Identification of Key Pathways and Genes in the Progression of Silicosis Fibrosis Based on WGCNA
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ORGANISM(S): Rattus norvegicus
PROVIDER: GSE203298 | GEO | 2025/05/16
REPOSITORIES: GEO
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Project description:Silicosis, a fibrotic granulomatous lung disease, may occur through accidental high-dose or occupational inhalation of silica, leading to acute/accelerated and chronic silicosis, respectively. While chronic silicosis has a long asymptomatic latency, lung inflammation and apoptosis are hallmarks of acute silicosis. In animal models, histiocytic granulomas develop within days after high-dose intratracheal silica instillation. However, following chronic inhalation of occupationally relevant doses of silica, discrete granulomas resembling human silicosis arise months after the final exposure without significant lung inflammation/apoptosis. To identify molecular events associated with chronic silicosis, lung RNAs from controls or chronically silica-exposed rats were analyzed by Affymetrix at 28 wk after silica exposures. Results suggested a significant upregulation of 144 genes and downregulation of seven genes. The upregulated genes included complement cascade, chemokines/chemokine receptors, G-protein signaling components, metalloproteases, and genes associated with oxidative stress. To examine the kinetics of gene expression relevant to silicosis, qPCR, ELISA, Luminex-bead assays, Western blotting, and/or zymography were performed on lung tissues from 4 d, 28 wk, and intermediate times after chronic silica exposure and compared with 14 d acute silicosis samples. Results indicated that genes regulating fibrosis (secreted phosphoprotein-1, CCL2, and CCL7), redox enzymes (superoxide dismutase-2 and arginase-1), and the enzymatic activities of matrix metalloproteinases 2 and 9 were upregulated in acute and chronic silicosis; however, proinflammatory cytokines were strongly upregulated only in acute silicosis. Thus, inflammatory cytokines are associated with acute but not chronic silicosis; however, genes regulating fibrosis, oxidative stress, and metalloproteases may contribute to both acute and chronic silicosis. 3 rats were chronically exposed to silica by inhalation. Briefly, exposure chambers were maintained with an airflow rate of ~15 cfm and temperature range of 22‚Äì26¬?C. Animals were exposed to 6.2 mg/m3 aerosolized silica (Min-U-Sil 5; U.S. Silica, Mill Creek, OK) with an average particle size of 1.75 ¬± 0.05 mm (mass median aerodynamic diameter) 6 h/d, 5 d/wk (Monday‚ÄìFriday) for 6 wk. 3 control animals received filtered air under similar inhalation conditions.
2012-01-01 | E-GEOD-29110 | biostudies-arrayexpress
Project description:Silicosis is caused by inhalation of crystalline silica dust particles and known as one of the most serious occupational diseases worldwide. However, little is known about intrinsic factors leading to disease susceptibility. Using single-cell sequencing of bronchoalveolar lavage fluid (BALF) of mine workers with silicosis and their co-workers who did not develop silicosis, we found that the impaired interferon (IFN)-γ signaling in myeloid cells was strongly associated with the occurrence of silicosis. In a murine model of silicosis, global or myeloid cell-specific deletion of interferon γ receptor (IFN-γR) markedly enhanced the silica crystals-induced pulmonary interstitial fibrosis and respiratory dysfunction in wild-type but not in mutant mice deficient in NOD-like receptor family pyrin domain-containing 3 (NLRP3). In vitro, IFN-γ priming of macrophages suppressed the crystalline silica-induced NLRP3 inflammasome activation partly by inducing the formation of spacious phagosomes with relatively reduced ratio of crystalline silica/phagosomal areas/volumes through the RAB20-dependent membrane trafficking pathway. RAB20 deficiency was associated with the elevated susceptibility to silicosis as well as the elevated NLRP3 inflammasome activation in a manner similar to the impaired IFN-γ signaling. Thus, these findings provide novel molecular insights into the intricate mechanisms underlying innate immunity-mediated host responses to environmental irritants, and shed light on the future development of novel therapies for the prevention of silicosis.
2022-05-19 | GSE174725 | GEO
Project description:Silicosis, a fibrotic granulomatous lung disease, may occur through accidental high-dose or occupational inhalation of silica, leading to acute/accelerated and chronic silicosis, respectively. While chronic silicosis has a long asymptomatic latency, lung inflammation and apoptosis are hallmarks of acute silicosis. In animal models, histiocytic granulomas develop within days after high-dose intratracheal silica instillation. However, following chronic inhalation of occupationally relevant doses of silica, discrete granulomas resembling human silicosis arise months after the final exposure without significant lung inflammation/apoptosis. To identify molecular events associated with chronic silicosis, lung RNAs from controls or chronically silica-exposed rats were analyzed by Affymetrix at 28 wk after silica exposures. Results suggested a significant upregulation of 144 genes and downregulation of seven genes. The upregulated genes included complement cascade, chemokines/chemokine receptors, G-protein signaling components, metalloproteases, and genes associated with oxidative stress. To examine the kinetics of gene expression relevant to silicosis, qPCR, ELISA, Luminex-bead assays, Western blotting, and/or zymography were performed on lung tissues from 4 d, 28 wk, and intermediate times after chronic silica exposure and compared with 14 d acute silicosis samples. Results indicated that genes regulating fibrosis (secreted phosphoprotein-1, CCL2, and CCL7), redox enzymes (superoxide dismutase-2 and arginase-1), and the enzymatic activities of matrix metalloproteinases 2 and 9 were upregulated in acute and chronic silicosis; however, proinflammatory cytokines were strongly upregulated only in acute silicosis. Thus, inflammatory cytokines are associated with acute but not chronic silicosis; however, genes regulating fibrosis, oxidative stress, and metalloproteases may contribute to both acute and chronic silicosis.
2012-01-01 | GSE29110 | GEO
Project description:The pathophysiology of silicosis is poorly understood, limiting development of therapies for those who have been exposed to the respirable particle. We explored mechanisms of silica-induced pulmonary fibrosis in human lung samples collected from patients with occupational exposure to silica and in a longitudinal mouse model of silicosis using multiple modalities including whole-lung single-cell RNA sequencing and histological, biochemical, and physiologic assessments. In addition to pulmonary inflammation and fibrosis, intratracheal silica challenge induced osteoclast-like differentiation of alveolar macrophages and recruited monocytes, driven by induction of the osteoclastogenic cytokine, receptor activator of nuclear factor κΒ ligand (RANKL) in pulmonary lymphocytes, and alveolar type II cells. Anti-RANKL monoclonal antibody treatment suppressed silica-induced osteoclast-like differentiation in the lung and attenuated pulmonary fibrosis. We conclude that silica induces differentiation of pulmonary osteoclast-like cells leading to progressive lung injury, likely due to sustained elaboration of bone-resorbing proteases and hydrochloric acid. Interrupting osteoclast-like differentiation may therefore constitute a promising avenue for moderating lung damage in silicosis.
2024-08-12 | GSE274372 | GEO
Project description:The pathophysiology of silicosis is poorly understood, limiting development of therapies for those who have been exposed to the respirable particle. We explored mechanisms of silica-induced pulmonary fibrosis in human lung samples collected from patients with occupational exposure to silica and in a longitudinal mouse model of silicosis using multiple modalities including whole-lung single-cell RNA sequencing and histological, biochemical, and physiologic assessments. In addition to pulmonary inflammation and fibrosis, intratracheal silica challenge induced osteoclast-like differentiation of alveolar macrophages and recruited monocytes, driven by induction of the osteoclastogenic cytokine, receptor activator of nuclear factor κΒ ligand (RANKL) in pulmonary lymphocytes, and alveolar type II cells. Anti-RANKL monoclonal antibody treatment suppressed silica-induced osteoclast-like differentiation in the lung and attenuated pulmonary fibrosis. We conclude that silica induces differentiation of pulmonary osteoclast-like cells leading to progressive lung injury, likely due to sustained elaboration of bone-resorbing proteases and hydrochloric acid. Interrupting osteoclast-like differentiation may therefore constitute a promising avenue for moderating lung damage in silicosis.
2025-02-14 | GSE288887 | GEO
Project description:Exposure to crystalline silica results in serious health effects, most notably, silicosis and cancer. An understanding of the silica-induced lung toxicity is critical for the intervention and/or prevention of its adverse health effects. Rats were exposed by inhalation to air or crystalline silica (15 mg/m3, 6 hours/day for 5 days). At post-exposure time intervals of 1, 3, 6, 9, 12, and 18 months, the control and silica exposed rats were euthanized, and lung toxicity and gene expression profiles determined. Histological changes indicative of lung toxicity detected in the silica exposed rats included infiltration of neutrophils, thickening of alveolar epithelium, and fibrosis. Significant increases in lactate dehydrogenase activity, number of phagocytes, and inflammatory cytokine levels were detected in the bronchoalveolar lavage (BAL) obtained from the silica exposed rats compared with the corresponding time-matched controls. Significant changes in lung gene expression profiles, corresponding to the changes in the lung toxicity parameters analyzed, were detected in the silica exposed rats. The BAL parameters of toxicity and inflammation peaked at the 12-months post-exposure time interval and declined subsequently. However, lung fibrosis continued to progress being highest at the 18-month post-exposure time interval. These results suggest that inflammation may be required for the initiation but not for the progression and/or maintenance of lung fibrosis in response to silica exposure in the rats.
2022-12-31 | GSE150689 | GEO
Project description:Identification of Key Pathways and Genes in the Progression of Silicosis Fibrosis Based on WGCNA
| PRJNA839386 | ENA
Project description: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-IIIeintervened 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.
2023-10-25 | GSE245655 | GEO
Project description:Occupational exposure to dust containing crystalline silica may result in serious adverse health effects including silicosis and cancer. Previous studies which employed animal models for inhalation exposure to crystalline silica revealed changes in blood gene expression profiles in association with the silica-induced lung toxicity. Currently, global gene expression profiles were determined in the whole blood samples obtained from control (not exposed to dust) and dust containing silica exposed individuals with or without clinically identified silicosis. Differences in the blood gene expression profiles were detected in the blood samples obtained from the control and the silica-containing dust exposed individuals. Between the two groups of the silica-containing dust exposed individuals, the number of significantly differentially expressed genes was more in the blood samples obtained from those with silicosis.
2024-12-31 | GSE165489 | GEO
Project description:Occupational exposure to crystalline silica results in serious health effects, most notably, silicosis and cancer. A proper understanding of the mechanism(s) underlying the initiation and progression of silica-induced pulmonary toxicity is critical for the intervention and/or prevention of the adverse health effects associated with crystalline silica exposure. Rats were exposed to crystalline silica by inhalation at a concentration of 15 mg/m3, 6 hours/day, 5 days/week for 3, 6 or 12 weeks. At the end of each exposure time point, toxicity and global gene expression changes were determined in the lungs. In general, silica exposure resulted in pulmonary toxicity that was dependent on the duration of silica exposure. A significant and silica exposure time-dependent increase in lactate dehydrogenase activity and accumulation of alveolar macrophages and infiltrating neutrophils in the bronchoalveolar lavage fluid suggested crystalline silica-induced pulmonary toxicity in the rats. Histological changes indicative of pulmonary toxicity were detectable only in the lungs of rats that were exposed to silica for 6- or 12-weeks. Minimal, sub-acute pulmonary inflammation consisting mainly of macrophage accumulation and infiltration of neutrophils was seen in 2 out of 8 rats in the 6-week silica exposure group. Chronic active inflammation, type II pneumocyte hyperplasia, and fibrosis were detected following 12-weeks of silica exposure in all rat lungs. In addition, crystalline silica was visible in the lungs of the rats belonging to the 12-week exposure group. A significant increase in the number of neutrophils seen in the blood indicated silica-induced systemic inflammation in the rats. Microarray analysis of the global gene expression profiles of the rat lungs detected significant differential expression (FDR p <0.05 and fold change >1.5) of 38, 77 and 99 genes in the rats exposed to silica for 3-, 6- and 12-weeks, respectively, compared to the time-matched controls. Bioinformatics analysis of the differentially expressed genes identified significant enrichment of functions, networks and pathways related to inflammation, cancer, oxidative stress, fibrosis and tissue remodeling in the lungs of the silica exposed rats. Collectively, the results of our study provided insights into the molecular mechanisms underlying pulmonary toxicity following sub-chronic exposure to silica in rats. 36 samples were analyzed in this experiment. 6 rats were exposed to crystalline silica by inhalation 15 mg/m3, 6 hours/day, 5 days, 3 weeks. 6 rats were exposed to crystalline silica by inhalation 15 mg/m3, 6 hours/day, 5 days, 6 weeks. 6 rats were exposed to crystalline silica by inhalation 15 mg/m3, 6 hours/day, 5 days, 12 weeks. 18 rats served as controls (6 for each 3 week, 6 week, and 12 week exposure) and were exposed to air during treatment times. Lung gene expression profiling was performed using RNA isolated from rat lung samples.
2014-07-01 | E-GEOD-49144 | biostudies-arrayexpress