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Markers of macrophage differentiation in experimental silicosis.

Macrophages are characterized by a marked phenotypic heterogeneity depending on their microenvironmental stimulation. Beside classical activation (M1), it has been shown that macrophages could follow a different activation pathway after stimulation with interleukin (IL)-4 or IL-13 (M2). Recently, it has been postulated that those "alternatively activated" macrophages may be critical in the control of fibrogenesis. In an experimental model of silicosis, where pulmonary macrophages play a central role, we addressed the question of whether lung fibrosis development would be associated with alternative macrophage activation. As available markers for alternative macrophage activation, type-1 arginase (Arg-1), Fizz1, Ym1/2, and mannose receptor expression were evaluated at the mRNA and/or protein levels at different stages of the disease. Nitric oxide synthase-2 (NOS-2) expression was also examined to investigate the classical counterpart. We found that the expression of Arg-1, Fizz1, and NOS-2 in adherent bronchoalveolar lavage cells was highly up-regulated 3 days after silica administration but returned to control levels during the fibrotic stage of the disease (60 days). By comparing the early response to silica in C57BL/6 and BALB/c mice, we observed that the amplitude of Arg-1 mRNA up-regulation was not associated with the severity of lung fibrosis. Using a model of manganese dioxide particles (resolutive alveolitis), we showed that this early Arg-1 mRNA was not specific to a fibrogenic lung response. Our data indicate that the modifications of M1/M2 marker expression are limited to the early inflammatory stage of silicosis and that the establishment of a fibrotic process is not necessarily associated with M2 polarization.

Animals↗

[Fas-Fas ligand system in silicosis patients].

The exposure to silica and related substances such as silicate (e.g. chrysotile asbestos; 3MgO.2SiO2.H2O) or silicone (-R2Si-O-)n, used in plastic surgery, has been known to induce autoimmune diseases. The pathogenesis of autoimmunity induced by such environmental factors, however, needs to be clarified. On the other hand, details about the relationship between autoimmunity and defective functioning of the Fas-Fas ligand system have been analyzed. In this report, we intend to summarize our results which suggest a suppressed apoptosis through the Fas-Fas ligand system in silicosis patients, and to speculate on the effects of silica on inappropriate cell survival which could induce the development of autoimmune reactions. We observed elevated levels of serum sFas and an increased expression of sFas mRNA in silicosis patients. sFas instead of membranous Fas binds competitively to the Fas ligand, and consequently, reduces the apoptosis of Fas positive cells. In addition, we observed polyclonal activation of human T cells by silica and silicate in vitro. In such cases, many autoreactive clones could be activated simultaneously. From these results, silica and silicate could play an important role in inducing autoimmune reactions by (1) repeated polyclonal activation of human T cells and (2) the suppression of apoptosis inducing the release of sFas into the sera of the patients.

Apoptosis↗

Silicosis and coal workers' pneumoconiosis.

Exposure to coal mine dust and/or crystalline silica results in pneumoconiosis with initiation and progression of pulmonary fibrosis. This review presents characteristics of simple and complicated coal workers' pneumoconiosis (CWP) as well as pathologic indices of acute and chronic silicosis by summarizing results of in vitro, animal, and human investigations. These results support four basic mechanisms in the etiology of CWP and silicosis: a) direct cytotoxicity of coal dust or silica, resulting in lung cell damage, release of lipases and proteases, and eventual lung scarring; b) activation of oxidant production by pulmonary phagocytes, which overwhelms the antioxidant defenses and leads to lipid peroxidation, protein nitrosation, cell injury, and lung scarring; c) activation of mediator release from alveolar macrophages and epithelial cells, which leads to recruitment of polymorphonuclear leukocytes and macrophages, resulting in the production of proinflammatory cytokines and reactive species and in further lung injury and scarring; d) secretion of growth factors from alveolar macrophages and epithelial cells, stimulating fibroblast proliferation and eventual scarring. Results of in vitro and animal studies provide a basis for proposing these mechanisms for the initiation and progression of pneumoconiosis. Data obtained from exposed workers lend support to these mechanisms.

Air Pollutants, Occupational↗

Liposomes in silicosis investigations.

The effects of quartz and sodium metasilicate on liposomes were studied in order to understand the mechanism of silicosis. 8-Hydroxyquinoline-5-sulfonic acid was tested for its in situ silicosis-prevention capacity. Two types of liposomes--(A) those incorporating cholesterol and (B) those without cholesterol--were used. The tests consisted of measuring permeability changes caused by the above-mentioned chemicals. Permeabilities were found to depend on membrane composition. Tests on quartz action led us to the conclusion that liposomes of this composition did not simulate the erythrocytes very well. It was also observed that absence or presence of cholesterol and the mode of contact altered the effect of quartz. Silicate destabilized type A liposomes, but this was less than that caused by quartz. This was explained by the concentration of monosilicic acid that dissolves out from quartz and silicate. When quartz was pretreated with the preventive, the type A liposomes were stabilized, but a slight destabilizing effect was observed on type B. 8-Hydroxyquinoline-5-sulfonic acid augmented the destabilizing effect of silicate, whereas it decreased the hemolytic activity of uncoated quartz, indicating a preventive potential in in vivo.

Animals↗

Some aspects of the problem of individual predisposition to silicosis.

Based on experimental and epidemiological data findings presented here, as well as on data of other investigators, the authors conclude that a wide interindividual variability of susceptibility to silicosis is a real phenomenon. This susceptibility depends on both intrinsic features of the host and the influence of many environmental factors. The effect of any such factor is realized at different stages of silicosis pathogenesis and in close interrelation with the influence of other factors. The necessity of multifactorial analysis is stressed, and an example of such analysis is presented.

Acclimatization↗

Acute silicosis responding to corticosteroid therapy.

The course of acute silicosis usually is relentlessly progressive. Death results from cor pulmonale and respiratory failure, with mycobacterial infection a frequent serious complication. Attempts to treat the illness generally have been unavailing. We report an unusual case of acute silicosis in which improvement in clinical status, chest x-ray film findings and pulmonary function occurred following therapy with corticosteroids. To our knowledge, this is the first such case reported in the medical literature.

Acute Disease↗

Exercise testing in radiologically-limited, simple pulmonary silicosis.

Forty-five consecutive patients (17 non-smokers and 28 smokers) affected by pulmonary silicosis with limited profusion of radiologic small opacities of "p" type underwent physical examination; resting standard pulmonary function tests (PFT); and progressive, multistage, treadmill-based exercise testing (ET). Results show that, in 78 percent of all patients, maximum oxygen uptake (VO2max) was below 80 percent of predicted, and in most cases this was accompanied by a reduction of anaerobic threshold and/or oxygen pulse. In our group, VO2max predicted was uncorrelated with PFT parameters, symptoms and x-ray picture. No significant differences in response to exercise were observed between smokers and non-smokers. Therefore, exercise was limited by factors other than ventilatory limitation. It is concluded that ET is not more sensitive than PFT for assessing ventilatory impairment in patients with early, simple silicosis, even though it may be valuable for providing information about other sources of exercise limitation.

Adult↗

Cysteine cathepsins and caspases in silicosis.

Silicosis is an occupational pneumoconiosis caused by inhalation of crystalline silica. It leads to the formation of fibrohyalin nodes that result in progressive fibrosis. Alternatively, emphysema may occur, with abnormal destruction of collagen fibres in the advanced stages. Although the pathophysiological mechanisms remain unclear, it has been established that the lung responds to silica by massive enrollment of alveolar macrophages, triggering an inflammatory cascade of reactions. An imbalance in the expression of lung proteases and their inhibitors is implicated in extracellular matrix remodelling and basement membrane disruption. Moreover, exposure to silica can initiate apoptotic cell death of macrophages. This review summarises the current knowledge on cysteine cathepsins that have been ignored so far during silicosis and outlines the recent progress on cellular pathways leading to silica-induced caspase activation, which have been partly delineated.

Apoptosis↗

Anti-caspase-8 autoantibody response in silicosis patients is associated with HLA-DRB1, DQB1 and DPB1 alleles.

We reported previously the autoantibodies directed to caspase-8 among patients with silicosis, systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) , and in healthy individuals. In this study, we analyzed the correlation between anti-caspase-8 autoantibody responses and HLA class II alleles in silicosis patients. The frequencies of HLA-DRB1*0406 were significantly higher in antibody positive patients (16.67%) than in control individuals (3.03%, p=0.0006). The lysine (K) at position 71 as in DRB1*0406 has been reported to be associated with rheumatoid arthritis (RA) and insulin dependent diabetes mellitus (IDDM). The haplotype HLA-DR4; DQB1*0302 was detected in 4 of 12 antibody positive patients. RA, IDDM, or pemphygus vulgaris link to the haplotype. The frequencies of DQB1*0401 were significantly lower in antibody positive patients (0%) than that in controls (13.33%, p=0.0390). The aspartic acid at position 57 in the DQB1 molecule as in DQB1*0401 is reported to play a role in the resistance to IDDM. The frequency of DPB1*0601 in antibody positive patients (5.88%) was significantly higher than that in controls (0.56%, p=0.0003). DPB1*0601 is reported to be a risk factor among RA patients, and glutamate at position 69 of the DPB1 molecule may be involved. Repeated and continuous screening of autoantibodies seems to be necessary among workers in contact with Si-related substances for the detection of immunological disorders in the early stage.

Alleles↗

[Behavior of urinary hydroxyproline and the effect of cigarette smoking in silicosis].

This study was conducted through regular pneumonoconiosis examination according to the law on 1,096 employees of medium and small-sized ceramic enterprises in Tokai district in 1981-82. Interview examination with BMRC questionnaire, X-ray examination and measurement of urinary hydroxyproline to creatinine ratio (HOP ratio) were carried out in order to elucidate the relationship between silicosis and urinary HOP ratio and to demonstrate the effect of smoking on pneumofibrosis. Grade of silicosis was classified into five types (0 to 4) based on the Japanese Classification of Radiographs of Pneumoconioses. In evaluating the behavior of urinary HOP ratio, when smoking factor is added in the early grade of pneumofibrosis (type 1 and type 2), collagen decomposition rate is rapidly repressed and fibroplastic conditions develop to the final grade as type 3 and 4, although smoking itself does not seem to induce pneumofibrosis. To exclude the effects of smoking, nonsmoking group was used for measurement of HOP ratio by grade. The HOP ratio in type 0 was lowest and HOP ratio increased in the order of type 1 and type 2. The turning point was found in type 2 and their HOP ratio decreased one after another. The turning point shifted from type 2 to type 3 in the case of non-smokers without any index symptoms by BMRC questionnaire and also shifted to type 1, in the case of non-smokers with them. Shifting of turning point suggests that index symptoms also promote fibroplastic activities.

Adult↗

Lung cancer complicated by silicosis: a clinical and histopathological study.

A clinicopathological analysis was carried out on 16 cases of lung cancer complicated by silicosis, which were diagnosed from April 1975 to March 1983, and the results were discussed with a review of the literature. All of the patients were male, and a smoking habit with a Brinkman index of more than 500 was found in 14 of them (87.5%). Twelve cases (75.0%) had advanced tumors of clinical stages III and IV, suggesting that the early detection of lung cancer complicated by silicosis is difficult. Tumors were uniformly found in all lobes of the lung. Histological types were mainly epidermoid or undifferentiated carcinoma, with very few adenocarcinomas. Carcinogens from smoking seemed to be responsible for the carcinogenesis. Two cases were thought to be scar carcinomas.

Adult↗

Treatment of secondary spontaneous pneumothorax complicating silicosis and progressive massive fibrosis.

To clarify the management and treatment for the refractory cases of secondary spontaneous pneumothorax (SSP), we analyzed the clinical features in SSP complicating three cases of advanced silicosis, and discussed the available treatment. All three cases were males of age ranging from 60 to 70 years, and had silicosis with massive progressive fibrosis (PMF), classified as type 4 (PR4) according to the ILO guidelines. There was no correlation between the onset of SSP and the smoking habit, or the duration of the occupational exposure to silica. In a total of ten episodes of SSP, a refractory episode occurred in each of the three patients. No surgical treatment was possible because of some complications. Therefore, we administered conservative treatments under mechanical ventilation. The conservative treatments used were tube drainage with suction in each episode and pleurodesis by the combination of minocycline and OK-432 in one case. Approximately one month was the average time required for the air leak cessation. A significant decline in arterial oxygen tension (PaO2) was observed after the treatment of one case, suggesting further respiratory deterioration. These results imply that the more aggressive treatments for refractory SSP should be limited because of the patient status and progression. More information might be required before performing these options safely and effectively.

Aged↗

Red blood cell anti-oxidant parameters in healthy elderly subjects versus silicosis patients.

The anti-oxidant phenotype was determined in red blood cell haemolysates of 62 healthy elderly persons (Mean age: 56) and a number of male silicosis patients (Mean age: 65, n = 19). Moreover, analysis of water-soluble fluorescent substances in plasma, recently introduced as a new test for in vivo lipid-peroxidation, was included. Within the control group results were analyzed on the effect of smoking (no effect), use of medication (lowered GSH-content) or gender (no differences apart from haemoglobin content). No simple relationship between any pair of the measured parameters in erythrocytes was present. When comparing the male control persons with the silicosis group a significantly higher red blood cell GSH-level was observed in the latter. Moreover, some factors of the anti-oxidant system are strongly correlated in the diseased, but not in the healthy subjects.

Aged↗

Mortality of workers compensated for silicosis during the period 1959-1963 in the Veneto region of Italy.

After reports appeared from other countries indicating an excess risk of lung cancer among silicotics, a cohort of workers compensated for silicosis during the period 1959-1963 in the Veneto region of Italy was constructed and followed for mortality through 1984. The results of the study showed a large mortality excess for infectious diseases (180 observed versus 9.5 expected), due to silicotuberculosis, and for diseases of the respiratory system (270 observed versus 33.5 expected) due to silicosis. An elevated standardized mortality ratio of 239 (70 observed versus 29.3 expected) from lung cancer was also detected. An increasing pattern was observed with time since first exposure, while the relationship with employment category and duration of exposure was less clear-cut. The lung cancer excess was also strongly associated with cigarette smoking, there being a dose-response relationship with daily cigarette consumption. The study confirms the results from other epidemiologic studies on silicotics which show this pathological condition to be associated with increased lung cancer mortality.

Humans↗

[Serum type III procollagen peptide in diagnosis of lung fibrosis due to silicosis and bleomycin toxicity].

Early diagnosis of lung fibrosis has been hampered by the lack of a simple, convenient and specific test. Measurement of serum type III procollagen peptide (Pro (III)-N-P) by the method originally developed by Rohde et al. has been shown to be useful for the evaluation of hepatic fibrosis. The present study, therefore, was carried out to investigate the usefulness of the measurement of Pro (III)-N-P in 24 patients with lung fibrosis due to silicosis, and in 7 patients with malignant lymphoma treated with bleomycin, antitumor antibiotic which was the adverse effect of producing fibrosis in the lung. The normal value of the peptide in adults was 8.60 +/- 2.35 ng/ml (mean +/- SD; n = 68) and the normal upper level was set at 13.4 ng/ml (mean +/- 2SD). Patients with silicosis had significantly but not extremely high levels of the peptide and 25% of the patients showed abnormally high values. The level of Pro (III)-N-P was associated with neither physical findings, chest X-p findings nor pulmonary function test results. Three of 7 patients showed increased levels during treatment with bleomycin. In one case, a total dose of 120 mg of bleomycin for over a period of 14 months markedly increased the level of the peptide. These observations suggest that the determination of Pro (III)-N-P may be useful for the detection of lung fibrosis.

Adult↗

[The mortality due to pulmonary silicosis in the Tuscany region in the last decade demonstrates that the health effects of work exposure to silica are still marked].

An analysis of death certificates from 1987 to 1996 among residents of the Tuscany Region identified 1518 deaths from pneumoconiosis, the large majority from silicosis, a disease explained by occupational exposure to silica dust. A dozen of deaths are from asbestosis, occurred at younger ages and are concentrated in a restricted area where a cement-asbestos factory was active. Deaths from pneumoconiosis occurred mainly among males, and the rates of the disease are decreasing only in the latest years. About 10% of deaths from silicosis are among subjects dying before 65 years of age. Mortality rates are very high in several areas of the Region, approximating those from lung cancer and ischaemic heart disease. For the above reasons the disease is still of concern from the point of view of public health and actions are suggested to obtain a description of prevalence and incidence of the disease.

Cause of Death↗

[Hemodynamic analysis of pulmonary circulation by microcatheter technique in healthy persons and in patients with pulmonary silicosis (author's transl)].

A comparison of hemodynamic analysis of pulmonary circulation in 18 healthy men (PM less than 20 Torr) and 19 patients with pulmonary silicosis (PM larger than or equal to 20 Torr) at rest and under work load gave following results: In most healthy persons pulmonary pressure rose under load while resistance of pulmonary circulation decreased significantly. In patients with silicosis pulmonary pressure being elevated at rest reached pathological values under load while resistance of circulation decreased less. There was no difference in cardiac time-volume between both groups. The authors found a linear correlation between cardiac time-volume and oxygen uptake related to body surface. They derived a formula of approximating cardiac time-volume by oxygen uptake and body surface.

Cardiac Output↗

[Bodyplethysmographic analysis in patients with silicosis (author's transl)].

Pulmonary airway resistance was measured in patients with silicosis and in normal subjects using a volume-constant bodyplethysmograph. Values of total resistance RT were compared with spirometric ventilation parameters, oxygen tension during steady-state-exercise and arterial blood pressure. The analysis shows a significant relationship between status of silicosis and the degree of resistance. Resistance values were found enhanced also in comparison with a decrease of vital capacity and FEV1 and with an increase of residual volume and arterial blood pressure.

Blood Pressure↗