Silica aggravates pulmonary fibrosis through disrupting lung microbiota and amino acid metabolites.

Silicosis, recognized as a severe global public health issue, is an irreversible pulmonary fibrosis caused by the long-term inhalation of silica particles. Given the intricate pathogenesis of silicosis, there is no effective intervention measure, which poses a severe threat to public health. Our previous study reported that dysbiosis of lung microbiota is associated with the development of pulmonary fibrosis, potentially involving the lipopolysaccharides/toll-like receptor 4 pathway. Similarly, the process of pulmonary fibrosis is accompanied by alterations in metabolic pathways. This study employed a combined approach of 16S rDNA sequencing and metabolomic analysis to investigate further the role of lung microbiota in silicosis delving deeper into the potential pathogenesis of silicosis. Silica exposure can lead to dysbiosis of the lung microbiota and the occurrence of pulmonary fibrosis, which was alleviated by a combination antibiotic intervention. Additionally, significant metabolic disturbances were found in silicosis, involving 85 differential metabolites among the three groups, which are mainly focused on amino acid metabolic pathways. The changed lung metabolites showed a substantial correlation with lung microbiota. The relative abundance of Pseudomonas negatively correlated with L-Aspartic acid, L-Glutamic acid, and L-Threonine levels. These results indicate that dysbiosis in pulmonary microbiota exacerbates silica-induced fibrosis through impacts on amino acid metabolism, providing new insights into the potential mechanisms and interventions of silicosis.

Stacking learning based on micro-CT radiomics for outcome prediction in the early-stage of silica-induced pulmonary fibrosis model.

Silicosis is a progressive pulmonary fibrosis disease caused by long-term inhalation of silica. The early diagnosis and timely implementation of intervention measures are crucial in preventing silicosis deterioration further. However, the lack of screening and diagnostic measures for early-stage silicosis remains a significant challenge. In this study, silicosis models of varying severity were established through a single exposure to silica with different doses (2.5mg/mice or 5mg/mice) and durations (4 weeks or 12 weeks). The diagnostic performance of computed tomography (CT) quantitative analysis was assessed using lung density biomarkers and the lung density distribution histogram, with a particular focus on non-aerated lung volume. Subsequently, we developed and evaluated a stacking learning model for early diagnosis of silicosis after extracting and selecting features from CT images. The CT quantitative analysis reveals that while the lung densitometric biomarkers and lung density distribution histogram, as traditional indicators, effectively differentiate severe fibrosis models, they are unable to distinguish early-stage silicosis. Furthermore, these findings remained consistent even when employing non-aerated areas, which is a more sensitive indicator. By establishing a radiomics stacking learning model based on non-aerated areas, we can achieve remarkable diagnostic performance to distinguish early-stage silicosis, which can provide a valuable tool for clinical assistant diagnosis. This study reveals the potential of using non-aerated lung areas as a region of interest in stacking learning for early diagnosis of silicosis, providing new insights into early detection of this disease.

Ultrastable halide perovskite CsPbBr3 photoanodes achieved with electrocatalytic glassy-carbon and boron-doped diamond sheets.

Halide perovskites exhibit exceptional optoelectronic properties for photoelectrochemical production of solar fuels and chemicals but their instability in aqueous electrolytes hampers their application. Here we present ultrastable perovskite CsPbBr3-based photoanodes achieved with both multifunctional glassy carbon and boron-doped diamond sheets coated with Ni nanopyramids and NiFeOOH. These perovskite photoanodes achieve record operational stability in aqueous electrolytes, preserving 95% of their initial photocurrent density for 168 h of continuous operation with the glassy carbon sheets and 97% for 210 h with the boron-doped diamond sheets, due to the excellent mechanical and chemical stability of glassy carbon, boron-doped diamond, and nickel metal. Moreover, these photoanodes reach a low water-oxidation onset potential close to +0.4 VRHE and photocurrent densities close to 8 mA cm-2 at 1.23 VRHE, owing to the high conductivity of glassy carbon and boron-doped diamond and the catalytic activity of NiFeOOH. The applied catalytic, protective sheets employ only earth-abundant elements and straightforward fabrication methods, engineering a solution for the success of halide perovskites in stable photoelectrochemical cells.

Investigation of the mechanism of silica-induced pulmonary fibrosis: The role of lung microbiota dysbiosis and the LPS/TLR4 signaling pathway.

The widespread manufacture of silica and its extensive use, and potential release of silica into the environment pose a serious human health hazard. Silicosis, a severe global public health issue, is caused by exposure to silica, leading to persistent inflammation and fibrosis of the lungs. The underlying pathogenic mechanisms of silicosis remain elusive. Lung microbiota dysbiosis is associated with the development of inflammation and fibrosis. However, limited information is currently available regarding the role of lung microbiota in silicosis. The study therefore is designed to conduct a comprehensive analysis of the role of lung microbiota dysbiosis and establish a basis for future investigations into the potential mechanisms underlying silicosis. Here, the pathological and biochemical parameters were used to systematically assessed the degree of inflammation and fibrosis following silica exposure and treatment with combined antibiotics. The underlying mechanisms were studied via integrative multi-omics analyses of the transcriptome and microbiome. Analysis of 16S ribosomal DNA revealed dysbiosis of the microbial community in silicosis, characterized by a predominance of gram-negative bacteria. Exposure to silica has been shown to trigger lung inflammation and fibrosis, leading to an increased concentration of lipopolysaccharides in the bronchoalveolar lavage fluid. Furthermore, Toll-like receptor 4 was identified as a key molecule in the lung microbiota dysbiosis associated with silica-induced lung fibrosis. All of these outcomes can be partially controlled through combined antibiotic administration. The study findings demonstrate that the dysbiosis of lung microbiota enhances silica-induced fibrosis associated with the lipopolysaccharides/Toll-like receptor 4 pathway and provided a promising target for therapeutic intervention of silicosis.

Inhibition of macrophage pyroptosis ameliorates silica-induced pulmonary fibrosis.

Macrophage pyroptosis has recently been involved in some inflammatory and fibrosis diseases, however, the role of macrophage pyroptosis in silica-induced pulmonary fibrosis has not been fully elucidated. In this study, we explored the role of macrophage pyroptosis in silicosis in vivo and in vitro. A mouse model of silicosis was established and mice were sacrificed at 7, 14, and 28 days after exposure of silica. The results revealed that the expression of GSDMD and other pyroptosis-related indicators was up-regulated obviously at 14 days after silica exposure, indicating that silica induced pyroptosis in vivo. In vitro, human monocytic leukemia cells (THP-1) and human lung fibroblasts (MRC-5) were used to detect the relationship between macrophage pyroptosis and lung fibroblasts. It showed that silica increased the levels of GSDMD and other pyroptosis-related indicators remarkably in macrophages and the supernatant of macrophage stimulated by silica could promote the upregulation of fibrosis markers in fibroblasts. However, GSDMD knockdown suppressed silica-induced macrophage pyroptosis and alleviated the upregulation of fibrosis markers in fibroblasts, suggesting the important role of macrophage pyroptosis in the activation of myofibroblasts during the progression of silicosis. Taken together, it showed that silica could induce macrophage pyroptosis and inhibiting macrophage pyroptosis could be a feasible clinical strategy to alleviate silicosis.

MiR-148a-3p within HucMSC-Derived Extracellular Vesicles Suppresses Hsp90b1 to Prevent Fibroblast Collagen Synthesis and Secretion in Silica-Induced Pulmonary Fibrosis.

Silicosis is a fatal occupational respiratory disease caused by the prolonged inhalation of respirable silica. The core event of silicosis is the heightened activity of fibroblasts, which excessively synthesize extracellular matrix (ECM) proteins. Our previous studies have highlighted that human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hucMSC-EVs) hold promise in mitigating silicosis and the significant role played by microRNAs (miRNAs) in this process. Delving deeper into this mechanism, we found that miR-148a-3p was the most abundant miRNA of the differential miRNAs in hucMSC-EVs, with the gene heat shock protein 90 beta family member 1 (Hsp90b1) as a potential target. Notably, miR-148a-3p's expression was downregulated during the progression of silica-induced pulmonary fibrosis both in vitro and in vivo, but was restored after hucMSC-EVs treatment (p < 0.05). Introducing miR-148a-3p mimics effectively hindered the collagen synthesis and secretion of fibroblasts induced by transforming growth factor-ß1 (TGF-ß1) (p < 0.05). Confirming our hypothesis, Hsp90b1 was indeed targeted by miR-148a-3p, with significantly reduced collagen activity in TGF-ß1-treated fibroblasts upon Hsp90b1 inhibition (p < 0.05). Collectively, our findings provide compelling evidence that links miR-148a-3p present in hucMSC-EVs with the amelioration of silicosis, suggesting its therapeutic potential by specifically targeting Hsp90b1, thereby inhibiting fibroblast collagen activities. This study sheds light on the role of miR-148a-3p in hucMSC-EVs, opening avenues for innovative therapeutic interventions targeting molecular pathways in pulmonary fibrosis.

MiR-26a-5p from HucMSC-derived extracellular vesicles inhibits epithelial mesenchymal transition by targeting Adam17 in silica-induced lung fibrosis.

Silicosis is one of several potentially fatal occupational pathologies caused by the prolonged inhalation of respirable crystalline silica. Previous studies have shown that lung epithelial-mesenchymal transition (EMT) plays a significant role in the fibrosis effect of silicosis. Human umbilical cord mesenchymal stem cells-derived Extracellular vesicles (hucMSC-EVs) have attracted great interest as a potential therapy of EMT and fibrosis-related diseases. However, the potential effects of hucMSC-EVs in inhibiting EMT in silica-induced fibrosis, as well as its underlying mechanisms, remain largely unknown. In this study, we used the EMT model in MLE-12 cells and observed the effects and mechanism of hucMSC-EVs inhibition of EMT. The results revealed that hucMSC-EVs can indeed inhibit EMT. MiR-26a-5p was highly enriched in hucMSC-EVs but was down-regulated in silicosis mice. We found that miR-26a-5p in hucMSC-EVs was over-expressed after transfecting miR-26a-5p expressing lentivirus vectors into hucMSCs. Subsequently, we explored if miR-26a-5p, attained from hucMSC-EVs, was involved in inhibiting EMT in silica-induced lung fibrosis. Our findings suggested that hucMSC-EVs could deliver miR-26a-5p into MLE-12 cells and cause the inhibition of the Adam17/Notch signalling pathway to ameliorate EMT in silica-induced pulmonary fibrosis. These findings might represent a novel insight into treating silicosis fibrosis.

Human umbilical cord mesenchymal stem cell-derived extracellular vesicles alleviated silica induced lung inflammation and fibrosis in mice via circPWWP2A/miR-223-3p/NLRP3 axis.

Silicosis is a progressive inflammatory disease with poorly defined mechanisms and limited therapeutic options. Recent studies found that microRNAs (miRNAs) and circular RNAs (circRNAs) were involved in the development of respiratory diseases; however, the function of non-coding RNAs in silicosis was still needed to be further explored. We found that miR-223-3p was significantly decreased in macrophages and lung tissues of mice after silica treatment, which were consistent with the results of GEO database microarray analysis. Notably, NLRP3 is a target gene downstream of miR-223-3p. And circular RNA PWWP2A (circPWWP2A) was significantly elevated after silica stimulation. To elucidate the role of these RNAs in silica-induced inflammation in macrophages and lung tissues, we investigated the upstream molecular mechanisms of circPWWP2A on the inflammatory response. The inhibitory effect of miR-223-3p on its target NLRP3 was suppressed by circPWWP2A, which led to lung fibrosis. Our study found that circPWWP2A could adsorb miR-223-3p to regulate NLRP3 after silica stimulation in pulmonary fibrosis. And our results revealed that the circPWWP2A-miR-223-3p-NLRP3 axis was potentially instrumental in managing silica-induced inflammation and fibrosis. Previous studies have demonstrated that human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hucMSC-EVs) exhibit anti-inflammatory and anti-fibrotic effects in multiple organs. However, the potential effectiveness of hucMSC-EVs against silicosis or the underlying mechanisms of their biological outcomes remains unclear. Therefore, we used 3D culture technology to extract hucMSC-EVs and observed their effects in macrophages and lung tissues, respectively. According to the EVmiRNA database, miR-223-3p was abundant in MSC-EVs. In addition, hucMSC-EVs may modulate lung function, reduce the secretion of inflammatory factors (NLRP3, IL-1ß, IL-18 and cleaved Caspase-1) and attenuate the deposition of fibrosis-related factors (Collagen Ⅰ, Collagen Ⅲ, fibronectin and α-SMA). In vitro results evinced that hucMSC-EVs reduced the inflammatory response of macrophages and restricted the activation and proliferation of fibroblasts. Moreover, our study showed that hucMSCs-EVs acted as a mediator to transfer miR-223-3p to suppress circPWWP2A, thereby alleviating pulmonary fibrosis through the NLRP3 signaling pathway. These data may provide potentially novel strategies for investigating the pathogenesis of silicosis and developing novel treatments for this disease.

microRNA-149-5p mediates the PM2.5-induced inflammatory response by targeting TAB2 via MAPK and NF-κB signaling pathways in vivo and in vitro.

Epidemiological evidence has shown that fine particulate matter (PM2.5)-triggered inflammatory cascades are pivotal causes of chronic obstructive pulmonary disease (COPD). However, the specific molecular mechanism involved in PM2.5-induced COPD has not been clarified. Herein, we found that PM2.5 significantly downregulated miR-149-5p and activated the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways and generated the inflammatory response in COPD mice and in human bronchial epithelial (BEAS-2B) cells. We determined that increased expression of interleukin-1ß (IL-1ß), IL-6, IL-8, and tumor necrosis factor-α (TNF-α) induced by PM2.5 was associated with decreased expression of miR-149-5p. The loss- and gain-of-function approach further confirmed that miR-149-5p could inhibit PM2.5-induced cell inflammation in BEAS-2B cells. The double luciferase reporter assay showed that miR-149-5p directly targeted TGF-beta-activated kinase 1 binding protein 2 (TAB2), which regulates the MAPK and NF-κB signaling pathways. We showed that miR-149-5p mediated the inflammatory response by targeting the 3'-UTR sequence of TAB2 and that it subsequently weakened the TAB2 promotor effect via the MAPK and NF-κB signaling pathways in BEAS-2B cells exposed to PM2.5. Thus, miR-149-5p may be a key factor in PM2.5-induced COPD. This study improves our understanding of the molecular mechanism of COPD.

Revealing the stochastic kinetics evolution of photocatalytic CO2 reduction.

Investigating kinetic mechanisms to design efficient photocatalysts is critical for improving photocatalytic CO2 reduction, but the stochastic photo-physical/chemical properties of kinetics remain unclear. Herein, we propose a statistical study to discuss the stochastic feature evolution of photocatalytic systems. The uncertainties of light absorption, charge carrier migration, and surface reaction are described by nonparametric estimation methods in the proposed model, which includes the effect of operational and material parameters. The density distribution of surface electrons shifts from a skewed distribution to an approximate uniform distribution as incident photon density increases. The system temperature rising induces the rate-determining step of surface reactions to change from charge carrier kinetics to reactant activation processes. Benefiting from the synergistic optimization between the operational parameter and active site density, the electron-capturing probability of active sites is boosted from 0.06 to 0.17. The modified reaction kinetic equation is constructed based on the distribution function of charge carrier kinetics. Furthermore, the experimental photoactivity results are consistent with the statistical analysis, which proves the feasibility of the established model. The characterization tests show that the gap between testing activities and theoretical efficiency is caused by a mismatch between charge carrier supply and mass transfer. Our work unveils the stochastic features in photocatalytic CO2 reduction, offering a comprehensive analytical framework for photocatalytic system optimization.

Saccharina japonica fucan suppresses high fat diet-induced obesity and enriches fucoidan-degrading gut bacteria.

Low molecular weight seaweed polysaccharides exhibit promising potential as novel therapeutics for the prevention of obesity and gut microbiota dysbiosis. The interplay between polysaccharides and gut microbiota may play crucial roles in their anti-obesity effects, but is largely unknown, including the impact of polysaccharides on the composition of the gut microbiota with polysaccharide-degrading capacity. The primary structure of a 5.1 kDa fucan (J2H) from Saccharina japonica was characterized and oral administration of J2H effectively suppressed high-fat diet-induced obesity, blood glucose metabolic dysfunction, dyslipidemia, and gut microbiota dysbiosis. Furthermore, the Jensen-Shannon divergence analysis demonstrated that J2H enriched at least four gut bacterial species with fucoidan-degrading potential, including Bacteroides sartorii and Bacteroides acidifaciens. Our findings suggest that the low molecular weight S. japonica fucan, J2H, is a promising potential agent for obesity prevention and its enrichment of gut bacteria with fucoidan-degrading potential may play a vital role in the anti-obesity effects.

What Role Does the Incident Light Intensity Play in Photocatalytic Conversion of CO2 : Attenuation or Intensification?

Artificial photoreduction of CO2 is vital for the sustainable development of human beings via solar energy storage in stable chemicals. This process involves intricate light-matter interactions, but the role of incident light intensity in photocatalysis remains obscure. Herein, the influence of excitation intensity on charge kinetics and photocatalytic activity is investigated. Model photocatalysts include the pure graphitic carbon nitride (g-C3 N4 ) and g-C3 N4 loaded with noble/non-noble-metal cocatalysts (Ag, TiN, and CuO). It is found that the increase of light intensity does not always improve the electron utilization. Overly high excitation intensities cause charge carrier congestion and changes the recombination mechanism, which is called the light congestion effect. The electron transport channels can be established to mitigate the light-induced effect via the addition of cocatalyst, leading to a nonlinear growth in the reaction rate with increasing light intensity. From experiments and simulations, it is found that the light intensity and active site density should be collectively optimized for increasing the energy conversion efficiency. This work elucidates the effect of light intensity on photocatalytic CO2 reduction and emphasizes the synergistic relationship of matching the light intensity and the photocatalyst category. The study provides guidance for the design of efficient photocatalysts and the operation of photocatalytic systems.

Lung microbiome and transcriptome reveal mechanisms underlying PM2.5 induced pulmonary fibrosis.

Airborne fine particulate matter (PM2.5) is considered to be a risk factor for lung fibrosis, and therefore, it has attracted public attention due to its various physicochemical features and its adverse effects on health. However, little remains to be known regarding the mechanism of PM2.5-induced pulmonary fibrosis. The lung microbiota may be a potential factor involved in the adverse outcomes of pulmonary fibrosis. Meanwhile, miRNAs are thought to be key regulators that participate in the complex interplay between the host and the microbiota. Hence, to investigate the potential mechanisms of pulmonary fibrosis, and to explore the impact of PM2.5-induced alterations in miRNAs and the lung microbiota and possible interaction patterns in mice models, we took advantage of 16S rDNA gene sequencing, miRNAs sequencing (miRNAs-Seq), and mining of public databases profiling. The results of 16S rDNA analysis showed that PM2.5 interfered with the microbial community composition, resulting in Proteobacteria becoming an additional dominant phylum. In addition, differentially expressed miRNAs were enriched in HIF-1 signaling, the IL-17 signaling, as well as Th17 cell differentiation pathways, which are closely related to microbial functional pathways. Significantly, a target miRNA, miR-149-5p, may be a key factor triggering the MAPK signal pathway related to pulmonary fibrosis and disturbing the homeostasis of lung bacterial flora. These results indicate that PM2.5 may lead to interaction between lung microbiota dysbiosis and an imbalance of miRNA levels to form a vicious cycle that promotes lung fibrogenesis. The current study provides new insights into the progression of pulmonary fibrosis.

Exosomal let-7i-5p from three-dimensional cultured human umbilical cord mesenchymal stem cells inhibits fibroblast activation in silicosis through targeting TGFBR1.

Silicosis of pulmonary fibrosis (PF) is related to long-term excessive inhalation of silica. The activation of fibroblasts into myofibroblasts is the main terminal effect leading to lung fibrosis, which is of great significance to the study of the occurrence and development of silicosis fibrosis and its prevention and treatment. Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-Exos) are considered to be a potential therapy of silica-induced PF, however, their exact mechanism remains unknown. Therefore, this study aims to explore whether hucMSC-Exos affect the activation of fibroblasts to alleviate PF. In this study, a three-dimensional (3D) method was applied to culture hucMSCs and MRC-5 cells (human embryonic lung fibroblasts), and exosomes were isolated from serum-free media, identified by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM) and Western blotting analysis. Then, the study used an animal model of silica-induced PF to observe the effects of hucMSC-Exos and MRC-5-Exos on activation of fibroblasts. In addition, the activation of fibroblasts was analyzed by Western blotting analysis, wound healing, and migration assay with the treatment of hucMSC-Exos and MRC-5-Exos in NIH-3T3 cells (mouse embryonic fibroblasts). Furthermore, differential expression of microRNAs (DE miRNAs) was measured between hucMSCs-Exos and MRC-5-Exos by high throughput sequence. HucMSC-Exos inhibited the activation of fibroblasts in mice and NIH-3T3 cells. Let-7i-5p was significantly up-regulated in hucMSCs-Exos compared to MRC-5-Exos, which was related to silica-induced PF. Let-7i-5p of hucMSCs-Exos was responsible for the activation of fibroblasts by targeting TGFBR1. Meanwhile, Smad3 was also an important role in the activation of fibroblasts. The study demonstrates that hucMSCs-Exos act as a mediator that transfers let-7i-5p to inhibit the activation of fibroblasts, which alleviates PF through the TGFBR1/Smad3 signaling pathway. The mechanism has potential value for the treatment of silica-induced PF.

A comparative study on the model of PM2.5 direct or indirect interaction with bronchial epithelial cells.

The impact of PM2.5 on epithelial cells is a pivotal process leading to many lung pathological changes and pulmonary diseases. In addition to PM2.5 direct interaction with epithelia, macrophages that engulf PM2.5 may also influence the function of epithelial cells. However, among the toxic researches of PM2.5, there is a lack of evaluation of direct or indirect exposure model on human bronchial epithelial cell against PM2.5. In this present research, PM2.5-exposed human bronchial epithelial cell line (BEAS-2B) serves as the direct interaction model. By contrast, a PM2.5-stimulated co-culture model of macrophages and epithelial cells based on the transwell system was adopted as indirect stimulation model. By comparing these two models of interaction, we examined the viability of BEAS-2B and mRNA/protein expression profile of oxidative stress and inflammatory response-related transcription factors Nrf2, NF-kB, and according inflammatory indicators such as IL-1, IL-6, and IL-8, with a view to evaluating the effects of different interaction models of PM2.5 on epithelial cell damage in vitro. Our results indicated that under the same doses, the direct stimulation model of PM2.5 could inhibit the viability of BEAS-2B. Furthermore, the indirect stimulation model strengthen inflammation response of epithelia under the higher concentration of PM2.5 and induce epithelia to undergo EMT under the lower concentration of PM2.5. Overall, we have found that macrophage involvement may protect epithelia from PM2.5 cytotoxic effect, while it strengthens the inflammation response and induce epithelia to undergo EMT.

Complete genome sequence of Micromonospora craniellae LHW63014T, a potential metal ion-chelating agent producer.

Micromonospora craniellae LHW63014T is a novel marine Micromonospora, isolated from a Craniella species sponge collected in the South China Sea. In this study, we report the complete genome sequence of M. craniellae LHW63014T, which is comprised of a circular chromosome of 6,839,926 bp with the G + C content of 70.9 mol%. The complete genome contained 6572 protein-coding genes, 48 tRNA genes, and 9 rRNA genes. Genomic annotations revealed that 79.09% of the protein-coding genes were assigned to the COG database, among which, the abundant genes were predicted to be involved in transcription, replication, recombination and repair, and amino acid transport and metabolism. Secondary metabolites prediction using antiSMASH revealed that 22 biosynthetic gene clusters (BGC) of secondary metabolites were located in the genome of M. craniellae LHW63014T, 19 of which showed low similarity (<50%) to known BGCs and 5 of which showed the closest homology with BGCs encoding metal ion-chelating agents, indicating the immense potential of M. craniellae LHW63014T to produce a wide variety of novel antibiotics, especially for metal ion-chelating agents.

Snail-mediated partial epithelial mesenchymal transition augments the differentiation of local lung myofibroblast.

The pathogenesis of pulmonary fibrosis diseases is considered to be related with environmental exposures, but the exact mechanism is unclear and there are no effective treatments. The contribution of epithelial-mesenchymal transition (EMT) to lung fibrosis has been controversial. It was found that partial EMT might play a vital role in renal fibrosis. We also found that partial EMT might be involved in fibrosis diseases. In this study, we used a silicosis animal model of pulmonary fibrosis to observe whether partial EMT existed in pulmonary fibrosis disease and a co-culture system culturing fibroblasts and alveolar epithelial cells stimulated by TGF-ß1 to evaluate the probable effects of partial EMT, thus determined the probable role of partial EMT in pulmonary fibrosis diseases. In vivo, the results revealed that partial EMT might exist in silica-induced lung fibrosis model and Snail which is a potent EMT inducer was involved during the process. In vitro, a co-culture system was used to evaluate the effects of EMT in murine alveolar epithelial type II (ATII) cells on the activation of underlying murine lung fibroblasts into myofibroblasts. The results showed that epithelial cells undergoing EMT promoted the differentiation of lung myofibroblast and this epithelial-mesenchymal crosstalk was mainly controlled by Snail. Following Snail silencing the EMT and the activation of NIH-3T3 into myofibroblast were obviously inhibited. It indicated that targeting this novel Snail might be a viable strategy for the treatment of lung fibrosis diseases.

Exosomes derived from three-dimensional cultured human umbilical cord mesenchymal stem cells ameliorate pulmonary fibrosis in a mouse silicosis model.

BACKGROUND: Silicosis is an occupational respiratory disease caused by long-term excessive silica inhalation, which is most commonly encountered in industrial settings. Unfortunately, there is no effective therapy to delay and cure the progress of silicosis. In the recent years, stem cell therapy has emerged as an attractive tool against pulmonary fibrosis (PF) owing to its unique biological characteristics. However, the direct use of stem cells remains limitation by many risk factors for therapeutic purposes. The exclusive utility of exosomes secreted from stem cells, rather than cells, has been considered a promising alternative to overcome the limitations of cell-based therapy while maintaining its advantages. METHODS AND RESULTS: In this study, we first employed a three-dimensional (3D) dynamic system to culture human umbilical cord mesenchymal stem cell (hucMSC) spheroids in a microcarrier suspension to yield exosomes from serum-free media. Experimental silicosis was induced in C57BL/6J mice by intratracheal instillation of a silica suspension, with/without exosomes derived from hucMSC (hucMSC-Exos), injection via the tail vein afterwards. The results showed that the gene expression of collagen I (COL1A1) and fibronectin (FN) was upregulated in the silica group as compared to that in the control group; however, this change decreased with hucMSC-Exo treatment. The value of FEV0.1 decreased in the silica group as compared to that in the control group, and this change diminished with hucMSC-Exo treatment. These findings suggested that hucMSC-Exos could inhibit silica-induced PF and regulate pulmonary function. We also performed in vitro experiments to confirm these findings; the results revealed that hucMSC-Exos decreased collagen deposition in NIH-3T3 cells exposed to silica. CONCLUSIONS: Taken together, these studies support a potential role for hucMSC-Exos in ameliorating pulmonary fibrosis and provide new evidence for improving clinical treatment induced by silica.

Sodium tanshinone IIA sulfonate attenuates silica-induced pulmonary fibrosis in rats via activation of the Nrf2 and thioredoxin system.

Silicosis is characterized by pulmonary fibrosis due to long-term inhalation of silica particles. Although the cause of this serious disease is known, its pathogenesis remains unclear and there are currently no specific treatments. Recent studies have shown that the anti-oxidant transcription factor Nrf2 is expressed at reduced levels in fibrotic foci, which may be related to disease progression. However, the molecular mechanisms by which this might occur have yet to be elucidated. Sodium tanshinone IIA sulfonate (STS), an extract of Salvia miltiorrhiza, is used in traditional Chinese medicine in the treatment of coronary heart disease. STS has been shown to play a strong anti-oxidative role in various organs. Here, we employed a rat model to explore the effects of STS on oxidative stress and the progression of fibrosis in silicosis. STS significantly reduced collagen deposition in the lungs, thereby antagonising silicosis. Immunohistochemical and immunofluorescence staining showed that Nrf2 was differentially expressed in lung cells during silica induced fibrosis, and chromatin immunoprecipitation-sequencing experiments demonstrated that Nrf2 promoted the expression of the antioxidant proteins thioredoxin and thioredoxin reductase. Our results suggest that the anti-fibrotic effects of STS may be related to upregulation of Nrf2 nuclear expression, especially in fibrotic lesions, and the promotion of thioredoxin and thioredoxin reductase expression. Our findings may open up new avenues for the development of STS as a treatment for silicosis.

Integrative characterization of fine particulate matter-induced chronic obstructive pulmonary disease in mice.

The impacts of ambient fine particulate matter (PM2.5) on public health are a worldwide concern. Epidemiological evidence has shown that PM2.5-triggered inflammatory cascades and lung tissue damage are important causes of chronic obstructive pulmonary disease (COPD). However, most laboratory studies of COPD have focused on animal models of cigarette smoke exposure or combined exposure to cigarette smoke and PM2.5. Furthermore, a single method is used to evaluate the development of COPD without integrality. In this study, we investigated pulmonary pathophysiological alterations using integrated functional, morphological, and biochemical techniques and a mouse model exposed to PM2.5 alone for 3 months. Emphysema in this model was confirmed by reconstructed three-dimensional micro-CT images. Typical histopathological signs were neutrophil/macrophage infiltration and accumulation at 2 months after exposure and emphysema/atelectasis at 3 months. Respiratory mechanical parameters confirmed that PM2.5 caused a decline in respiratory function. PM2.5 also triggered complex cytokine profile changes in the lungs with characteristic inflammation-related tissue destruction. This study showed that chronic PM2.5 exposure impaired lung function, triggered emphysematous lesions, and induced pulmonary inflammation and airway wall remodeling. Most importantly, prolonged exposure to PM2.5 alone caused COPD in mice. These results improve the understanding of the mechanisms and mediators underlying PM2.5-induced COPD.