UMLS:C0037116 - FACTA Search

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Query: UMLS:C0037116 (silicosis)
1,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Crystalline silica was recently classified as a human carcinogen by the International Agency for Research on Cancer (IARC). However, the direct genotoxic effect of silica in humans remains unclear. We examined the p53 and K-ras gene mutations in lung cancer in workers with silicosis (LCWS). DNA was extracted from paraffin-embedded tissues and examined by PCR-RFLP, PCR-SSCP, and DNA sequencing. The mutation frequencies of p53 gene were high, but the mutation distributions in exons and among the histological types of LCWS differed from those of common (i.e., not silicosis-related) lung cancer. Furthermore, no mutations in codon 12 of K-ras gene (predominant in common lung cancer) were found in LCWS. These findings in the mutational spectrum support a carcinogenic effect of silica dust at the DNA molecular level.
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PMID:A distinct mutational spectrum of p53 and K-ras genes in lung cancer of workers with silicosis. 1090 1

In 1997, the International Agency for Research on Cancer (IARC) upgraded its evaluation of crystalline silica to a Group 1 human carcinogen. Criticism against such decision is based on the lack of consistency in experimental results across animal species, violation of an important principle for causality, such as the replication of findings under different circumstances of exposure, and the lack of a clear dose-response curve. The most recent epidemiological literature on the silica-silicosis-lung cancer link replicates the inconsistent findings that have been characterising 50 years of scientific debate in the occupational arena. Exposure circumstances capable of modifying the silica-lung cancer association include chronic bronchitis, composition of the dust mixing, particularly concerning co-occurrence of other known or probable lung carcinogens, total respirable dust, concentration of silica in respirable dust, type of crystalline silica and particle surface characteristics. The hypothesis of a silicosis-mediated pathway points toward an unspecific mechanism shared with other fibrotic conditions, for which silica might be just one of the triggers. In envisaging a multivariate multistep model of lung cancer among silica-exposed workers, silica might be considered as a "passive components of the sufficient cause", i.e., one of the associated risk factors, concurrent or subsequent to the "active component(s) of the sufficient cause" (including, for instance, smoking, asbestos, radon-daughters, arsenic, hexavalent chromium, nickel, polycyclic aromatic hydrocarbons (PAH), and diesel exhausts among the external risk factors; and DNA repair enzymes polymorphism and spontaneous inactivation of tumour suppressor genes among the internal risk factors), which adds up in modulating the tumoral development in not easily predictable directions. If silica acts as a human lung carcinogen depending on certain occupational exposure circumstances, perhaps those circumstances and not silica itself should be classified for their human carcinogenicity potential.
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PMID:Multifactorial aetiology of lung cancer among silica-exposed workers. 1160 27

Numerous investigations have been conducted to elucidate mechanisms involved in the initiation and progression of silicosis. However, most of these studies involved bolus exposure of rats to silica, i.e. intratracheal instillation or a short duration inhalation exposure to a high dose of silica. Therefore, the question of pulmonary overload has been an issue in these studies. The objective of the current investigation was to monitor the time course of pulmonary reactions of rats exposed by inhalation to a non-overload level of crystalline silica. To accomplish this, rats were exposed to 15 mg/m3 silica, 6 h/day, 5 days/week for up to 116 days of exposure. At various times (5-116 days exposure), animals were sacrificed and silica lung burden, lung damage, inflammation, NF-KB activation, reactive oxygen species and nitric oxide production, cytokine production, alveolar type II epithelial cell activity, and fibrosis were monitored. Activation of NF-KB/DNA binding in BAL cells was evident after 5 days of silica inhalation and increased linearly with continued exposure. Parameters of pulmonary damage, inflammation and alveolar type II epithelial cell activity rapidly increased to a significantly elevated but stable new level through the first 41 days of exposure and increased at a steep rate thereafter. Pulmonary fibrosis was measurable only after this explosive rise in lung damage and inflammation, as was the steep increase in TNF-alpha and IL-1 production from BAL cells and the dramatic rise in lavageable alveolar macrophages. Indicators of oxidant stress and pulmonary production of nitric oxide exhibited a time course which was similar to that for lung damage and inflammation with the steep rise correlating with initiation of pulmonary fibrosis. Staining for iNOS and nitrotyrosine was localized in granulomatous regions of the lung and bronchial associated lymphoid tissue. Therefore, these data demonstrate that the generation of oxidants and nitric oxide, in particular, is temporally and anatomically associated with the development of lung damage, inflammation, granulomas and fibrosis. This suggests an important role for nitric oxide in the initiation of silicosis.
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PMID:Effect of inhaled crystalline silica in a rat model: time course of pulmonary reactions. 1216 31

Plant alkaloid tetrandrine (Tet), purified from Chinese herb Han-Fang Chi, is a potent immunomodulator used to treat rheumatic disorders, silicosis and hypertension in mainland China. We previously demonstrated that Tet effectively suppresses cytokine production and proliferation of CD28-costimulated T cells. In the present study, we investigated the possible involvement of nuclear factor kappa B (NF-kappaB) transcription factors, critical in CD28 costimulation, in Tet-mediated immunosuppression in human peripheral blood T cells. We showed that Tet inhibited NF-kappaB DNA-binding activities induced by various stimuli, including CD28 costimulation. At equal molar concentrations, Tet was as strong as methotrexate in suppressing CD28-costimulated NF-kappaB activities. Since Tet itself did not affect NF-kappaB binding to its corresponding DNA sequence, the results suggested that Tet might regulate NF-kappaB upstream signaling molecules. Further studies demonstrated that Tet could prevent the degradation of IkappaBalpha and inhibit nuclear translocation of p65 by blocking IkappaBalpha kinases alpha and beta activities. In addition, the activation of mitogen-activated protein kinases such as c-jun N-terminal kinase, p38 and extracellular signal-regulated kinase and activator protein-1 DNA-binding activity were all downregulated by Tet. Transfection assays performed in purified human peripheral blood T cells also confirmed the inhibition of NF-kappaB transcriptional activity by Tet. When four Tet analogues were readily compared, dauricine appeared to preserve the most potent inhibition on CD28-costimulated but not on H(2)O(2)-induced NF-kappaB DNA-binding activities. Our results provide the molecular basis of immunomodulation of Tet for being a potential disease-modifying antirheumatic drug in the therapy of autoimmune disorders like rheumatoid arthritis.
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PMID:Plant alkaloid tetrandrine downregulates IkappaBalpha kinases-IkappaBalpha-NF-kappaB signaling pathway in human peripheral blood T cell. 1550 55

Occupational exposure to mineral dusts, such as silica, has been associated with progressive pulmonary inflammation, lung cancer, and fibrosis. However, the mechanisms involved in this process are poorly understood. Because p53 is a key transcription factor regulating many important apoptosis-related genes, we hypothesized that p53 may play a key role in silica-induced apoptosis and that abnormal regulation of p53 by silica may contribute to development of lung cancer as well as silicosis. We used both in vitro and in vivo studies to test this hypothesis. Treatment of JB6 cells carrying a p53-luciferase reporter plasmid with silica caused dose-dependent p53 transactivation. Western blot indicates that silica not only stimulated p53 protein expression but also caused p53 phosphorylation at Ser392. TUNEL and DNA fragmentation analysis show that silica caused apoptosis in both JB6 cells and wild-type p53 (p53+/+) fibroblasts but not in p53-deficient (p53-/-) fibroblasts. Similar results were obtained by in vivo studies. Intratracheal instillation of mice with silica induced apoptosis in the lung of p53+/+ mice, whereas this induction was significantly inhibited in p53-/- mice. Confocal image analysis indicates that most apoptotic cells induced by silica were alveolar macrophages. These results demonstrate for the first time that silica induces p53 transactivation via induction of p53 protein expression and phosphorylation of p53 protein and that p53 plays a crucial role in the signal transduction pathways of silica-induced apoptosis. This finding may provide an important link in understanding the molecular mechanisms of silica-induced carcinogenesis and pathogenesis in the lung.
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PMID:Essential role of p53 in silica-induced apoptosis. 1555 88

The development of our studies on silica carcinogenesis and its mechanisms is reviewed. Starting from an analysis of the cellular reactions to silica in the pathogenesis of silicosis in the rat, followed by an analysis of the carcinogenic response to silica in the lungs of rats (but not in mice and hamsters), we went on to develop cellular models for culture and neoplastic transformation of rat alveolar epithelial cells. We studied the binding of silica to DNA, the generation of reactive oxygen species and the DNA damage mediated by hydroxyl radicals, showing marked differences among silica samples of varying purity. Then we investigated the role of peptides induced by silica in various cells, including cytokines and growth factors. Tumor necrosis factor (TNF)-alpha, which can cause activation of DNA transcription and is required for silica-induced fibrosis, was found to inhibit neoplastic transformation by quartz in cell cultures. Transforming growth factor (TGF)-beta was found to be produced in hyperplastic alveolar type II cells and to reach fibroblasts, macrophages and the connective tissue matrix adjacent to silicotic granulomas. Neuroendocrine cells and their peptides were found to be increased in alveolar and bronchiolar epithelia of silica lesions in rats, in contrast with mice and hamsters. Expression of adhesion molecules was found to be altered in silica-induced carcinogenesis and epithelial-mesenchymal transition was revealed by mesenchymal markers in the induced carcinomas. Promoter hypermethylation of adhesion genes in the induced carcinomas indicated a role for epigenetic mechanisms.
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PMID:Silicosis and lung cancer: a fifty-year perspective. 1635 May 47

Tetrandrine (TET), a bis-benzylisoquinoline alkaloid isolated from the dried root of Hang-Fang-Chi (Stephania tetrandra S. Moore), is well known to possess activities including antioxidant, anti-inflammation, anti-fibrotic and anticancer. It is used clinically to treat hypertension and silicosis. In the present study, the anti-proliferative and apoptotic effects of TET were evaluated on three different hepatoma cell lines, namely Hep G2, PLC/PRF/5 and Hep 3B. Using XTT assay, results showed that the IC50 values of TET were 4.35 microM for Hep G2, 9.44 microM for PLC/PRF/5 and 10.41 microM for Hep 3B cells. The CC50 of TET against BNL-CL.2 mouse normal liver cells was 31.12 microM. Interestingly, TET exhibited a lower IC50 value and better selectivity against Hep G2 and PLC/PRF/5 cells than cisplatin. Microscopic observation study, DNA fragmentation assay and flow cytometric analysis further supported apoptotic effect of TET on both PLC/PRF/5 and Hep 3B cells. The cell cycle of PLC/PRF/5 treated with TET appeared to arrest at G2/M phase in a dose-dependent manner, whereas no effect was noted on the cell cycle of Hep 3B cells. The present study concludes that TET exhibited anti-proliferative effect on Hep G2, PLC/PRF/5 and Hep 3B cells in a dose-dependent manner. TET also possesses a lower IC50 and better SI value than cisplatin against Hep G2 and PLC/PRF/5 cells. The effect of TET on cell cycle progression was found to vary with the type of hepatoma cells, suggesting the genetic make-up of the cells play an important role in the response to drug treatment.
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PMID:Antiproliferative and apoptotic effects of tetrandrine on different human hepatoma cell lines. 1643 45

Clinical detection of silicosis is currently dependent on radiological and lung function abnormalities, both late manifestations of disease. Markers of prediction and early detection of pneumoconiosis are imperative for the implementation of timely intervention strategies. Understanding the underlying mechanisms of the etiology of coal workers pneumoconiosis (CWP) and silicosis was essential in proposing numerous biomarkers that have been evaluated to assess effects following exposure to crystalline silica and/or coal mine dust. Human validation studies have substantiated some of these proposed biomarkers and argued in favor of their use as biomarkers for crystalline silica- and CWP-induced pneumoconiosis. A number of "ideal" biological markers of effect were identified, namely, Clara cell protein-16 (CC16) (serum), tumor necrosis factor-alpha (TNF-alpha) (monocyte release), interleukin-8 (IL-8) (monocyte release), reactive oxygen species (ROS) measurement by chemiluminescence (neutrophil release), 8-isoprostanes (serum), total antioxidant levels measured by total equivalent antioxidant capacity (TEAC), glutathione, glutathione peroxidase activity, glutathione S-transferase activity, and platelet-derived growth factor (PDGF) (serum). TNF-alpha polymorphism (blood cellular DNA) was identified as a biomarker of susceptibility. Further studies are planned to test the validity and feasibility of these biomarkers to detect either high exposure to crystalline silica and early silicosis or susceptibility to silicosis in gold miners in South Africa.
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PMID:Mechanistically identified suitable biomarkers of exposure, effect, and susceptibility for silicosis and coal-worker's pneumoconiosis: a comprehensive review. 1699 Feb 19

Ataxia-telangiectasia is an autosomal recessive disease characterized by neurological and immunological symptoms, radiosensitivity and cancer predisposition. Heterozygous carriers of an ataxia-telangiectasia gene mutation are predisposed to epithelial cancers. We initiated a study to elucidate the frequency and clinical relevance of ATM gene mutations in former uranium miners exposed to high levels of radiation from radon and its decay products. Former uranium miners with Schneeberg lung cancer (n=48), former uranium miners suffering from silicosis (n=60) and uranium miners without occupational lung disorders (n=102) were investigated for nine mutations in the ATM gene. One gastric and one prostate cancer occurred in the group of miners without occupational lung diseases. Mutation analyses for S707P, IVS10-6Tright curved arrow G, 2250Gright curved arrow A, E1978X, R2443X, 3801delG, S49C and D2625E-A2626P were performed using genomic DNA obtained from peripheral blood samples. Three ATM gene alterations (S707P, S49C or IVS10-6Tright curved arrow G) were observed. Of all cancer patients, 8.0% were heterozygous, but only 1.9% of the non-cancer controls were [OR=4.6; 95% confidence interval (CI), 0.8-26.8]. In this pilot study a major role of six ATM gene mutations could not be revealed for cancer predisposition in former uranium miners. The results leave the possibility of a moderate risk associated with more subtle ATM gene alterations.
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PMID:ATM gene mutations in former uranium miners of SDAG Wismut: a pilot study. 1720 91

Occupational exposure to respirable crystalline silica is associated with the development of silicosis, lung cancer and airways diseases. In order to assess cytotoxic effects and direct-oxidative DNA damage induced by short-term exposure to different doses of respirable alpha-quartz (NIST SRM1878a), we conducted a study using A549 cells. The cells were exposed to alpha-quartz at 25, 50, 100 microg/ml for 4 h and analysed by scanning electron microscope (SEM) and LDH release assay for cytotoxic effect evaluation. Cells were also exposed to 10, 25, 50, 100 microg/ml of alpha-quartz for 2 h and 4 h and analysed by Fpg comet test to evaluate direct and oxidative DNA damage. SEM observations of treated cells showed bleb development at lower doses and alterations of microvilli morphology at the highest dose. A slight LDH release was found only at 100 microg/ml. Fpg comet test showed a dose-related oxidative DNA damage in cells exposed for 2 h to quartz. Cells exposed for 4h at the same concentrations showed a dose-related direct DNA damage and the presence of oxidative DNA damage at lower doses. The bleb induction on cell surface evidenced by SEM at lower doses correlates with the presence of oxidative DNA damage at 4 h. The cell surface modifications observed by SEM at 100 microg/ml indicate that high doses of quartz induce more evident cytotoxic effects confirmed by LDH analysis and correlate with the genotoxicity showed by comet assay.
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PMID:Cytotoxicity and DNA-damage in human lung epithelial cells exposed to respirable alpha-quartz. 1725 9

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