Plasma retinol, carotene and vitamin E concentrations and lung function in a crocidolite-exposed cohort from Wittenoom, Western Australia: a cohort study.
(33/189)
BACKGROUND: Increased rates of death from asbestos related diseases have been reported for people previously employed in the mining and milling operations at Wittenoom (Western Australia), and people who lived in the nearby town, where they were environmentally exposed to crocidolite. METHODS: Annual measurements of forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) and plasma concentrations of retinol, carotene and vitamin E have been made since 1992. Mixed effects models were used to examine the associations between lung function and the plasma vitamin levels of retinol, carotene and vitamin E. RESULTS: After adjusting for potential confounders, higher plasma retinol and carotene concentrations were significantly associated with higher levels of lung function at entry into the study, while vitamin E concentrations were associated with lower entry lung function. Retinol was associated with a less steep decline of lung function over time, while carotene concentrations were associated with an increased decline of lung function over time and vitamin E levels were not associated with changes of lung function over time. CONCLUSION: These results support a beneficial relationship between plasma concentrations of retinol on the levels and rates of change of lung function, while showing no such consistent beneficial effect for plasma levels of beta-carotene or vitamin E. (+info)
A mouse model recapitulating molecular features of human mesothelioma.
(34/189)
Malignant mesothelioma has been linked to asbestos exposure and generally has a poor prognosis because it is often diagnosed in advanced stages and is refractory to conventional therapy. Human malignant mesotheliomas accumulate multiple somatic genetic alterations, including inactivation of the NF2 and CDKN2A/ARF tumor suppressor genes. To better understand the significance of NF2 inactivation in malignant mesothelioma and identify tumor suppressor gene alterations that cooperate with NF2 loss of function in malignant mesothelioma pathogenesis, we treated Nf2 (+/-) knockout mice with asbestos to induce malignant mesotheliomas. Asbestos-exposed Nf2 (+/-) mice exhibited markedly accelerated malignant mesothelioma tumor formation compared with asbestos-treated wild-type (WT) littermates. Loss of the WT Nf2 allele, leading to biallelic inactivation, was observed in all nine asbestos-induced malignant mesotheliomas from Nf2 (+/-) mice and in 50% of malignant mesotheliomas from asbestos-exposed WT mice. For a detailed comparison with the murine model, DNA analyses were also done on a series of human malignant mesothelioma samples. Remarkably, similar to human malignant mesotheliomas, tumors from Nf2 (+/-) mice showed frequent homologous deletions of the Cdkn2a/Arf locus and adjacent Cdkn2b tumor suppressor gene, as well as reciprocal inactivation of Tp53 in a subset of tumors that retained the Arf locus. As in the human disease counterpart, malignant mesotheliomas from the Nf2 (+/-) mice also showed frequent activation of Akt kinase, which plays a central role in tumorigenesis and therapeutic resistance. Thus, this murine model of environmental carcinogenesis faithfully recapitulates many of the molecular features of human malignant mesothelioma and has significant implications for the further characterization of malignant mesothelioma pathogenesis and preclinical testing of novel therapeutic modalities. (+info)
The effect of asbestosis on lung cancer risk beyond the dose related effect of asbestos alone.
(35/189)
AIMS: To determine if the presence of asbestosis is a prerequisite for lung cancer in subjects with known exposure to blue asbestos (crocidolite). METHODS: Former workers and residents of Wittenoom with known amounts of asbestos exposure (duration, intensity, and time since first exposure), current chest x ray and smoking information, participating in a cancer prevention programme (n = 1988) were studied. The first plain chest radiograph taken at the time of recruitment into the cancer prevention programme was examined for radiographic evidence of asbestosis according to the UICC (ILO) classification. Cox proportional hazards modelling was used to relate asbestosis, asbestos exposure, and lung cancer. RESULTS: Between 1990 and 2002 there were 58 cases of lung cancer. Thirty six per cent of cases had radiographic evidence of asbestosis compared to 12% of study participants. Smoking status was the strongest predictor of lung cancer, with current smokers (OR = 26.5, 95% CI 3.5 to 198) having the greatest risk. Radiographic asbestosis (OR = 1.94, 95% CI 1.09 to 3.46) and asbestos exposure (OR = 1.21 per f/ml-year, 95% CI 1.02 to 1.42) were significantly associated with an increased risk of lung cancer. There was an increased risk of lung cancer with increasing exposure in those without asbestosis. CONCLUSION: In this cohort of former workers and residents of Wittenoom, asbestosis is not a mandatory precursor for asbestos related lung cancer. These findings support the hypothesis that it is the asbestos fibres per se that cause lung cancer, which can develop with or without the presence of asbestosis. (+info)
Increased sensitivity to asbestos-induced lung injury in mice lacking extracellular superoxide dismutase.
(36/189)
Asbestosis is a chronic form of interstitial lung disease characterized by inflammation and fibrosis that results from the inhalation of asbestos fibers. Although the pathogenesis of asbestosis is poorly understood, reactive oxygen species may mediate the progression of this disease. The antioxidant enzyme extracellular superoxide dismutase (EC-SOD) can protect the lung against a variety of insults; however, its role in asbestosis is unknown. To determine if EC-SOD plays a direct role in protecting the lung from asbestos-induced injury, intratracheal injections of crocidolite were given to wild-type and ec-sod-null mice. Bronchoalveolar lavage fluid (BALF) from asbestos-treated ec-sod-null mice at 24 h, 14 days, or 28 days posttreatment showed increased inflammation and total BALF protein content compared to that of wild-type mice. In addition, lungs from ec-sod-null mice showed increased hydroxyproline content compared to those of wild-type mice, indicating a greater fibrotic response. Finally, lungs from ec-sod-null mice showed greater oxidative damage, as assessed by nitrotyrosine content compared to those of their wild-type counterparts. These results indicate that depletion of EC-SOD from the lung increases oxidative stress and injury in response to asbestos. (+info)
Smoking, exposure to crocidolite, and the incidence of lung cancer and asbestosis.
(37/189)
In 1979 all former workers from the Wittenoom asbestos industry who could be traced to an address were sent a questionnaire to determine smoking history. Occupational exposure to crocidolite was known from employment records. Of 2928 questionnaires sent, satisfactory replies were received from 2400 men and 149 women. Eighty per cent of these had smoked at some time and 50% were still smoking. Since that time 40 cases of lung cancer and 66 cases of compensatable asbestosis have occurred in this cohort. The incidence of both lung cancer and asbestosis was greatest in those subjects with the highest levels of exposure to crocidolite and in ex-smokers. Statistical modelling of the joint effects of these exposures on the incidence of each disease indicated that crocidolite exposure multiplied the rates of lung cancer due to smoking and that smoking has no measurable effect on the rates of asbestosis. There was also some evidence that the incidence rate of lung cancer is falling with time. (+info)
Matrix metalloproteinases promote inflammation and fibrosis in asbestos-induced lung injury in mice.
(38/189)
Inhalation of asbestos fibers causes pulmonary inflammation and eventual pulmonary fibrosis (asbestosis). Although the underlying molecular events are poorly understood, protease/antiprotease and oxidant/antioxidant imbalances are believed to contribute to the disease. Implicated in other forms of pulmonary fibrosis, the matrix metalloproteinases (MMPs) have not been examined in asbestosis. We therefore hypothesized that MMPs play a pathogenic role in asbestosis development. Wild-type C57BL/6 mice were intratracheally instilled with 0.1 mg crocidolite asbestos, causing an inflammatory response at 1 d and a developing fibrotic response at 7, 14, and 28 d. Gelatin zymography demonstrated an increase in MMP-9 (gelatinase B) during the inflammatory phase, while MMP-2 (gelatinase A) was profoundly increased in the fibrotic phase. Immunohistochemistry revealed MMP-9 in and around bronchiolar and airspace neutrophils that were often associated with visible asbestos fibers. MMP-2 was found in fibrotic regions at 7, 14, and 28 d. No increases in RNA levels of MMP-2, MMP-9, or MMP-8 were found, but levels of MMP-7, MMP-12, and MMP-13 RNA did increase at 14 d. The MMP inhibitors, TIMP-1 and TIMP-2, were also increased at 7-28 d after asbestos exposure. To confirm the importance of MMP activity in disease progression, mice exposed to asbestos were given daily injections of the MMP inhibitor, GM6001. MMP inhibition reduced inflammation and fibrosis in asbestos-treated mice. Collectively, these data suggest that MMPs contribute to the pathogenesis of asbestosis through effects on inflammation and fibrosis development. (+info)
Fibre distribution in the lungs and pleura of subjects with asbestos related diffuse pleural fibrosis.
(39/189)
The lungs from 13 cases of diffuse pleural fibrosis associated with a history of exposure to asbestos were examined. Samples were taken from the visceral pleura and central and subpleural zones of the lungs for histopathological and mineralogical studies. The fibre type, size, and number were estimated for each of these regions by transmission electron microscopy and energy dispersive x ray analysis. Amphibole fibre counts were raised when compared with a non-occupationally exposed group and matched those seen in cases of pleural plaques, mild asbestosis, and mesothelioma. A wide case to case variation of distribution was seen. No significant difference was apparent between central and subpleural zones, whereas low asbestos counts were found in the pleura; these were mainly short chrysotile fibres. Within the lungs more (45%) of the longer (greater than 4 microns) and thinner (less than 0.25 micron) amphibole fibres were retained in keeping with other studies implicating such fibre profiles in the pathogenesis of asbestos related disease. (+info)
The effect of asbestos and stone-wool fibres on some chemokines and redox system of pulmonary alveolar macrophages and pneumocytes type II.
(40/189)
The in vitro effect of stone-wool has been studied in primary cultures of pulmonary alveolar macrophages (AM) and type II pneumocytes (T2) by morphological, biochemical and immunological methods. UICC crocidolite was applied as a positive control. Although stone-wool brought about frustrated phagocytosis, it did not induce serious membrane damage, whereas crocidolite gave rise to very severe membrane alterations. Stone-wool significantly reduced the activity of Cu,Zn/superoxide dismutase (SOD) in alveolar macrophages and significantly decreased the activity of gamma-glutamyl transpeptidase (GGT) in pneumocytes type II. Crocidolite, on the other hand, decreased the activity of all enzymes (glutathione peroxidase - GSH-Px, glutathione reductase - GSH-Rd) of glutathione metabolism in alveolar macrophages. It decreased the activity of all enzymes in pneumocytes type II except for Cu,Zn/SOD. After exposure to stone-wool, the production of inflammatory proteins, macrophage chemoattractant protein-1 (MCP-1) and macrophage inhibitory protein-1alpha (MIP-1alpha) increased in both cultured cells but did not reach the level induced by crocidolite. Although this study provided a useful insight in the toxicity of the stone-wool, we can not draw the conclusions how the intact pulmonary tissue may respond on the exposure to these fibres, exclusively based on the in vitro tests. (+info)