Silica-induced Lung Inflammation Research Articles

Preliminary Study on the Effect and Molecular Mechanism of Tetrandrine in Alleviating Pulmonary Inflammation and Fibrosis Induced by Silicon Dioxide.

This study aims to explore the molecular mechanism of tetrandrine (Tet) in alleviating pulmonary inflammation and fibrosis induced by silica (SiO2) from the perspective of autophagy. C57BL/6J mice were selected as experimental animals, and SiO2 was exposed by intranasal instillation. Tet was intervened by oral gavage. The mice were euthanized on the 7th and 42nd day of SiO2 exposure, and lung tissues were collected for histopathological, molecular biological, immunological, and transmission electron microscopy analysis. The results showed that SiO2 exposure could lead to significant lung inflammation and fibrosis, while Tet could significantly reduce SiO2 exposure-induced lung inflammation and fibrosis. Molecular mechanism research indicated that, compared with SiO2 expose group, Tet intervention could significantly reduce the expression levels of inflammatory cytokines and fibrosis markers (TNF-α, IL-1β, MCP-1, TGF-β1, HYP, Col-I, and Fn), and regulate the expression of key molecules ATG7, microtubule-associated protein 1 light chain 3B (LC3B), and P62 in the autophagy pathway to improve the blocking of autophagic flux, promote the recovery of autophagic lysosomal system function, and inhibit apoptosis. In summary, Tet can alleviate silica-induced lung inflammation and fibrosis, which may be achieved by regulating the expression of key molecules in the autophagy process and associated apoptotic pathway.

Baicalin Alleviates Silica-Induced Lung Inflammation and Fibrosis by Inhibiting TLR4/NF-κB Pathway in Rats

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-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) in lung tissues. The protein expression of collagen I (Col-1), α-smooth muscle actin (α-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-κB) pathway was enabled at 28 days after silica infusion, and the treatment of Baicalin diminished the expression of TLR4 and NF-κB 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-κB pathway.

Gasdermin D membrane pores orchestrate IL-1α secretion from necrotic macrophages after NFS-rich silica exposure

IL-1α is an intracellular danger signal (DAMP) released by macrophages contributing to the development of silica-induced lung inflammation. The exact molecular mechanism orchestrating IL-1α extracellular release from particle-exposed macrophages is still unclear. To delineate this process, murine J774 and bone-marrow derived macrophages were exposed to increasing concentrations (1–40 cm2/ml) of a set of amorphous and crystalline silica particles with different surface chemical features. In particular, these characteristics include the content of nearly free silanols (NFS), a silanol population responsible for silica cytotoxicity recently identified. We first observed de novo stocks of IL-1α in macrophages after silica internalization regardless of particle physico-chemical characteristics and cell stress. IL-1α intracellular production and accumulation were observed by exposing macrophages to biologically-inert or cytotoxic crystalline and amorphous silicas. In contrast, only NFS-rich reactive silica particles triggered IL-1α release into the extracellular milieu from necrotic macrophages. We demonstrate that IL-1α is actively secreted through the formation of gasdermin D (GSDMD) pores in the plasma membrane and not passively released after macrophage plasma membrane lysis. Our findings indicate that the GSDMD pore-dependent secretion of IL-1α stock from macrophages solely depends on cytotoxicity induced by NFS-rich silica. This new regulated process represents a key first event in the mechanism of silica toxicity, suitable to refine the existing adverse outcome pathway (AOP) for predicting the inflammatory activity of silicas.

The Effects of Resveratrol on Silica-Induced Lung Oxidative Stress and Inflammation in Rat

BackgroundChronic exposure to silica is related with the provocation of an inflammatory response and oxidative stress mechanism. Vitamin D has multiple benefits in biological activities particularly respiratory system disease. MethodIn this research, 20 male Wistar rats were randomly allocated into four groups (5 rats /group) as follow: Group1 received saline as (negative control) group. The group 2 received a single IT instillation of silica (positive control) group; the group 3 was co-administrated with single IT silica and Vitamin D (20 mg/kg/day) daily for a period of 90 days. The rats of group 4 received Vitamin D daily for a period of 90 days. ResultsSilica significantly increased serum and lung total Oxidant Status (TOS). Meanwhile, silica reduced serum and lung total antioxidant capacity (TAC), GSH and tumor necrosis factor-α (TNF-a). Vitamin D treatment meaningfully reversed oxidative stress, antioxidants status and inflammatory response. Also, Vitamin D improved histopathological changes caused by silica. ConclusionThese findings indicate that Vitamin D exerts protective effects against silica-induced lung injury. It seems that Vitamin D has potential use as a therapeutic object for silica induced lung injure.

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-1β, 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.

NLRP3 Inflammasome Mediates Silica-induced Lung Epithelial Injury and Aberrant Regeneration in Lung Stem/Progenitor Cell-derived Organotypic Models.

Silica-induced lung epithelial injury and fibrosis are vital pathogeneses of silicosis. Although the NOD-like receptor protein 3 (NLRP3) inflammasome contributes to silica-induced chronic lung inflammation, its role in epithelial injury and regeneration remains unclear. Here, using mouse lung stem/progenitor cell-derived organotypic systems, including 2D air-liquid interface and 3D organoid cultures, we investigated the effects of the NLRP3 inflammasome on airway epithelial phenotype and function, cellular injury and regeneration, and the potential mechanisms. Our data showed that silica-induced NLRP3 inflammasome activation disrupted the epithelial architecture, impaired mucociliary clearance, induced cellular hyperplasia and the epithelial-mesenchymal transition in 2D culture, and inhibited organoid development in 3D system. Moreover, abnormal expression of the stem/progenitor cell markers SOX2 and SOX9 was observed in the 2D and 3D organotypic models after sustained silica stimulation. Notably, these silica-induced structural and functional abnormalities were ameliorated by MCC950, a selective NLRP3 inflammasome inhibitor. Further studies indicated that the NF-κB, Shh-Gli and Wnt/β-catenin pathways were involved in NLRP3 inflammasome-mediated abnormal differentiation and dysfunction of the airway epithelium. Thus, prolonged NLRP3 inflammasome activation caused injury and aberrant lung epithelial regeneration, suggesting that the NLRP3 inflammasome is a pivotal target for regulating tissue repair in chronic inflammatory lung diseases.

The aggravate role of exosomal circRNA11:120406118|12040782 on macrophage pyroptosis through miR-30b-5p/NLRP3 axis in silica-induced lung fibrosis.

Silica dust inhalation could lead to silicosis, and there is no specific biomarker for its early diagnosis and no effective treatment due to the lack of research on its pathogenesis. The homeostasis of macrophages was considered to be crucial during the development of silicosis from persistent chronic inflammation to irreversible fibrosis. However, its regulatory mechanism and the communication between macrophages and others are still not clear. Exosomal circRNAs emerge as favorable candidates for cellular communication. Therefore, our study aimed to illustrate the regulatory mechanism of silicosis from the view of exosomal circRNAs. Our study identified a novel exosomal circRNA, circRNA11:120406118|12040782, in the peripheral serum of silicosis patients. Furthermore, the detailed role of circRNA11:120406118|12040782 was investigated both in silicosis mouse model and in silica-stimulated macrophages and fibroblasts. On the one hand, circRNA11:120406118|12040782 was shown to regulate silica-stimulated macrophage pyroptosis through circRNA11:120406118|12040782/miR-30b-5p/NLRP3 network. And this macrophage-derived cirRNA could promote the activation of fibroblasts. On the other hand, overexpressing miR-30b-5p, the crucial component of circRNA11:120406118|12040782/miR-30b-5p/NLRP3 regulatory network, could inhibit pyroptosis and attenuate silica-induced lung inflammation and fibrosis in mice. Our findings suggested that exosomal circRNA11:120406118|12040782 could aggravate NLRP3-mediated macrophages pyroptosis through sponging miR-30b-5p in silicosis development, which provide an experimental basis and shed light on the early diagnosis and treatment of silicosis.

Macrophage-derived exosomal lncRNA MSTRG.91634.7 inhibits fibroblasts activation by targeting PINK1 in silica-induced lung fibrosis

Silicosis is a fibrotic lung disease caused by the inhalation of free crystalline silica. Its pathogenesis is extremely complex and involves a variety of cells. Exosomes emerge as a favorable candidate for communication between cells. LncRNA is a major component transported by exosomes in many inflammatory diseases. However, the role of exosomal lncRNA in the pathogenesis of silicosis is still unclear. In this study, the decreased expression of a novel exosomal lncRNA MSTRG.91634.7 in silicosis patients was identified according to high-throughput sequencing. Then, this macrophage-derived exosomal lncRNA MSTRG.91634.7 could regulate the fibroblast’s activation by targeting PINK1 in a co-culture system of THP-1 and MRC-5. Finally, the mouse was exposed to 3 mg/50 μL silica to set up the silicosis model. AAV-ov-Pink1 was intratracheally injected to overexpress PINK1 in mice lungs. Our results suggested that PINK1, the target protein of lncRNA MSTRG.91634.7, participated in restricting the silica-induced lung inflammation and fibrosis in mice.

Alveolar macrophage-derived progranulin mediated pro-inflammatory Il-6 expression via regulating Creb1 in silicosis model

Progranulin (PGRN) is a secreted factor involved in inflammatory diseases. However, the function of PGRN in silica-induced lung inflammation has not been elucidated. In this study, we demonstrated that PGRN in serum and lung tissues was markedly increased in silicosis mouse model. And immunohistochemistry results showed that PGRN was mainly expressed in alveolar macrophages, which was further confirmed in silica-treated alvelar macrophages cell line (MH-S) in vitro. PGRN promoted pro-inflammatory cytokines transcription such as interleukin (Il)-6, tumor necrosis factor-α (Tnf-α) and Il-1β in MH-S cells, and the increasing of Il-6 was most obvious. Knockdown of PGRN blocked the silica-induced elevation of intracellular Il-6 in MH-S cells. Furthermore, we also found that PGRN could increase the phosphorylation of Cyclic AMP-responsive element-binding protein 1 (Creb1), a transcriptional regulator of Il-6. Inhibition of p-Creb1 by the phosphorylation inhibitor of Creb1 (666–15) decreased PGRN-induced intracellular Il-6 production in MH-S cells. In conclusion, PGRN was highly increased in silicosis mouse model and upregulated inflammatory cytokines expression. These findings suggested that PGRN might be a key mediator in silica-induced inflammation and provided a new clue for the diagnosis and drug therapy of silicosis.

Neutralization of interleukin-11 attenuates silica particles-induced pulmonary inflammation and fibrosis in vivo

Environmental exposure to crystalline silica particles can lead to silicosis, which is one of the most serious pulmonary interstitial fibrosis around the world. Unfortunately, the exact mechanism on silicosis is unclear, and the effective treatments are lacking to date. In this study, we aim to explore the molecular mechanism by which interleukin-11 (IL-11) affects silica particles-induced lung inflammation and fibrosis. We observed that IL-11 expressions in mouse lungs were significantly increased after silica exposure, and maintained at high levels across both inflammation and fibrosis phase. Immunofluorescent dual staining further revealed that the overexpression of IL-11 mainly located in mouse lung epithelial cells and fibroblasts. Using neutralizing anti-IL-11 antibody could effectively alleviate the overexpression of pro-inflammatory cytokines (i.e., interleukin-6 and tumor necrosis factor-α) and fibrotic proteins (i.e., collagen type I and matrix metalloproteinase-2) induced by silica particles. Most importantly, the expressions of IL-11 receptor subunit α (IL-11Rα), Glycoprotein 130 (GP130), and phosphorylated extracellular signal-regulated kinase (p-ERK) were significantly increased in response to silica, whereas blocking of IL-11 markedly reduced their levels. All findings suggested that the overexpression of IL-11 was involved in the pathological of silicosis, while neutralizing IL-11 antibody could effectively alleviate the silica-induced lung inflammation and fibrosis by inhibiting the IL-11Rα/GP130/ERK signaling pathway. IL-11 might be a promising therapeutic target for lung inflammation and fibrosis caused by silica particles exposure.

Pirfenidone ameliorates silica-induced lung inflammation and fibrosis in mice by inhibiting the secretion of interleukin-17A.

Silicosis is a global occupational disease characterized by lung dysfunction, pulmonary inflammation, and fibrosis, for which there is a lack of effective drugs. Pirfenidone has been shown to exert anti-inflammatory and anti-fibrotic properties in the lung. However, whether and how pirfenidone is effective against silicosis remains unknown. Here, we evaluated the efficacy of pirfenidone in the treatment of early and advanced silicosis in an experimental mouse model and explored its potential pharmacological mechanisms. We found that pirfenidone alleviated silica-induced lung dysfunction, secretion of inflammatory cytokines (TNF-α, IL-1β, IL-6) and deposition of fibrotic proteins (collagen I and fibronectin) in both early and advanced silicosis models. Moreover, we observed that both 100 and 200 mg/kg pirfenidone can effectively treat early-stage silicosis, while 400 mg/kg was recommended for advanced silicosis. Mechanistically, antibody array and bioinformatic analysis showed that the pathways related to IL-17 secretion, including JAK-STAT pathway, Th17 differentiation, and IL-17 pathway, might be involved in the treatment of silicosis by pirfenidone. Further in vivo experiments confirmed that pirfenidone reduced the production of IL-17A induced by silica exposure via inhibiting STAT3 phosphorylation. Neutralizing IL-17A by anti-IL-17A antibody improved lung function and reduced pulmonary inflammation and fibrosis in silicosis animals. Collectively, our study has demonstrated that pirfenidone effectively ameliorated silica-induced lung dysfunction, pulmonary inflammation and fibrosis in mouse models by inhibiting the secretion of IL-17A.

Triiodothyronine ameliorates silica-induced pulmonary inflammation and fibrosis in mice

Environmental exposure to silica or particles is very common in natural, agricultural and industrial activities. Chronic silica exposure can lead to silicosis, which remains one of the most serious interstitial lung diseases all through the world, while viable therapeutic choices are restricted. Triiodothyronine (T3) has been shown to exert a defensive role in many pulmonary diseases, however, rare data are available regarding the role of T3 on silica-induced injury. We constructed an experimental silicosis mouse model and T3 was intraperitoneally administrated after instillation of silica to observe the effect of T3 on silica-induced lung inflammation and fibrosis. Our results showed that the silicosis mouse model was accompanied by changes in thyroid morphology and function, and T3 supplement reduced silica-induced lung damage, inflammation and collagen deposition. The protective properties of T3 on silica-induced lung injury could be partially mediated through thyroid hormone receptors. And the mechanism by which T3 treatment ameliorated silica-induced fibrosis appeared to be via the reduction of glycolysis. Also, T3 could sufficiently postpone the progression of pulmonary fibrosis in established silicosis. Our findings reveal that administration of T3 could down-regulate the inflammatory response, pulmonary fibrosis and other lung damage caused by silica. The reduction of glycolysis may be one of the mechanisms.

Gas6 or Mer deficiency ameliorates silica-induced autophagosomes accumulation in mice lung

Published evidences have shown that autophagy plays an important role in silica-induced lung inflammation and collagen deposition. Our previous study found that the level of growth arrest-specific protein 6 (Gas6) in bronchoalveolar lavage fluid was increased after silica exposure. However, it is unclear whether Gas6 is involved in the regulation of silica-induced autophagy dysfunction. In this study, we observed an autophagosomes accumulation in wild-type C57BL/6 (WT) mice lung after silica intratracheal instillation and then investigated whether genetic loss of Gas6 (Gas6−/−) could ameliorate it. Our data showed that Gas6−/− mice exhibited a limited autophagosomes accumulation from days 7–84 after silica exposure, revealed by reduced induction and increased degradation of autophagosomes in mice lung tissue. Interestingly, silica particles could elevate the expression of Mer receptor, which was significantly decreased in Gas6−/− mice (P < 0.05). Furthermore, we found that Mer deficiency (Mer−/−) could also reduce the formation of autophagosomes and restore the function of impaired lysosomes in silica-treated mice. Taken together, our results indicate that genetic loss of Gas6 attenuates silica-induced autophagosomes accumulation partly through down-regulating the expression of Mer receptor. Targeting Gas6/Mer-mediated autophagy pathway may provide a novel insight into the prevention and therapy of silica-induced pulmonary fibrosis.

P2Y12 Receptor Antagonist Clopidogrel Attenuates Lung Inflammation Triggered by Silica Particles.

Silicosis is an occupational lung disease caused by inhalation of silica particles. It is characterized by intense lung inflammation, with progressive and irreversible fibrosis, leading to impaired lung function. Purinergic signaling modulates silica-induced lung inflammation and fibrosis through P2X7 receptor. In the present study, we investigate the role of P2Y12, the G-protein-coupled subfamily prototype of P2 receptor class in silicosis. To that end, BALB/c mice received an intratracheal injection of PBS or silica particles (20 mg), without or with P2Y12 receptor blockade by clopidogrel (20 mg/kg body weight by gavage every 48 h) – groups CTRL, SIL, and SIL + Clopi, respectively. After 14 days, lung mechanics were determined by the end-inflation occlusion method. Lung histology was analyzed, and lung parenchyma production of nitric oxide and cytokines (IL-1β, IL-6, TNF-α, and TGF-β) were determined. Silica injection reduced animal survival and increased all lung mechanical parameters in relation to CTRL, followed by diffuse lung parenchyma inflammation, increased neutrophil infiltration, collagen deposition and increased pro-inflammatory and pro-fibrogenic cytokine secretion, as well as increased nitrite production. Clopidogrel treatment prevented silica-induced changes in lung function, and significantly reduced lung inflammation, fibrosis, as well as cytokine and nitrite production. These data suggest that inhibition of P2Y12 signaling improves silica-induced lung inflammation, preventing lung functional changes and mortality. Our results corroborate previous observations of silica-induced lung changes and expand the understanding of purinergic signaling in this process.

Genetic loss of Gas6/Mer pathway attenuates silica-induced lung inflammation and fibrosis in mice

Long-term inhalation of crystalline silica particles leads to silicosis characterized by pulmonary inflammation and interstitial fibrosis. The growth arrest-specific protein 6 (Gas6) and its tyrosine receptor Mer have been implicated to involve in the regulation of inflammation, innate immunity and tissue repair. However, the role of Gas6 or Mer in silica-induced lung inflammation and fibrosis has not been investigated previously. In this study, we observed a remarkable increase of Gas6 in bronchoalveolar lavage fluid (BALF) from wild-type C57BL/6 mice after silica intratracheal administration. Then, we investigated whether genetic loss of Gas6 or Mer could attenuate silica-induced lung inflammation and fibrosis. Our results showed that Gas6−/− and Mer−/− mice exhibited reduced lung inflammation response from days 7 to 84 after silica exposure. We also uncovered an overexpression of the suppressor of cytokine signaling protein 1 in silica-treated deficient mice. Moreover, Gas6 or Mer deficiency attenuated silica-induced collagen deposition by inhibiting the expression of transforming growth factor-β. We conclude that gene absence of Gas6 or Mer is protective against silica-induced lung inflammation and fibrosis in mice. Targeting Gas6/Mer pathway may be a potential therapeutic approach to treat pulmonary fibrosis in patients with silicosis.

IL-9 Blockade Suppresses Silica-induced Lung Inflammation and Fibrosis in Mice.

Recapitulative animal models of idiopathic pulmonary fibrosis (IPF) and related diseases are lacking, which inhibits our ability to fully clarify the pathogenesis of these diseases. Although lung fibrosis in mouse models is often induced by bleomycin, silica-induced lung fibrosis is more sustainable and more progressive. Therefore, in this study, we sought to elucidate the mediator(s) responsible for the pathogenesis of lung fibrosis, through the use of a mouse model of silica-induced lung fibrosis. With a single nasal administration of 16 mg of silica, lung inflammation (assessed by elevated cellular components in the BAL fluids [BALFs]) and lung fibrosis (assessed by lung histology and lung hydroxyproline levels) were induced and sustained for as long as 24 weeks. Of the mediators measured in the BALFs, IL-9 was characteristically elevated gradually, and peaked at 24 weeks after silica administration. Treatment of silica-challenged mice with anti-IL-9-neutralizing antibody inhibited lung fibrosis, as assessed by lung hydroxyproline level, and suppressed the levels of major mediators, including IL-1β, IL-6, IL-12, CCL2, CXCL1, and TNF-α in BALFs. Moreover, human lung specimens from patients with IPF have shown high expression of IL-9 in alveolar macrophages, CD4-positive cells, and receptors for IL-9 in airway epithelial cells. Collectively, these data suggest that IL-9 plays an important role in the pathogenesis of lung fibrosis in diseases such as IPF.

Polyphenol-rich blue honeysuckle extract alleviates silica-induced lung fibrosis by modulating Th immune response and NRF2/HO-1 MAPK signaling

Blue honeysuckles are rich in polyphenol compounds that exert many beneficial effects. Previously, we demonstrated that polyphenol-rich blue honeysuckle extract (BHE) could alleviate silica-induced lung inflammation; however, its role in anti-fibrosis effects remains unknown. Here, we applied polyphenol-rich BHE to silica-injured mice to investigate its anti-fibrosis effect and the underlying mechanism. The results showed that BHE alleviated silica-induced pulmonary fibrosis in mice by altering regulatory T cell activity and mitigating T helper (Th)1/Th17 responses, resulting in reduced Th2 cytokine and transcription-factor mRNA levels. Additionally, cell-signaling detection revealed that p38 and c-Jun N-terminal kinase phosphorylation were effectively blocked by BHE treatment, which also downregulated the expression of inducible nitric oxide synthase and upregulated two antioxidant mediators [nuclear factor (erythroid-derived 2)-like 2 and heme oxygenase-1] in the lung. These findings support the use of BHE as functional food to modulate immune responses and alleviate lung fibrosis.

STING-dependent sensing of self-DNA drives silica-induced lung inflammation

Silica particles induce lung inflammation and fibrosis. Here we show that stimulator of interferon genes (STING) is essential for silica-induced lung inflammation. In mice, silica induces lung cell death and self-dsDNA release in the bronchoalveolar space that activates STING pathway. Degradation of extracellular self-dsDNA by DNase I inhibits silica-induced STING activation and the downstream type I IFN response. Patients with silicosis have increased circulating dsDNA and CXCL10 in sputum, and patients with fibrotic interstitial lung disease display STING activation and CXCL10 in the lung. In vitro, while mitochondrial dsDNA is sensed by cGAS-STING in dendritic cells, in macrophages extracellular dsDNA activates STING independent of cGAS after silica exposure. These results reveal an essential function of STING-mediated self-dsDNA sensing after silica exposure, and identify DNase I as a potential therapy for silica-induced lung inflammation.

Nicorandil ameliorates pulmonary inflammation and fibrosis in a rat model of silicosis

Nicorandil, an antianginal and potassium channel opener agent, has different useful impacts on cardiovascular and respiratory systems. Its effect against silicosis has not been discussed yet, therefore, this is an attempt to decide whether nicorandil can reduce silica-induced lung injury in rats. Silica model was induced by intranasal instillation of silica dust once. Rats were given nicorandil for 56 days after exposure to silica. Results showed that nicorandil significantly alleviated silica-induced inflammation as it decreased the elevated levels of total and differential cell counts, pulmonary edema (revealed by decreased lung/body weight ratio and W/D weight ratio), LDH and total protein levels in BALF. Notably, nicorandil decreased collagen deposition as evidenced by reduction in levels of hydroxyproline and collagen in lung tissues as well as obvious alleviation in silica-induced fibrosis in histopathological findings. Nicorandil effectively reduced the increased expression of NF-κB and iNOS and decreased MPO levels in lung tissues. Moreover, nicorandil abolished oxidative and nitrosative stress via reducing levels of pulmonary MDA and NOx concomitant with elevating levels of pulmonary GSH and SOD. Meanwhile, nicorandil decreased the levels of TNF-α and TGF-β, up regulated Nrf-2 and HO-1 levels in BALF suggesting antioxidant, anti-inflammatory and antifibrotic properties. In summary, nicorandil can confer protection against silica-induced lung inflammation and fibrosis. This impact might be due to its ability to down regulate the production of inflammatory and fibrotic cytokines in addition to restoring oxidant/antioxidant balance.

Effects of autophagy in silica induced lung inflammation and fibrosis

Effects of autophagy in silica induced lung inflammation and fibrosis