Integrative Transcriptomic and Proteomic Analysis Reveals Mechanisms of Silica-induced Pulmonary Fibrosis in Rats
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PROVIDER: PRJNA779254 | ENA |
REPOSITORIES: ENA
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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:To explore proteomic and transcriptomic changes in rat model of silicosis, transcriptomic analysis by microarray and tandem mass tags (TMT)-based proteomic analysis were performed to reveal the expression of mRNAs and proteins in lung tissues. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were applied to analyze the alterated genes and proteins. The integrated analysis was performed between transcriptome and proteome. Furthermore, the data were further verified by RT-qPCR and parallel reaction monitoring (PRM). In total, 244 differentially expressed proteins (DEPs) showed the same trend as that of the corresponding differentially expressed genes (DEGs) (named DEPs/DEGs). GM2a, CHI3L1, LCN2 and GNAI1, which were validated consistently by RT-qPCR and PRM, are involved in the extracellular matrix (ECM) and inflammation contributed to fibrosis in silicosis.
2022-01-12 | GSE188520 | GEO
Project description:Previous studies have shown that smoking induces oxidative stress and inflammation, known factors that coincide with the development and progression of silicosis. Nevertheless, the precise role of cigarette smoke exposure in silicosis and the underlying mechanisms are not clearly understood. Therefore, the objective of the present study was to determine the effect of smoking, if any, on silica-induced pulmonary response and the underlying mechanisms. Pulmonary toxicity and lung gene expression profiles were determined in male Fischer 344 rats exposed to air, crystalline silica, cigarette smoke or cigarette smoke plus crystalline silica. Silica exposure resulted in significant pulmonary toxicity which was further exacerbated by cigarette smoke exposure in the rats. Significant differences in the gene expression profiles were detected in the lungs of the rats exposed to cigarette smoke, silica or a combination of both compared with the control rats.
2020-11-01 | GSE136945 | GEO
Project description:microRNAs (miRNAs) play a critical biological role in a variety of pathophysiological processes by suppressing their target genes. However, little is known on the miRNAs expression profiles of lung tissues in silica-induced pulmonary fibrosis. To investigate miRNAs of interest in regulation of pulmonary fibrosis, total RNA was isolated from mice lungs collected at day 0, day 3, day 7, day 14, day 28 and day 56 after silica exposure. Then, miRNA microarray was performed with one mouse lung at each time point. miRNA microarray was performed with one mouse lung at day 0, day 3, day 7, day 14, day 28 and day 56 after silica exposure to investigate the miRNAs expression profiles of lung tissues in silica-induced pulmonary fibrosis.
2014-01-29 | GSE54463 | GEO
Project description:The capability to detect target organ toxicity as well as to determine the molecular mechanisms underlying such toxicity by employing surrogate biospecimens that can be obtained by a non-invasive or minimally invasive procedure has significant advantage in occupational toxicology. Pulmonary toxicity and global gene expression profile in the lungs, peripheral blood and bronchoalveolar lavage (BAL) cells were determined in rats at 44-weeks following pulmonary exposure to crystalline silica (15 mg/m3, 6-hours/day, 5 days). A significant elevation in lactate dehydrogenase activity and albumin content observed in the BAL fluid suggested the induction of pulmonary toxicity in the silica exposed rats. Similarly, the observation of histological alterations, mainly type II pneumocyte hyperplasia and fibrosis, in the lungs further confirmed silica-induced pulmonary toxicity in the rats. A significant increase in the number of neutrophils and elevated monocyte chemotactic protein 1 level in the BAL fluids suggested silica-induced pulmonary inflammation in the rats. Determination of global gene expression profile in the lungs, BAL cells, and peripheral blood of the silica exposed rats identified 144, 236, and 51 significantly differentially expressed genes (SDEGs), respectively, compared with the corresponding control samples. Bioinformatics analysis of the SDEGs demonstrated a remarkable similarity in the biological functions, molecular networks and canonical pathways that were significantly affected by silica exposure in the lungs, BAL cells and blood of the rats. Induction of inflammation was identified, based on the bioinformatics analysis of the significantly differentially expressed genes in the lungs, blood and BAL cells, as the major molecular mechanism underlying the silica-induced pulmonary toxicity. The findings of our study demonstrated the potential application of global gene expression profiling of peripheral blood and BAL cells as a valuable minimally invasive approach to study silica-induced pulmonary toxicity in rats.
2017-06-20 | GSE41572 | GEO
Project description:microRNAs (miRNAs) play a critical biological role in a variety of pathophysiological processes by suppressing their target genes. However, little is known on the miRNAs expression profiles of lung tissues in silica-induced pulmonary fibrosis. To investigate miRNAs of interest in regulation of pulmonary fibrosis, total RNA was isolated from mice lungs collected at day 0, day 3, day 7, day 14, day 28 and day 56 after silica exposure. Then, miRNA microarray was performed with one mouse lung at each time point. miRNA microarray was performed with one mouse lung at day 0, day 3, day 7, day 14, day 28 and day 56 after silica exposure to investigate the miRNAs expression profiles of lung tissues in silica-induced pulmonary fibrosis. Mouse lung tissues were selected at each time point after treatment for RNA extraction and hybridization on Affymetrix microarrays. We sought to obtain homogeneous populations of lungs at each fibrotic stage in order to increase the temporal resolution of expression profiles. To that end, we hand-selected lung tissues according to morphological criteria at five time-points: before silica exposure, i.e. day 0 (D0), the early inflammation phase day 3 (D3) and day 7 (D7), the late inflammation phase, day 14 (D14), the fibrosis phase,i.e. day 28 (D28) and day (D56).
2014-01-29 | E-GEOD-54463 | biostudies-arrayexpress
Project description:Identification of molecular target(s) and mechanism(s) of silica-induced pulmonary toxicity is important for the intervention and/or prevention of diseases associated with occupational exposure to crystalline silica. Rats were exposed to crystalline silica by inhalation (15 mg/m3, 6 h/day, 5 days) and global gene expression profile was determined in the lungs by microarray analysis at 1, 2, 4, 8, and 16 weeks following termination of silica exposure. The number of significantly differentially expressed genes (>1.5 fold change and <0.01 FDR p value) detected in the lungs during the post-exposure time intervals analyzed exhibited a steady increase in parallel with the progression of silica-induced pulmonary toxicity noticed in the rats. Quantitative real-time PCR analysis of a representative set of 10 genes confirmed the microarray findings. The various biological functions, canonical pathways, and molecular networks affected by silica exposure, as identified by the bioinformatics analysis of the significantly differentially expressed genes, also exhibited a steady increase similar to the silica-induced pulmonary toxicity. Genes involved in oxidative stress, inflammation, respiratory diseases, cancer, and tissue remodeling and fibrosis were significantly differentially expressed in the rat lungs; however, unresolved lung inflammation was the single most significant biological response to pulmonary exposure to crystalline silica. Excessive mucus production, as implicated by significant overexpression of the pendrin coding gene, SLC26A4, was identified as a novel mechanism for silica-induced pulmonary toxicity. Collectively, the findings of our study provided insights into the molecular mechanisms underlying the progression of crystalline silica-induced pulmonary toxicity in the rat and these findings may be useful in future to develop strategies to prevent occupational silicosis.
2012-06-30 | GSE32147 | GEO
Project description:Pulmonary osteoclast-like cells in silica induced pulmonary fibrosis
| PRJNA1146078 | ENA
Project description:Identification of molecular target(s) and mechanism(s) of silica-induced pulmonary toxicity is important for the intervention and/or prevention of diseases associated with occupational exposure to crystalline silica. Rats were exposed to crystalline silica by inhalation (15 mg/m3, 6 h/day, 5 days) and global gene expression profile was determined in the lungs by microarray analysis at 1, 2, 4, 8, and 16 weeks following termination of silica exposure. The number of significantly differentially expressed genes (>1.5 fold change and <0.01 FDR p value) detected in the lungs during the post-exposure time intervals analyzed exhibited a steady increase in parallel with the progression of silica-induced pulmonary toxicity noticed in the rats. Quantitative real-time PCR analysis of a representative set of 10 genes confirmed the microarray findings. The various biological functions, canonical pathways, and molecular networks affected by silica exposure, as identified by the bioinformatics analysis of the significantly differentially expressed genes, also exhibited a steady increase similar to the silica-induced pulmonary toxicity. Genes involved in oxidative stress, inflammation, respiratory diseases, cancer, and tissue remodeling and fibrosis were significantly differentially expressed in the rat lungs; however, unresolved lung inflammation was the single most significant biological response to pulmonary exposure to crystalline silica. Excessive mucus production, as implicated by significant overexpression of the pendrin coding gene, SLC26A4, was identified as a novel mechanism for silica-induced pulmonary toxicity. Collectively, the findings of our study provided insights into the molecular mechanisms underlying the progression of crystalline silica-induced pulmonary toxicity in the rat and these findings may be useful in future to develop strategies to prevent occupational silicosis. A total of 60 rat lung samples were analyzed in this gene expression experiment. Rats were exposed to crystalline silica at a concentration of 15 mg/m³, 6-hours/day for 5 consecutive days. Rats exposed simultaneously to filtered air served as the controls. The control (n=4) and silica exposed (n=8) rats were sacrificed at post-exposure time intervals of 1, 2, 4, 8, and 16 weeks following termination of silica exposure and lung gene expression profile was determined.
2012-06-29 | E-GEOD-32147 | biostudies-arrayexpress
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.
2014-07-01 | GSE49144 | GEO