammatory activities of Qu by CS-NPs delivery was a result of achieving this remarkable improvement in curative effects. Combined with negligible systemic toxicity, nano-decorated Qu may provide a feasible therapeutic option for silicosis therapy., (© 2023 Wiley Periodicals LLC.)

Silicosis, characterized by irreversible pulmonary fibrosis, remains a major global public health problem. Nowadays, cumulative studies are focusing on elucidating the pathogenesis of silicosis in order to identify preventive or therapeutic antifibrotic agents. However, the existing research on the mechanism of silica-dust-induced pulmonary fibrosis is only the tip of the iceberg and lags far behind clinical needs. Idiopathic pulmonary fibrosis (IPF), as a pulmonary fibrosis disease, also has the same problem. In this study, we examined the relationship between silicosis and IPF from the perspective of their pathogenesis and fibrotic characteristics, further discussing current drug research and limitations of clinical application in silicosis. Overall, this review provided novel insights for clinical treatment of silicosis with the hope of bridging the gap between research and practice in silicosis., Competing Interests: The authors declare no conflict of interest.

Silicosis is a devastating interstitial lung disease characterized by silicon nodules and diffuse pulmonary fibrosis. To date, inefficient therapy is still a challenge of this disease due to its complicated pathogenesis. Hepatocyte growth factor (HGF) which is highly expressed in hepatocyte with anti-fibrotic and anti-apoptotic function was downregulated in silicosis. In addition, the upregulation of transforming growth factor-beta (TGF-β), another pathological molecular was observed to aggravate the severity and accelerate the progression of silicosis. Here AAV expressed HGF with targeting pulmonary capillaries and SB431542, the inhibitor of TGF-β signal pathway, were simultaneously adopted to synergistically reduce silicosis fibrosis. In vivo result demonstrated that the cooperation of HGF with SB431542 showed strong anti-fibrosis effects on the silicosis mice via tracheal administration of silica, compared to the separate treatment. The high efficacy was mainly achieved by remarkably by reducing ferroptosis of lung tissue. In our point, the combination of AAV9-HGF with SB431542 provide an alternative to relieve silicosis fibrosis from the perspective of targeting pulmonary capillaries., Competing Interests: Conflict of interest statement The authors declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Silicosis is an occupational lung disease caused by inhaling silica dust. The disease is characterized by early lung inflammation and late irreversible pulmonary fibrosis. Here we report the effect of Baicalin, a main flavonoid compound from the roots of Chinese herbal medicine Huang Qin on silicosis in a rat model. Results showed Baicalin (50 or 100 mg/kg/day) can mitigate the silica-induced lung inflammation and reduce the harm of alveolar structure and the blue region of collagen fibers in rat lung at 28 days after administration. At the same time, Baicalin also diminished the level of interleukin-1beta (IL-1beta, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta1 (TGF-beta1) in lung tissues. The protein expression of collagen I (Col-1), alpha-smooth muscle actin (alpha-SMA) and vimentin were down-regulated while E-cadherin (E-cad) was increased in Baicalin-treated rats. In addition, the Toll Like Receptor 4 (TLR4)/ nuclear factor kappaB (NF-kappaB) pathway was enabled at 28 days after silica infusion, and the treatment of Baicalin diminished the expression of TLR4 and NF-?B in the lungs of rat with silicosis. These results suggested that Baicalin inhibited the pulmonary inflammatory and fibrosis in a rat model of silicosis, which could be attributed to inhibition of the TLR4/NF-kappaB pathway.

Atractylenolide III (ATL-III) is a major active constituent of the natural plant Atractylodes rhizome. Our previous study has shown that ATL-III may alleviate alveolar macrophage apoptosis via the inhibition of the mammalian target of rapamycin (mTOR)-mediated autophagy of human silicosis. Therefore, we aimed to further explore the function of ATL-III in autophagy, apoptosis, and pulmonary fibrosis by establishing the ATL-III-intervened silicosis mouse model in this study. Meanwhile, we sought and then verified potential autophagy-related signaling pathways by matching differentially expressed genes (attained by RNA sequencing) and the autophagy database. In this study, RNA-sequencing results implied that the epidermal growth factor receptor, the crucial upstream activator of mTOR, was seen as a potential autophagy-regulatory molecule in the ATL-III-intervened silicosis mouse model. The finding of this study was that ATL-III might improve the disorder of autophagic degradation via the activation of epidermal growth factor receptor-mTOR signals in the pulmonary tissue of the silicosis mouse model. ATL-III also alleviated cell apoptosis and silicotic fibrosis. Overall, we supposed that ATL-III might be a potential protective medicine, which had a regulatory effect on autophagy, for the intervention of silicotic fibrosis. In the future, the therapeutic drugs for silicosis should be further focused on the development and application of such natural autophagy agents., (Copyright © 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Inhalation of silica particles causes inflammatory changes leading to fibrotizing silicosis. Considering a lack of effective therapy, and a growing information on the wide actions of green tea polyphenols, particularly epigallocatechin-3-gallate (EGCG), the aim of this study was to evaluate the early effects of EGCG on markers of inflammation and lung fibrosis in silicotic rats. The silicosis model was induced by a single transoral intratracheal instillation of silica (50 mg/mL/animal), while controls received an equivalent volume of saline. The treatment with intraperitoneal EGCG (20 mg/kg, or saline in controls) was initiated the next day after silica instillation and was given twice a week. Animals were euthanized 14 or 28 days after the treatment onset, and the total and differential counts of leukocytes in the blood and bronchoalveolar lavage fluid (BALF), wet/dry lung weight ratio, and markers of inflammation, oxidative stress, and fibrosis in the lung were determined. The presence of collagen and smooth muscle mass in the walls of bronchioles and lung vessels was investigated immunohistochemically. Early treatment with EGCG showed some potential to alleviate inflammation, and a trend to decrease oxidative stress-induced changes, including apoptosis, and a prevention of fibrotic changes in the bronchioles and pulmonary vessels. However, further investigations should be undertaken to elucidate the effects of EGCG in the lung silicosis model in more detail. In addition, because of insufficient data from EGCG delivery in silicosis, the positive and eventual adverse effects of this herbal compound should be carefully studied before any preventive use or therapy with EGCG may be recommended.

Silicosis is a refractory disease. Previous studies indicate that damaged alveolar epithelial cells act as a driver in pulmonary fibrosis. Our results show that epithelial cells that acquire the mesenchymal phenotype are associated with the pathogenesis of silicosis. c-Src kinase, a non-receptor tyrosine kinase, has been shown to be a positive regulator of organ fibrosis, but specific mechanisms remain unclear and rarely researched in silicosis. The activated Phosphatidylinositol-3 kinases/AKT(PI3K/AKT) pathway promotes fibrosis. We aimed to determine whether c-Src regulates fibrosis via the PI3K/AKT signaling pathway in the development of silicosis. C57/BL mice were intratracheally perfused with 10 mg silica suspension to establish a model of silicosis. In vivo, silica particles induced lung fibrosis. The profibrotic cytokine transforming growth factor-β1 (TGF-β1) exhibited a high expression in pulmonary fibrosis. The phosphorylated c-Src protein was increased and the PI3K/AKT pathway was activated in model lung tissue. In vitro, silica increased the expression of TGF-β1- and TGF-β1-induced mesenchymal phenotype and fibrosis in a mouse epithelial cells line. siRNA-Src inhibited the c-Src, the phosphorylation of the PI3K/AKT pathway, and the mesenchymal phenotype induced by TGF-β1. LY294002, a specific inhibitor of PI3K, suppressed the phosphorylation of PI3K/AKT but did not affect Src activation. SU6656, a selective Src inhibitor, attenuated fibrosis in silicosis model. In summary, c-Src promotes fibrosis via the PI3K/AKT pathway in silica-induced lung fibrosis, and Src kinase inhibitors are potentially effective for silicosis treatment.

Silicosis is a diffuse fibrotic lung disease in which excessive inflammatory responses are triggered by silica exposure. Pyroptosis, a pro-inflammatory mode of programmed cell death, is mediated by gasdermin and may play a pivotal role in the development of silicosis. The caspase-1 inhibitor, VX-765, was used in vivo and in vitro to investigate the effects of silica-induced early inflammatory injury and later lung fibrosis. Our findings show that VX-765 reduces inflammatory lung injury by inhibiting silica-induced pyroptosis of alveolar macrophages in a silicosis mouse model. VX-765 limits the infiltration of inflammatory M1 alveolar macrophages, decreasing expression of inflammatory cytokines, including IL-1β, TNF-α, IL-6, CCL2, and CCL3, and down-regulating endogenous DAMPs and inflammatory immune-related cell pattern recognition receptors TLR4 and NLRP3. Furthermore, VX-765 alleviates fibrosis by down-regulating α-smooth muscle actin (α-SMA), collagen, and fibronectin. In this study, we illustrate that Alveolar macrophages pyroptosis occur in the early stages of silicosis, and VX-765 can alleviate the development of silicosis by inhibiting the pyroptosis signaling pathway. These results may provide new insight into the prevention and treatment of early-stage silicosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Nicotinamide mononucleotide (NMN) is a natural antioxidant approved as a nutritional supplement and food ingredient, but its protective role in silicosis characterized by oxidative damage remains unknown. In this study, we generated a silicosis model by intratracheal instillation of silica, and then performed histopathological, biochemical, and transcriptomic analysis to evaluate the role of NMN in silicosis. We found that NMN mitigated lung damage at 7 and 28 days, manifested as a decreasing coefficient of lung weight and histological changes, and alleviated oxidative damage by reducing levels of reactive oxygen species and increasing glutathione. Meanwhile, NMN treatment also reduced the recruitment of inflammatory cells and inflammatory infiltration in lung tissue. Transcriptomic analysis showed that NMN treatment mainly regulated immune response and glutathione metabolism pathways. Additionally, NMN upregulated the expression of antioxidant genes Gstm1 , Gstm2 , and Mgst1 by promoting the expression and nuclear translocation of nuclear factor-erythroid 2 related factor 2 (Nrf2). Gene interaction analysis showed that Nrf2 interacted with Gstm1 and Mgst1 through Gtsm2 . Promisingly, oxidative damage mediated by these genes occurred mainly in fibroblasts. In summary, NMN alleviates silica-induced oxidative stress and lung injury by regulating the endogenous glutathione metabolism pathways. This study reveals that NMN supplementation might be a promising strategy for mitigating oxidative stress and inflammation in silicosis.

Millions of patients suffer from silicosis, but it remains an uncurable disease due to its unclear pathogenic mechanisms. Though the Nlrp3 inflammasome is involved in silicosis pathogenesis, inhibition of its classic downstream factors, Caspase-1 and Gsdmd, fails to block pyroptosis and cytokine release. To clarify the molecular mechanism of silicosis pathogenesis for new therapy, we examined samples from silicosis patients and genetic mouse models. We discovered an alternative pyroptotic pathway which requires cleavage of Gsdme by Caspases-3/8 in addition to Caspase-1/Gsdmd. Consistently, Gsdmd-/-Gsdme-/- mice showed markedly attenuated silicosis pathology, and Gsdmd-/-Gsdme-/- macrophages were resistant to silica-induced pyroptosis. Furthermore, we found that in addition to Caspase 1, Caspase-8 cleaved IL-1β in silicosis, explaining why Caspase-1-/- mice also suffered from silicosis. Finally, we found that inhibitors of Caspase-1, -3, -8 or an FDA approved drug, dimethyl fumarate, could dramatically alleviate silicosis pathology through blocking cleavage of Gsdmd and Gsdme. This study highlights that Caspase-1/Gsdmd and Caspase-3/8/Gsdme-dependent pyroptosis is essential for the development of silicosis, implicating new potential targets and drug for silicosis treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Kang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The small diameter crystalline silica is inhaled into the lung and cannot be cleared. As a result, the patient suffers from silicosis, a lung disease for which there is no effective treatment except lung transplantation. The aim of this study is to reveal the histological, cytological and metabolic characteristics of mice with pulmonary fibrosis induced by different doses of silica, and to provide an ideal animal model for drug development and disease research of pulmonary fibrosis. The experimental mice were divided into five groups. The mice were sacrificed 42 d later by nasal inhalation of normal saline and suspension containing silica 1 mg, 2 mg, 4 mg and 8 mg. Lung specimens and bronchoalveolar lavage fluid (BALF) were collected for histological and cytological examination. Carotid blood was collected and centrifuged to obtain serum for UHPLC-QE-MS non-target metabolomics detection. Compared with the normal control group, except 1 mg silica group, the other dosage groups showed different degree of disease characteristics. Metabolomics analysis showed that arginine and proline metabolism, pentose phosphate pathway, histidine metabolism, cysteine and methionine metabolism, ascorbic acid and aldoglucose metabolism were important metabolic pathways. This study reveals the histological, cytological and metabolic features of four-dose-gradient silica-induced pulmonary fibrosis mouse models.