Increased manganese superoxide dismutase protein in type II epithelial cells of rat lungs after inhalation of crocidolite asbestos or cristobalite silica.
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Manganese-containing superoxide dismutase (Mn-SOD) is a mitochondrial enzyme implicated in cellular defense from oxidative damage. We investigated the immunocytochemical distribution and protein concentration of Mn-SOD in rat lungs in response to aerosolized crocidolite asbestos or cristobalite silica, fibrogenic minerals eliciting generation of oxidants by cellular and acellular pathways. Rats were exposed to 7-10 mg/m3 dust for 6 hours a day for 10 days. Experimental and sham control rats were euthanized 10 days after cessation of exposure, and lungs prepared for immunocytochemistry and determination of amounts of Mn-SOD protein. Quantitation of Western blots showed that the amount of immunodetectable Mn-SOD increased in lungs exposed to asbestos or silica by approximately 1.3- and 2.4-fold, respectively, when compared with sham controls. Immunoelectron microscopy using the protein A-gold technique showed that Mn-SOD was located predominantly in mitochondria of type II epithelial cells. Fibroblasts contained little immunodetectable Mn-SOD, whereas type I epithelial cells, polymorphonuclear leukocytes (PMNs), and endothelial cells contained no detectable protein. Some alveolar macrophages (AMs) were found with labeled mitochondria, whereas most interstitial macrophages had no detectable protein. Quantitative analysis of type II cells showed that the number of immunogold particles per unit of mitochondrial area increased in the terminal airways of lungs exposed to asbestos or silica by 2.2-fold and 3.6-fold, respectively, over controls. Morphometric analyses indicated that the size of type II cells, as well as the number of interstitial macrophages and PMNs, increased in the terminal respiratory tissue of silica-exposed lungs. Less pronounced histopathologic changes were evident in asbestos-exposed lungs. These results indicate that the relative concentration of Mn-SOD increases preferentially in type II epithelial cells subsequent to inhalation of silica or asbestos. The magnitude of induction of Mn-SOD protein in these cells and whole lung correlated with the inflammatory potential of these minerals. (+info)
The mortality of amphibole miners in South Africa, 1946-80.
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A cohort was established in 1981 of all 7317 white male employees in the amosite and crocidolite mines in South Africa whose names had appeared in the personnel records (initiated between 1945 and 1955) of the major companies. Some of the men had been employed as early as 1925, but only 8% had had more than 10 years of service. Three subcohorts were defined: 3212 men whose only exposure to asbestos was to amosite; 3430 exposed to crocidolite; and 675 to both amphiboles. No deaths or losses to view occurred before 1946, and 5925 men (81%) were known to be alive at the end of 1980. Losses to view numbered 167 (2%), and there had been 1225 deaths (17%), an excess of 331 over the number of deaths expected on the basis of the mortality of all white South African males. The fibre related excesses were of mesothelioma, lung cancer, and other respiratory diseases, but there were other excesses perhaps mainly related to socioeconomic factors including lifestyle. When cause of death was determined according to "best evidence" (after study of clinical, radiological, biopsy, and necropsy reports in conjunction with the death certificate), there were 30 deaths due to mesothelioma (22 pleural, six peritoneal, two other) and 65 due to cancer of trachea, bronchus, and lung. Various analyses of these deaths showed that crocidolite had higher toxicity than amosite for lung cancer and this was most pronounced for mesothelioma; there can now be no question that crocidolite is far more dangerous than amosite at least in so far as mesothelioma is concerned. Nevertheless, crocidolite induced mesothelioma appeared only in men who had been exposed for long periods, at least 12 months, but on average about 15 years. (+info)
Activation of p38 MAP kinase by asbestos in rat mesothelial cells is mediated by oxidative stress.
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Asbestos fibers are biopersistent particles that are capable of stimulating chronic inflammatory responses in the pleura of exposed individuals. Exposure of pleural mesothelial cells, the progenitor cell of malignant mesothelioma, to asbestos induces an array of cellular responses. The present studies investigated whether the p38 mitogen-activated protein kinase cascade was induced under asbestos-exposed conditions. p38 plays a vital role in the response to stressful stimuli and enables the cell to enter an inflammatory state characterized by cytokine production. Western blot and in vitro kinase assays showed increases in dual phosphorylation and actual activity of p38 after exposure to fibrous and nonfibrous (milled) crocidolite; in contrast, polystyrene beads and iron (III) oxide had no such effects. In common with other asbestos-induced events, this was shown to be an oxidative stress-sensitive effect, inasmuch as preincubation with N-acetyl-L-cysteine or -tocopherol (vitamin E) ameliorated the effect. The present studies show that p38 activity is important for crocidolite-induced activator protein-1 DNA binding, inasmuch as an inhibitor of p38, SB-203580, reduced this activity. Crocidolite-induced cytotoxicity was also reduced with SB-203580, indicating a role for p38 in asbestos-mediated cell death. Our studies suggest that p38 activity could be a crucial factor in the chronic immune response elicited by asbestos and may represent a target for future pharmacological intervention. (+info)
Malignant pleural and peritoneal mesotheliomas in former miners and millers of crocidolite at Wittenoom, Western Australia.
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AIMS: To report the number of malignant pleural and peritoneal mesotheliomas that have occurred in former Wittenoom crocidolite workers to the end of 2000, and to compare this with earlier predictions. METHODS: A group of 6493 men and 415 women who had worked at the former Wittenoom crocidolite mine and mill at some time between 1943 and 1966 have been followed up throughout Australia and Italy to the end of 2000. RESULTS: The cumulative number of mesotheliomas up to 2000 was 235 in men (202 pleural, 33 peritoneal) and seven (all pleural) in women. There had been 231 deaths with mesothelioma (9% of known deaths). CONCLUSIONS: The number of deaths in men with mesothelioma between 1987 and 2000 was at the low end of the predictions made earlier based on the number of cases to 1986. If this trend continues, it is predicted that about another 110 deaths with mesothelioma will occur in men by 2020. (+info)
Asbestos-derived reactive oxygen species activate TGF-beta1.
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Transforming growth factor-beta1 (TGF-beta1) is a potent peptide that inhibits epithelial and mesenchymal cell proliferation and stimulates the synthesis of extracellular matrix components. This cytokine is produced in a biologically latent complex bound to a latent-associated peptide (LAP), and it is the disassociation of this complex that regulates TGF-beta activity. A number of mechanisms have been shown to activate TGF-beta1. We show here that reactive oxygen species (ROS), generated by the iron in chrysotile or crocidolite asbestos, mediate the biological activity of TGF-beta1. Recombinant human latent TGF-beta1 was activated in a cell free system in the presence of asbestos and ascorbic acid. Latent TGF-beta1 was overexpressed in both A549 and mink lung epithelial cell lines through an adenovirus vector containing the full-length construct for porcine TGF-beta1. This latent TGF-beta1 was activated in a concentration-dependant fashion by introducing asbestos into the cell cultures. This activation was reduced significantly through the use of superoxide dismutase, catalase or deferoxamine. Amino-acid constituents of the LAP were oxidized as demonstrated by the appearance of carbonyls detected by Western analysis. The oxidized LAP could no longer form a complex with TGF-beta1. Our data support the postulate that ROS derived from asbestos provide a mechanism for activating TGF-beta1 in the alveolar environment by oxidizing amino acids in LAP. (+info)
Simian virus 40 infection down-regulates the expression of nitric oxide synthase in human mesothelial cells.
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The cytotoxic effects of asbestos are partly mediated by the production of free radicals, including nitric oxide (NO). SV40 has been suggested to synergize with asbestos in the pathogenesis of malignant mesothelioma. Crocidolite asbestos fibers induced in human mesothelial and malignant mesothelioma cells a significant increase of NO synthase activity and expression, which was absent in SV40-infected cells. Furthermore, SV40 infection prevented the NF kappa B activation elicited by crocidolite in both mesothelial and mesothelioma cells. These data suggest that SV40, by inhibiting the synthesis of NO, could favor the survival of transformed, potentially neoplastic cells. (+info)
The duration of nuclear extracellular signal-regulated kinase 1 and 2 signaling during cell cycle reentry distinguishes proliferation from apoptosis in response to asbestos.
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Asbestos exposure causes activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in lung epithelial cells, the targets of asbestos-associated lung carcinomas. The functional significance of ERK1/2 activation in pulmonary epithelial and mesothelial cells is unclear. Using serum-stimulated mouse alveolar type II epithelial cells as a model for cell cycle reentry, we show that the duration of phospho-ERK1/2 in the nucleus determines cell fate in response to crocidolite asbestos. In response to 10% serum, a proliferative stimulus, phosphorylated ERK1/2 initially accumulated in the nucleus, and reduction of nuclear phospho-ERK1/2 after 2 to 4 hours was followed by expression of cyclin D1 and S-phase entry. Low levels of asbestos (<0.5 microg/cm2) promoted S-phase entry in low (2%) serum through an epidermal growth factor receptor-dependent pathway but did not promote cell cycle progression or induce apoptosis in the presence of high (10%) serum-containing medium. Higher levels of asbestos (1.0 to 5.0 microg/cm2) prolonged the localization of phospho-ERK1/2 in the nucleus in the presence of high serum, impeded S-phase entry, and induced apoptosis in a dose-dependent manner. Immunofluorescence microscopy indicated that the duration of signaling by phospho-ERK1/2 in the nucleus was predictive of cell fate at any concentration of asbestos. After 8 hours of exposure, cells with nuclear phospho-ERK1/2 also were positive for nuclear localization of apoptosis-inducing factor (AIF), an early event in apoptosis. In contrast, asbestos-exposed cells that displayed cytoplasmic phospho-ERK1/2 at 8 hours expressed cyclin D1 and proceeded to S phase. Our studies show that prolonged localization of phospho-ERK1/2 in the nucleus is incompatible with expression of cyclin D1 and is predictive of asbestos-associated cell death by AIF, thereby providing an approach for determining cell fate in asbestos-induced tumorigenesis. (+info)
Effects of asbestos and smoking on the levels and rates of change of lung function in a crocidolite exposed cohort in Western Australia.
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BACKGROUND: Increased rates of death from asbestos related diseases have been reported in former workers and residents exposed to crocidolite (blue asbestos) at Wittenoom, Western Australia. Exposure to asbestos is associated with reduced static lung volumes, gas transfer and lung compliance, and a restrictive ventilatory abnormality. METHODS: The effects of crocidolite exposure and smoking history on levels and rates of change of lung function were evaluated using a linear mixed model. Lung function was measured as forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC. RESULTS: Cumulative doses of asbestos and the presence of radiographic asbestosis were associated with lower levels of FEV1 and FVC and a steeper decline during the period of observation. Subjects exposed to asbestos at a younger age had lower levels of FEV1 and FVC. Current smokers had lower levels and a steeper decline in lung function than never smokers. No significant interactions between crocidolite exposure and smoking on the levels or rates of change of lung function were found. CONCLUSIONS: The deleterious effects of crocidolite exposure on lung function persist in this population, despite asbestos exposure having ceased more than 30 years ago. No significant interactions were found in this population between asbestos and smoking at the first visit or longitudinally. (+info)