Silica-mediated airway chronic inflammation promotes lung carcinogenesis through the activation of preneoplastic lesions in the context of an immunosuppressive microenvirontment
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Daniel Ajona
PROVIDER: E-GEOD-43453 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Basic studies on preneoplastic lesions are important to determine the molecular alterations that take place in early steps of lung carcinogenesis. Little is known about the molecular events preceding the development of lung cancer in the context of an inflammatory environment. In this study we report the generation of a chemical-induced lung carcinogenesis mouse model in the presence of silicotic chronic inflammation. Silica-induced lung inflammation, strongly promoted incidence of lung cancer in mice treated with NDMA, a carcinogen found in tobacco smoke. Histological and molecular analysis revealed that permanent inflammation contributed to lung tumorigenesis through the adquisition of preneoplastic changes in lung epithelial cells. Inflammatory milieu increased the expression of PDCD1, TGFβ-1, MCP-1, LAG3, and Foxp3 and the presence of regulatory T cells within preneoplastic lesions. In addition concomitant chronic inflammation changed the K-ras mutational profile of the generated tumors from Q61R to G12D transition. In summary, these data identify early molecular mechanisms underlying lung carcinogenesis in an inflammatory context at different steps, providing a novel approach for the identification of drivers from preneoplastic to neoplastic lesions
2016-01-03 | GSE43453 | GEO
Project description:Ulcerative colitis (UC) patients have a greater risk of developing colorectal cancer through inflammation-dysplasia-carcinoma sequence of transformation. The histopathological diagnosis of dysplasia is therefore of critical clinical relevance, but dysplasia may be difficult to distinguish from inflammatory changes. A proteomic pilot study on 5 UC colorectal dysplastic patients highlighted proteins differentially distributed between paired dysplastic, inflammatory and normal tissues. The best candidate marker was selected and immunohistochemistry confirmation was performed on AOM/DSS mouse model lesions, 37 UC dysplasia, 14 UC cancers, 23 longstanding UC, 35 sporadic conventional adenomas, 57 sporadic serrated lesions and 82 sporadic colorectal cancers. Differential proteomics found 11 proteins significantly more abundant in dysplasia compared to inflammation, including Solute carrier family 12 member 2 (SLC12A2) which was confidently identified with 8 specific peptides and was below the limit of quantitation in both inflammatory and normal colon. SLC12A2 immunohistochemical analysis confirmed the discrimination of preneoplastic and neoplastic lesions from inflammatory lesions in mice, UC and in sporadic contexts. A specific SLC12A2 staining pattern termed “loss of gradient” reached 89% sensitivity, 95% specificity and 92% accuracy for UC-dysplasia diagnosis together with an inter-observer agreement of 95.24% (multirater κfree of 0.90; IC95%: 0.78 – 1.00). Such discrimination could not be obtained by Ki67 staining. This specific pattern was also associated with sporadic colorectal adenomas and cancers. We found a specific SLC12A2 immunohistochemical staining pattern in precancerous and cancerous colonic UC-lesions which could be helpful for diagnosing dysplasia and cancer in UC and non-UC patients.
2020-09-16 | PXD018679 | Pride
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:Silica-mediated airway chronic inflammation promotes lung carcinogenesis through the activation of preneoplastic lesions in the context of an immunosuppressive microenvirontment
| PRJNA186440 | 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:A proper understanding of the mechanisms underlying crystalline silica-induced pulmonary toxicity has implications in the management and potential prevention of the adverse health effects associated with silica exposure including silicosis, cancer and several auto-immune diseases. Human lung type II epithelial cells and rat lungs exposed to crystalline silica were employed as experimental models to determine global gene expression changes in order to understand the molecular mechanisms underlying silica-induced pulmonary toxicity. The differential gene expression profile induced by silica correlated with its toxicity in the A549 cells. The biological processes perturbed by silica exposure in the A549 cells and rat lungs, as identified by the bioinformatic analysis of the differentially expressed genes, demonstrated significant similarity. Functional categorization of the differentially expressed genes identified cancer, cellular movement, cellular growth and proliferation, cell death, inflammatory response, cell cycle, cellular development, and genetic disorder as top-ranking biological functions perturbed by silica exposure in the A549 cells and rat lungs. The involvement of oxidative stress and apoptosis in the silica-induced pulmonary toxicity was confirmed by ELISA and confocal microscopy analysis, respectively, of the silica-exposed A549 cells. Results of our study, in addition to confirming several previously identified molecular targets and mechanisms involved in silica toxicity, identified novel molecular targets and mechanisms potentially involved in silica-induced pulmonary toxicity. Further investigations, including those focused on the novel molecular targets and mechanisms identified in the current study, may result in a better management and, possibly, reduction and/or prevention of the potential adverse health effects associated with crystalline silica exposure. 20 samples were analyzed in this experiment. RNA from rat lung samples was isolated for gene expression studies. Rats were exposed to crystalline silica by inhalation (15 mg/m3, 6 hours/day, 5 days) or air. Lung gene expression profiling was performed using rat lung samples, 8 for silica exposed and 12 for air-exposed controls at 0 weeks post-exposure time period.
2012-06-29 | E-GEOD-30178 | biostudies-arrayexpress
Project description:The present research aimed to investigate peripheral blood gene expression profiling as a minimally invasive surrogate approach to study silica-induced pulmonary toxicity. Rats were exposed to crystalline silica by inhalation (15 mg/m3, 6 hours/day, 5 days). Pulmonary damage and blood gene expression profiles were determined at various latency periods (0 - 16 weeks). Silica exposure resulted in pulmonary toxicity and this was evidenced by histological changes in the lungs and elevation of LDH activity, and total protein and albumin contents in the bronchoalveolar lavage fluid (BALF) of the rats. Microarray analysis of global gene expression profiles in the blood of the rats identified genes that were differentially expressed in response to silica exposure and toxicity. The number of significantly differentially expressed genes in the blood of silica exposed rats correlated with the severity of silica-induced pulmonary toxicity. Genes involved in biological functions such as inflammatory response, cancer, pulmonary damage, oxidative stress, energy metabolism, fibrosis, etc, were found differentially expressed in the blood of the silica exposed rats compared with the controls. Induction of pulmonary inflammation in the silica exposed rats, as suggested by differential expression of inflammatory response genes in the blood, was supported by significant increases in the number of macrophages and infiltrating neutrophils as well as the activity of pro-inflammatory chemokines M-bM-^@M-^S MCP1 and MIP2, observed in the BALF of the silica exposed rats. A silica-responsive blood gene expression signature developed using the gene expression data predicted with significant accuracy the exposure of rats to lower concentrations (1 and 2 mg/m3) of silica. Taken together our findings suggest the potential application of peripheral blood gene expression profiling as a minimally invasive and efficient surrogate approach to detect and study silica-induced pulmonary toxicity. 96 samples were analyzed in this experiment. The RNA from rat blood samples was isolated for gene expression studies. Rats (48) were exposed to crystalline silica by inhalation (15 mg/m3, 6 hours/day, 5 days) and air (24). Blood gene expression profiling was performed using rat blood samples, 8 each for silica exposed and 4 each for air exposed controls at various post-exposure time periods (0, 1, 2, 4, 8, and 16 weeks). A silica-responsive blood gene expression signature was developed using the gene expression data obtained from the 0 week post-exposure group and the control rats. The signature was tested for predicting silica exposure and resulting toxicity in the rats exposed to lower concentrations (1 and 2 mg/m3) of silica (8 rats per group) and air (8 rats).
2011-12-02 | E-GEOD-27023 | biostudies-arrayexpress
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:A proper understanding of the mechanisms underlying crystalline silica-induced pulmonary toxicity has implications in the management and potential prevention of the adverse health effects associated with silica exposure including silicosis, cancer and several auto-immune diseases. Human lung type II epithelial cells and rat lungs exposed to crystalline silica were employed as experimental models to determine global gene expression changes in order to understand the molecular mechanisms underlying silica-induced pulmonary toxicity. The differential gene expression profile induced by silica correlated with its toxicity in the A549 cells. The biological processes perturbed by silica exposure in the A549 cells and rat lungs, as identified by the bioinformatic analysis of the differentially expressed genes, demonstrated significant similarity. Functional categorization of the differentially expressed genes identified cancer, cellular movement, cellular growth and proliferation, cell death, inflammatory response, cell cycle, cellular development, and genetic disorder as top-ranking biological functions perturbed by silica exposure in the A549 cells and rat lungs. The involvement of oxidative stress and apoptosis in the silica-induced pulmonary toxicity was confirmed by ELISA and confocal microscopy analysis, respectively, of the silica-exposed A549 cells. Results of our study, in addition to confirming several previously identified molecular targets and mechanisms involved in silica toxicity, identified novel molecular targets and mechanisms potentially involved in silica-induced pulmonary toxicity. Further investigations, including those focused on the novel molecular targets and mechanisms identified in the current study, may result in a better management and, possibly, reduction and/or prevention of the potential adverse health effects associated with crystalline silica exposure. 20 samples were analyzed in this experiment. Exponentially growing human lung epithelial cells (1.5x10^5 cells) were cultured in 6-well cell culture plates. When the cells were approximately 70% confluent, they were treated with crystalline silica (0, 100, 200 and 400 M-BM-5g/ml) in serum-free medium. Following 6 hours of culturing at 37oC, total RNA was isolated for gene expression studies.
2012-06-29 | E-GEOD-30200 | biostudies-arrayexpress
Project description:A proper understanding of the mechanisms underlying crystalline silica-induced pulmonary toxicity has implications in the management and potential prevention of the adverse health effects associated with silica exposure including silicosis, cancer and several auto-immune diseases. Human lung type II epithelial cells and rat lungs exposed to crystalline silica were employed as experimental models to determine global gene expression changes in order to understand the molecular mechanisms underlying silica-induced pulmonary toxicity. The differential gene expression profile induced by silica correlated with its toxicity in the A549 cells. The biological processes perturbed by silica exposure in the A549 cells and rat lungs, as identified by the bioinformatic analysis of the differentially expressed genes, demonstrated significant similarity. Functional categorization of the differentially expressed genes identified cancer, cellular movement, cellular growth and proliferation, cell death, inflammatory response, cell cycle, cellular development, and genetic disorder as top-ranking biological functions perturbed by silica exposure in the A549 cells and rat lungs. The involvement of oxidative stress and apoptosis in the silica-induced pulmonary toxicity was confirmed by ELISA and confocal microscopy analysis, respectively, of the silica-exposed A549 cells. Results of our study, in addition to confirming several previously identified molecular targets and mechanisms involved in silica toxicity, identified novel molecular targets and mechanisms potentially involved in silica-induced pulmonary toxicity. Further investigations, including those focused on the novel molecular targets and mechanisms identified in the current study, may result in a better management and, possibly, reduction and/or prevention of the potential adverse health effects associated with crystalline silica exposure. 10 samples were analyzed in this experiment. Exponentially growing human lung epithelial cells (1.5x10^5 cells) were cultured in 6-well cell culture plates. When the cells were approximately 70% confluent, they were treated with crystalline silica (0 or 200 M-BM-5g/ml) in serum-free medium. Following 2 hours of culturing at 37oC, total RNA was isolated for gene expression studies.
2012-06-29 | E-GEOD-30214 | biostudies-arrayexpress