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PubMed1984

Lung transfer factor and KCO at cardiac frequency 100 beats/min as a guide to impaired function of lung parenchyma.

Transfer factor (TL) and KCO have been measured by the single breath carbon monoxide method in 39 patients with confirmed or suspected lung disease, mostly of occupational origin, and 37 healthy subjects. TL and KCO at an exercise cardiac frequency of 100 beats/min (TL100 and KCO100) and the slopes of the regression of exercise transfer factor and KCO on exercise cardiac frequency (delta TL/delta fC and delta KCO/delta fC) were obtained. The discriminatory performance of these indices in detecting defective gas transfer was compared with that of TL and KCO at rest (TLrest and KCOrest). The slope indices did not distinguish between healthy subjects and patients with emphysema or conditions of the lung parenchyma, including asbestosis. The slope indices also failed to distinguish between individuals with normal and abnormal gas transfer at rest. The indices TL100 and KCO100 contributed additional information not contained in the indices at rest and they merit further study.

Adult↗
PubMed1984

Diffuse pleural thickening in asbestos workers: disability and lung function abnormalities.

Data from 37 asbestos workers with diffuse pleural fibrosis have been analysed. None had radiological evidence of asbestosis or physiological evidence of airflow obstruction. Forty per cent had breathlessness of MRC grade 3 or higher. Vital capacity was significantly lower in the subjects in the higher grades of breathlessness and in those with greater radiographic pleural abnormality. No relationship was demonstrated between dust exposure and either radiographic abnormality or grade of breathlessness. Diffuse pleural thickening, particularly when extensive and bilateral, causes functional impairment and disability.

Asbestos↗
PubMed1987

Asbestos induced diffuse pleural fibrosis: pathology and mineralogy.

Lungs from seven cases of diffuse pleural fibrosis with known asbestos exposure were studied to determine the gross and microscopic pathological features and relate these to the analysed mineral fibre content of the lung. All seven individuals had had substantial exposure, ranging from two to 25 years, and chronic chest problems and at necropsy all cases met the criteria for compensatable disease. Macroscopically, all had extensive visceral pleural fibrosis and extensive areas of adhesions, and four also had discrete parietal pleural plaques. The histological features were similar in all the cases--most strikingly the basket weave pattern of the thickened pleura and a dense subpleural parenchymal interstitial fibrosis with fine honeycombing, extending up to 1 cm into the underlying lung. The similar histological appearances raise the possibility that diffuse pleural fibrosis and pleural plaques have a similar pathogenesis. Amphibole asbestos (crocidolite and amosite) counts were high in six of the seven cases and chrysotile counts in four; four cases had high mullite counts, but the importance of this is not known. It is concluded that diffuse pleural fibrosis is a specific asbestos associated entity, of uncertain pathogenesis, with mineral fibre counts falling between those found with plaques and those in minimal asbestosis.

Asbestos↗
PubMed1989

Relation of airway responsiveness to duration of work in a dusty environment.

Health selection within a workforce has been found in several industries and appears to be more pronounced in dustier occupations. In this study of airway disease among workers exposed to asbestos and man made mineral fibres, 215 of 246 construction insulators 50 years old or less and currently working in the Montreal area were examined. Spirometry was completed successfully in 214 workers without known asbestosis and 207 underwent methacholine bronchoprovocation testing. Airway responsiveness was expressed as PC15, the concentration of methacholine causing a 15% fall in the forced expiratory volume in one second (FEV1). Exposure to asbestos and synthetic mineral fibre dust was estimated from the total hours of work in the trade since first employment. After the effect of age, height, and pack years of smoking had been taken into account, no relation was found between hours of work and any indices obtained from the forced expiratory manoeuvre (FEV1/FVC, MMF). After the effect of airway calibre (FEV1/FVC), age, and pack years of cigarette consumption had been taken into account, airway responsiveness decreased as the total hours of work in the trade increased. These findings suggest that workers with greater levels of airway responsiveness are more sensitive to exposure in a dusty workplace and in consequence are less likely to continue. In studies of workforces a survivor effect of this nature will tend to weaken the relation between lung function abnormality and occupational exposure.

Adult↗
PubMed1993

Malignant mesothelioma in women.

BACKGROUND: Malignant mesothelioma reportedly shows different epidemiology and pathology in females, and a proportion are believed to arise spontaneously. METHODS: One hundred and seventy seven cases of malignant mesothelioma in females were reviewed, examined by histochemistry and immunohistochemistry, assessed for asbestosis and lung fibre burden by transmission electron microscopy with energy dispersive x ray analysis, and compared with 31 female controls. RESULTS: Two of one hundred and three cases tested for carcinoembryonic antigen were positive and were excluded from further analysis. Tumour cases showed increased amphibole burdens; in those in whom exposure information was known, 74 (80%) of 93 patients had a history of exposure to asbestos. Seventy two (47%) of 152 patients had lung fibrosis. Tumour site and histological type were little different from those reported in adult males. Mixed type histological pattern, lung fibrosis, and peritoneal site were associated with heavier lung asbestos burdens, but not exclusively. Thirty five (30%) of 117 patients had amphibole burdens of less than 2 x 10(6) fibres/g; the sites affected and the histological pattern of tumours in this group were similar to those in cases with amphibole fibre counts of > or = 2 x 10(6)/g lung. A higher lung amphibole burden than the mean burden in control females was found in 115 (98%) of 117 patients tested. CONCLUSIONS: The pathology of malignant mesothelioma appears to be similar in women and in men, and in cases associated and unassociated with asbestos.

Adolescent↗
PubMed1995

Value of adenosine deaminase in the diagnosis of tuberculous pleural effusions in young patients in a region of high prevalence of tuberculosis.

BACKGROUND: Pleural biopsy is usually considered important for the diagnosis of pleural effusions, especially for distinguishing between tuberculosis and neoplasia, even though tuberculous pleural fluid contains sensitive biochemical markers. In regions with a high prevalence of tuberculosis, and in patient groups with a low risk of other causes of pleurisy, the positive predictive value of these markers is increased. The criteria for performing a pleural biopsy under these circumstances have been investigated, using adenosine deaminase (ADA) as a pleural fluid marker for tuberculosis. METHODS: One hundred and twenty nine patients with a pleural effusion aged < or = 35 years (mean (SD) 25.2 (4.9) years) were studied. Seventy three were men. Eighty one effusions (62.8%) were tuberculous, 12 (9.3%) parapneumonic, and 10 (7.7%) neoplastic, five were caused by pulmonary thromboembolism, four by systemic lupus erythematosus, seven by empyema, three following surgery, one was the result of asbestosis, and one of nephrotic syndrome. In five cases no definitive diagnosis was reached. ADA levels were determined by the method of Galanti and Giusti. RESULTS: The diagnostic yield of procedures not involving biopsy was 94.5% (122/129). Pleural biopsy provided a diagnosis in a further two cases, but not in the remaining five. All tuberculous cases had pleural fluid levels of ADA of > 47 U/l (mean (SD) 111.1 (36.6) U/l). The only other cases in which ADA exceeded this level were six of the seven patients with empyema. Cytological examination of the pleural fluid diagnosed eight of the 10 neoplastic cases, compared with six diagnosed by pleural biopsy. CONCLUSIONS: In a region with a high prevalence of tuberculosis procedures not involving pleural biopsy have a very high diagnostic yield in patients with a pleural effusion aged < or = 35 years, making biopsy necessary only in cases in which pleural levels of ADA are below 47 U/l, pleural fluid cytology is negative and, in the absence of a positive basis for some other diagnosis, neoplasia is suspected.

Adenosine Deaminase↗
PubMed1997

Malignant mesothelioma in south east England: clinicopathological experience of 272 cases.

BACKGROUND: Malignant mesothelioma is a rare pleural tumour associated with asbestos exposure. The proportion of malignant mesothelioma unrelated to asbestos exposure, and any differentiating features between exposed and unexposed cases, are not well described. This study describes occupational, clinical, and pathological features in a large cohort of cases of malignant mesothelioma from south east England. METHODS: All 272 cases from this region were studied, either in life or after death when necropsy examination suggested malignant mesothelioma. Detailed information was gathered regarding the occupational history, clinical course, and mode of death. Necropsies were performed in 98% of cases. Lung tissue was examined histologically to confirm the diagnosis, subtype of tumour, presence or absence of asbestosis and asbestos bodies. RESULTS: Exposure to asbestos was documented in 87% of cases, while in the remainder, no asbestos exposure was found nor were asbestos bodies seen; 94.5% were pleural, 5.1% peritoneal, and 0.4% pericardial. Right sided tumours were more common than left sided tumours (ratio 1.6:1). Patients usually presented with breathlessness and chest pain, but 33% presented with pleural effusion in the absence of chest pain. The mean (SD) time from first exposure to asbestos to symptoms was 40 (12) years with a median (interquartile range (IQR) survival of 14 (12.5) months. The median (IQR) survival time in sarcomatous, epithelial, and mixed cell type malignant mesothelioma was 9.4 (10) months, 12.5 (18) months, and 11 (14) months, respectively, and was significantly greater in cases detected by chance. Clinical features were similar in asbestos related and non-asbestos related malignant mesothelioma. CONCLUSIONS: In south east England most cases of malignant mesothelioma are associated with asbestos exposure. Clinical features do not differentiate between asbestos related and non-asbestos related disease.

Adult↗
PubMed1978

Peritoneal mesothelioma.

Five cases of malignant peritoneal mesothelioma are reported. Its radiographic manifestations consisted of a desmoplastic mesenteric process with or without a localized mass displacing gastrointestinal structures. Appreciation of the nature of this tumor permits pathologic-radiologic correlation and an understanding of the radiographic changes. Though numerous conditions may produce similar findings, combining a history of asbestos exposure or chest radiograph findings of asbestosis with gastrointestinal findings of desomplasia should narrow the diagnostic possibilities.

Adult↗
PubMed1992

High-resolution CT of parenchymal lung disease: precise correlation with histologic findings.

To provide a precise correlation between high-resolution computed tomographic (CT) findings and histologic studies of various parenchymal lung diseases, 20 fixed and inflated lungs were studied as follows: (a) Every lung was cut at the corresponding CT level into 1.5-mm-thick sections, (b) selected slices were cut into small blocks to prepare histologic slides, (c) each slide was photographed, and (d) the image of the entire lung section was reconstituted with the enlarged photographs (assembled as in a jigsaw puzzle). Results obtained in cases of normal lungs, pulmonary edema, alveolitis, hypersensitivity pneumonitis, emphysema, Pneumocystis carinii pneumonia, silicosis-asbestosis, and idiopathic pulmonary fibrosis demonstrated the method to be accurate in correlating high-resolution CT findings and the corresponding histologic data.

Alveolitis, Extrinsic Allergic↗
PubMed1993

Asbestos directly increases lung epithelial permeability.

Asbestos causes the fibrotic lung disease asbestosis, but the biologic basis for this is unknown. Lung epithelial dysfunction including increased permeability is hypothesized to contribute to lung scarring in other forms of pulmonary fibrosis. Lung epithelial permeability is increased in both animals and humans exposed to asbestos. It is not known whether the increased epithelial permeability results from direct effects of asbestos or occurs as a result of the inflammatory reaction to asbestos fibers. To address this question we used a cultured human lung epithelial model, and we measured the direct effect of asbestos on lung epithelial barrier integrity as measured by mannitol permeability. We exposed the monolayer to chryogenically ground, respirable-sized chrysotile asbestos particles. This chrysotile asbestos caused a dose- and time-dependent increase in mannitol permeability across the epithelial monolayer. Increased mannitol permeability occurred both in the presence and in the absence of serum, was not due to cytotoxicity as measured by lactate dehydrogenase release, and was not associated with altered actin cytoskeleton at the light microscopic level. Permeability to 70 kDa neutral dextran also increased after asbestos exposure; however, the absolute permeability to dextran was less than mannitol permeability. Neither latex beads nor tantalum caused any change in permeability, suggesting that our findings are not explained by nonspecific effects of particles. Increased permeability did not reverse in the continued presence of asbestos and persisted even after removing the asbestos. Finally, surface-bound iron did not appear to be necessary for this effect because neither chelating iron with deferoxamine nor iron-loading the asbestos altered the effect on mannitol permeability. These results show that asbestos has direct effects on lung epithelial permeability. Together with the recent observation that asbestos directly increases epithelial fibrinolytic activity, our results suggest a novel mechanism for asbestos-induced lung injury.

Asbestos↗
PubMed1996

Asbestos induces apoptosis in human alveolar macrophages.

Asbestos refers to a group of fibrous minerals implicated in the development of several lung diseases, including fibrosis (asbestosis), cancer, and malignant mesothelioma. Although major health risks exist in occupationally exposed individuals, low-level exposures of asbestos may still contribute to health problems. The mechanism by which asbestos causes lung disease is not clearly understood but has been proposed to involve the alveolar macrophage (AM). We propose that asbestos induces apoptosis of AM, resulting in the development of an inflammatory state. In this study, we examined two forms of asbestos, chrysotile (CHR) and crocidolite (CRO), along with a control fiber, wollastonite (WOL), to characterize their relative cytotoxicity and ability to stimulate apoptosis in vitro. AM were cultured for 24 h with these particulates and examined for cell viability (trypan blue exclusion) and apoptosis (morphology, levels of cytosolic oligonucleosomal DNA fragments, and DNA ladder). In the absence of a decrease in cell viability, both CHR and CRO produced changes in cell morphology consistent with apoptosis. In addition, levels of cytoplasmic oligonucleosomal DNA (Cell Death Detection enzyme-linked immunosorbent assay) were significantly enhanced for CHR (3-25 micrograms/ml) and CRO (25-75 micrograms/ml) in a dose-dependent manner (a process that was inhibitable by 10 microM Z-Val-Ala-Asp fluoromethyl ketone, an interleukin-converting enzyme inhibitor). In contrast, WOL (up to 400 micrograms/ml) produced no significant DNA fragmentation in a 24-h culture. Neither CHR nor CRO caused DNA ladder formation in 24-h cell cultures. However, in 48-h cell cultures, both CHR- and CRO-exposed cells, but not WOL, resulted in the formation of DNA ladders characteristic of apoptosis. In summary, these results suggest that, unlike nonfibrogenic particulates, low doses of asbestos fibers cause apoptosis in cultured human AM that may be an early step in the development of lung fibrosis.

Apoptosis↗
PubMed1998

Asbestos-induced lung epithelial permeability: potential role of nonoxidant pathways.

Asbestos fibers are an important cause of lung fibrosis; however, the biological mechanisms are incompletely understood. The lung epithelium serves an important barrier function in the lung, and disrupting the epithelial barrier can contribute to lung fibrosis. Lung epithelial permeability is increased in patients with asbestosis, and asbestos fibers increase permeability across cultured human lung epithelium. However, the mechanism of this increased permeability is not known. Many of the biological effects of asbestos are postulated to be due to its ability to generate oxidants, and oxidants are known to increase epithelial permeability. However, we previously reported that altering the iron content of asbestos (important in oxidant generation) had no effect on its ability to increase permeability. For that reason, we undertook these studies to determine whether asbestos increases epithelial permeability through nonoxidant pathways. Both extracellular (H2O2) and intracellular (menadione) oxidants increase paracellular permeability across human lung epithelial monolayers. Extracellular catalase but not superoxide dismutase prevented increased permeability after both oxidant exposures. However, catalase offered no protection from asbestos-induced permeability. We next depleted the cells of glutathione or catalase to determine whether depleting normal cellular antioxidants would increase the sensitivity to asbestos. Permeability was the same in control cells and in cells depleted of these antioxidants. In addition to generating oxidants, asbestos also activates signal transduction pathways. Blocking protein kinase C activation did not prevent asbestos-induced permeability; however, blocking tyrosine kinase with tyrophostin A25 did prevent asbestos-induced permeability, and blocking tyrosine phosphatase with sodium vanadate enhanced the effect of asbestos. These data demonstrate that asbestos may increase epithelial permeability through nonoxidant pathways that involve tyrosine kinase activation. This model offers an important system for studying pathways involved in regulating lung epithelial permeability.

Amitrole↗
PubMed1999

Effect of asbestos-related pleural fibrosis on excursion of the lower chest wall and diaphragm.

To examine mechanisms responsible for reduced lung volumes (restriction) in asbestos-related pleural fibrosis (APF), we studied diaphragm function and lower rib-cage excursion in 26 subjects with previous asbestos exposure and no evidence of asbestosis. Using posteroanterior (PA) and lateral chest radiographs taken at residual volume and at 25%, 70%, and 100% vital capacity (VC) during a slow inspiratory maneuver, we measured fractional expansion of the lower rib cage (FErc), fractional shortening of the diaphragm (FSdi), and changes (Delta) in diaphragm dome height (Hdo) and subphrenic volume (Vdi). Vdi was estimated by measuring the major and minor axes of the subphrenic space at 1-cm intervals, assuming an elliptical cross-sectional shape, and correcting for the volume of spinal and paraspinal tissues. Seven subjects had no evidence of APF (control), 12 had pleural plaques (PP), and seven had diffuse pleural thickening with costophrenic obliteration (DPT). Over the range of VC, results (mean +/- SEM, normalized for height) in control subjects were VC = 101.2 +/- 4.0 % predicted and DeltaVdi = 326 +/- 8 ml/m(3), and for the right hemithorax and hemidiaphragm on the PA film, FErc = 0.07 +/- 0.02, FSdi = 0.32 +/- 0.02 and DeltaHdo = 0.8 +/- 0.2 cm/m. Relative to controls: DPT subjects had reduced VC (77.4 +/- 4.9%, p < 0.01), DeltaVdi (256 +/- 2 ml/m(3), p < 0.01), FErc (0.01 +/- 0.02, p < 0.01), FSdi (0.24 +/- 0.01, p < 0.001), and DeltaHdo (-0.9 +/- 0.06 cm/m, p < 0.01); PP subjects had reduced FSdi (0.25 +/- 0.01, p < 0.001) and DeltaVdi (233 +/- 47 ml/m(3), p < 0.01), and no difference in FErc, DeltaHdo, or VC. We conclude that restriction in DPT is due to obliteration of the zone of apposition, and that by limiting separation of the diaphragm from the rib cage during inspiration, this reduces volume contributed by motion of the diaphragm and lower rib cage. Reduction in the latter contribution was the main cause of restriction, because the reduction in volume contributed by the diaphragm was partly compensated by flattening of its dome.

Asbestos↗
PubMed1989

Asbestos and cancer: human natural killer cell activity is suppressed by asbestos fibers but can be restored by recombinant interleukin-2.

Inhalation of asbestos fibers is associated with a marked increase in the risk of developing pulmonary malignancy, particularly bronchogenic carcinoma. As natural killer (NK) cells are specialized lymphocytes that are considered to have an important in vivo role in the recognition and destruction of malignant cells, we examined the capacity of asbestos fibers (chrysotile, amosite, and crocidolite) to interfere with the NK activity of nylon wool-nonadherent, human blood lymphocytes (51Cr-release assay, K562 target cells, 14 h effector-to-target ratio = 50:1). Final asbestos concentrations used were 1 to 1,000 micrograms/ml. None of the fibers altered spontaneous target cell lysis or lymphocyte viability. All types of asbestos suppressed NK activity in a dose-dependent fashion. This effect was most marked with chrysotile, which exerted a profound inhibitory effect on blood NK cell activity; at 100 micrograms/ml, NK activity was inhibited 84 +/- 2% (p less than 0.001). The suppressive effects of asbestos were exerted directly on the NK cells (large granular lymphocytes, 91 +/- 2% inhibition at 100 micrograms/ml; p less than 0.001). Exposure of lymphocytes to recombinant interleukin-2 (IL-2, 150 units/ml) for 24 h prior to exposure to asbestos restored the level of activity to 99 +/- 6% of the original value (p less than 0.001), and lung lymphocytes that were exposed to IL-2 in vivo (active sarcoidosis) were resistant to suppression by asbestos. Similar results were observed in a group of patients with asbestosis. This suppression of NK activity may contribute to the increased susceptibility of asbestos-exposed persons to the development of pulmonary malignancy.

Asbestos↗
PubMed1990

Pulmonary fibrosis in aluminum oxide workers. Investigation of nine workers, with pathologic examination and microanalysis in three of them.

Epidemiologic surveys have indicated an excess of nonmalignant respiratory disease in workers exposed to aluminum oxide (Al2O3) during abrasives production. However, clinical, roentgenographic, histologic, and microanalytic description of these workers are lacking. This is a report of nine Al2O3-exposed workers with abnormal chest roentgenograms (profusion greater than or equal to 1/0, ILO/UC) from a plant engaged in the production of Al2O3 abrasives from alundum ore. Mean duration of exposure was 25 yr, and time since first exposure was 28 yr. in a subgroup of three, the severity of symptoms, reduction in the forced vital capacity (67% predicted) and diffusing capacity (51% predicted), and progressive roentgenographic changes (profusion greater than or equal to 2/2) prompted open lung biopsy. Lung tissue was analyzed by scanning electron microscopy and electron microprobe analysis. In each of the three biopsies, interstitial fibrosis with honeycombing was seen on routine section. In one biopsy, silica and asbestos fiber counts were at the low end of the range seen with silicosis and asbestosis; however, the absence of asbestos bodies and silicotic nodules suggested that the fibrosis was due to another cause. Metals occurred in amounts several orders of magnitude above background, and the majority was aluminum as Al2O3 and aluminum alloys. The findings in these nine workers suggests a common exposure as the possible cause. The nonspecific pathologic findings, absence of asbestos bodies and silicotic nodules, and the striking number of aluminum-containing particles suggest that Al2O3 is that common exposure. The possibility of "mixed dust" fibrosis should also be considered.

Adult↗
PubMed1986

Dental technician's pneumoconiosis. A report of two cases.

Diagnosis of pneumoconiosis was made in 2 dental technicians presenting with interstitial lung disease. The occupational origin of inhaled dust was confirmed by mineralogic analyses, which disclosed mainly large amounts of chromium-cobalt-molybdenum particles originating from Vitallium prostheses, but also showed abrasives (silica and silicon carbide) and asbestos in 1 patient. The presence of Vitallium and its chemical stability in bronchoalveolar lavage and lung several years after cessation of exposure confirm the resistance of this alloy to corrosion by body fluids. This contrasts with the high solubility of cobalt described in cobalt or hard metal disease. We suggest that dental technician's pneumoconiosis is a complex pneumoconiosis distinct from silicosis, asbestosis, or hard metal disease and that Cr-Co-Mo alloys play a role in its pathogenesis.

Adult↗
PubMed1987

Mast cells, atypical lymphocytes, and neutrophils in bronchoalveolar lavage in extrinsic allergic alveolitis. Comparison with other interstitial lung diseases.

Bronchoalveolar lavage (BAL) samples from exposed patients with extrinsic allergic alveolitis (EAA) contained mast cells in increased numbers in addition to lymphocytes. The counts rarely exceeded 0.5% in sarcoidosis, cryptogenic fibrosing alveolitis, or asbestosis or in control samples, but they were as much as 10-fold higher in EAA (p less than 0.001). Higher concentrations of histamine were demonstrated in EAA BAL-cell lysates, and histamine was released from cells challenged with anti-IgE. Electron microscopic examination confirmed that the cells were mast cells that differed from mast cells in dermal connective tissue and alveolar interstitial tissue but resembled bronchial subepithelial tissue mast cells in showing more features suggestive of activation. However, they showed more marked degranulation, and many were young. By light microscopy, they also resembled "mucosal" rather than "connective" tissue mast cells since granule staining was prevented by formaldehyde. Mast cell counts fell to normal after removal of patients from exposure, but lymphocyte increases, including atypical "blast" forms, persisted despite clinical recovery. Neutrophils were also increased before, but rarely after, removal. We suggest that EAA may provide an example of a human disease to support recent evidence that some delayed hypersensitivity disorders involve mast cells as well as lymphocytes.

Alveolitis, Extrinsic Allergic↗
PubMed1996

Asbestos induction of nuclear transcription factors and interleukin 8 gene regulation.

Proinflammatory cytokines and chemotactic peptides are strongly implicated as mediators of the pathophysiologic responses of asbestosis and other chronic inflammatory lung diseases. Recent studies in our laboratory have demonstrated that asbestos fibers stimulate lung epithelial cells to produce interleukin-8 (IL-8), the major neutrophil chemoattractant in the lung. The mechanisms by which asbestos regulates IL-8 expression were studied using the pulmonary type II-like epithelial cell line A549. Membrane permeable hydroxyl scavengers inhibited asbestos induced IL-8 expression. Using A549 cells transfected with the -546 IL-8 construct linked to a chloramphenicol acetyl transferase reporter gene, we have shown that these antioxidants directly inhibited asbestos-stimulated IL-8 promoter-dependent transcription. Asbestos fibers as well as reactive oxygen species generating systems hypoxanthine-xanthine oxidase and hydrogen peroxide stimulated DNA binding activity to the regulatory elements in the IL-8 promoter, binding sites of nuclear factor (NF)-kappaB- and NF-IL-6-like transcription factors. Asbestos-inducible DNA binding activity was partially inhibited by tetramethylthiourea, a hydroxyl radical scavenger. IL-8 secretion was also suppressed by staurosporine, an inhibitor of protein kinase C, and by inhibitors of tyrosine kinase such as herbimycin A and genistein. The suppression paralleled the effect of these inhibitors on asbestos-induced DNA binding to the NF-kappaB- and NF-IL-6-like binding sites of the IL-8 promoter. Taken together, the results suggest that asbestos-induced redox changes and phosphorylation events, mediated by staurosporine-sensitive and tyrosine kinase(s), activate nuclear proteins which recognize the NF-kappaB/NF-IL-6 binding sites of the IL-8 promoter and contribute to the regulation of IL-8 gene expression.

Antioxidants↗