Chronic Silicosis Research Articles

A biphasic response to silica: I. Immunostimulation is restricted to the early stage of silicosis in lewis rats.

Inhalation of crystalline silica may lead to acute or chronic silicosis. Although chronic silicosis is associated with increased incidence/exacerbation of autoimmune disorders, the immunologic effects of chronic silicosis are not completely understood. In an animal model of chronic silicosis, Lewis rats were exposed to filtered air or silica (1.75 microm average particle size) at an exposure concentration of 6.2 mg/m(3), 6 h/d, 5 d/wk for 6 wk, and observed up to 27 wk after the exposure. Based on silica burden, lung histopathology, and immunologic changes, two distinct stages were identified in the development of chronic silicosis. Stage 1 (4-28 d after exposure) was characterized by silica deposition in various tissues, and augmented antibody and cellular immunity. Although bronchoalveolar lavage contained an increased number of activated macrophages, protein and lactate dehydrogenase levels were comparable to controls. In Stage 2 (>/= 10 wk), silica was localized in epithelioid macrophages, and T cell immunity had returned to normal, but the lavage fluids contained increased protein concentration and lactate dehydrogenase activity. Moreover, lungs from silica-treated animals contained neutrophils and lymphocytes, and exhibited granulomatous changes around the silica-containing epithelioid macrophages. Thus, in the early stages of silicosis, silica activates the immune system; however, the progression of lung granulomas does not depend on a continually activated adaptive immune system.

Dust exposure during small-scale mining in Tanzania: a pilot study.

Small-scale mining in developing countries is generally labour-intensive and carried out with low levels of mechanization. In the Mererani area in the northern part of Tanzania, there are about 15000 underground miners who are constantly subjected to a poor working environment. Gemstones are found at depths down to 500 m. The objectives of this pilot study were to monitor the exposure to dust during work processes, which are typical of small-scale mining in developing countries, and to make a rough estimation of whether there is a risk of chronic pulmonary diseases for the workers. Personal sampling of respirable dust (n = 15) and 'total' dust (n = 5) was carried out during three consecutive days in one mine, which had a total of 50 workers in two shifts. Sampling started immediately before the miners entered the shaft, and lasted until they reappeared at the mine entrance after 5-8 h. The median crystalline silica content and the combustible content of the respirable dust samples were 14.2 and 5.5%, respectively. When drilling, blasting and shovelling were carried out, the exposure measurements showed high median levels of respirable dust (15.5 mg/m(3)), respirable crystalline silica (2.4 mg/m(3)), respirable combustible dust (1.5 mg/m(3)) and 'total' dust (28.4 mg/m(3)). When only shovelling and loading of sacks took place, the median exposures to respirable dust and respirable crystalline silica were 4.3 and 1.1 mg/m(3). This study shows that the exposure to respirable crystalline silica was high during underground small-scale mining. In the absence of personal protective equipment, the miners in the Mererani area are presumably at a high risk of developing chronic silicosis.

Silicosis and lung function decrements among female ceramic workers in Italy.

It is well known that male ceramic workers have elevated risks of chronic silicosis. The objective of this study was to assess whether female ceramic workers also have an increased risk of silicosis and whether these women have decreased lung function related to silica exposure. Ceramic workers from Civitacastellana, Italy, were enrolled in health surveillance during the 1970s. A total of 642 women were under surveillance; a respiratory monitoring program was conducted from 1974 to 1987, with follow-up through 1991 that included annual chest radiography and measurement of lung function. Radiography findings were defined as silicosis if the chest films were > or =1/0 with small, rounded opacities. Multiple linear regression models for repeated measures (generalized estimating equations) were run to evaluate associations of forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV(1)) with years of exposure and radiograph opacities. Nine cases of silicosis were identified on the basis of radiographic evidence. Silicosis risk was not associated with smoking but was related to employment before 1970 and demonstrated a dose-response gradient for years of exposure. FVC and FEV(1) both showed significant (p < 0.05) associations with duration of exposure and with positive radiography findings. The results for female ceramic workers are consistent with those for male employees regarding exposure to fibrogenic dusts.

Establishment of cohort to study lung cancer in Yunnan tin miners

To establish a cohort for the study of risk factors of lung cancer, and to support the study of early biomarkers and prevention of lung cancer. Designed a special population-based prospectively dynamic cohort among radon- and arsenic-exposed tin miners aged 40 or more years old with at least 10 years of occupational exposure in Yunnan Province, P.R.China. The mass screenings with sputum cytology and chest X-ray were conducted annually. The baseline information was collected for assessing demographic characteristics and risk factors. The multiple sputum specimens, chest radiographs and numerous biologic specimens have been collected and stored. From 1992-1999, 9143 miners have been enrolled and 460 new cases of lung cancer have been found. There had 47655 person-time chest radiographs and 46625 person-time sputum cytology among the cohort in 8 years. The relative risks of age-adjusted exposure to chronic bronchitis, silicosis, and tobacco were 1.73, 1.46, and 1.32 respectively. A cohort of unique occupationally-exposed tin miners with an extensive biologic specimen repository and data bank has been successfully established. Although occupational exposures are the predominant risk factors among the high risk miners, lung cancer risk is also associated with chronic obstructive lung disease (chronic bronchitis and silicosis) and a number of measures of exposure to tobacco smoke, including early age of first use, duration, and cumulative exposure.

Long Term iNOS Expression in Thoracic Lymph Nodes of Silicotic Rats

Beside the lung, thoracic lymph nodes are most affected during silicosis. The mechanisms leading to enlargement of the lymph nodes and partial activation of lymph node cells are still unclear. The present study demonstrates an increase in iNOS mRNA expression in the lung draining lymph nodes of rats at 1, 2, and 8 months following silica exposure. Histopathological analysis revealed that iNOS protein was exclusively expressed by macrophages located within the granulomatous areas of the enlarged lymph nodes. In contrast, no differences in mRNA expression and number of iNOS-positive cells were found in the lungs of silica-exposed and non-exposed rats. In vitro experiments showed that silica particles alone did not induce NO release in primary alveolar macrophages (AMs) or the alveolar macrophage cell line NR8383. However, the addition of interferon (IFN)-gamma led to a significant nitric oxide production by primary AMs. NR8383 cells responded only when a combination of IFN-gamma and silica particles was applied. These results indicate that the macrophage activator IFN-gamma, which has already been shown to be expressed at elevated levels by lymphocytes of the silicotic lymph nodes, may be responsible for the long-lasting iNOS expression in thoracic lymph nodes. Our observations support the hypothesis that the mutual activation of lymphocytes and macrophages is a central process in the development of chronic silicosis.

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.

Experimental silicosis: a shift to a preferential IFN-γ-based Th1 response in thoracic lymph nodes

In chronic silicosis, mechanisms leading to lymphocyte activation are still poorly understood, although it is well known that not only the lung but also the draining lymph nodes are affected. In the present study, we investigated T-cell activation by analysis of cytokine expression in the enlarged thoracic lymph nodes of rats 2 mo after an 8-day silica aerosol exposure. In the case of helper T cell (Th) type 1 cytokines, we found a significant increase in interferon (IFN)-gamma mRNA expression, whereas interleukin (IL)-2 expression remained unchanged. In contrast, gene transcription for the Th2-type cytokines IL-4 and IL-10 was diminished. In addition, with use of an in vitro lymphocyte-macrophage coculture system, an enhanced IFN-gamma and a reduced IL-10 release were shown with cells from silicotic animals. With regard to IFN-gamma-inducing cytokines, we observed enhanced IL-12 mRNA levels in vivo, whereas IL-18 gene expression was slightly decreased. These data indicate that a persistent shift toward an IFN-gamma-dominated type 1 (Th1/cytotoxic T cell type 1) T-cell reaction pattern occurred within the thoracic lymph nodes of silicotic animals. Thus a mutual activation of lymphocytes and macrophages may maintain the chronic inflammatory changes that characterize silicosis.

FROM COAL MINE DUST TO QUARTZ: Mechanisms of Pulmonary Pathogenicity

Exposure to coal mine dust or crystalline silica can result in the initiation and progression of interstitial lung disease. Pathogenesis is the consequence of damage to lung cells and resulting lung scarring associated with activation of fibrotic processes. This review presents the radiologic and histologic characteristics of simple and complicated coal workers' pneumoconiosis (CWP) as well as pathological indices of acute and chronic silicosis. This presentation also reviews the results of in vitro, animal, and human investigations that elucidate mechanisms involved in the development of these pneumoconioses. Results support the involvement of four basic mechanisms in the etiology of CWP and silicosis: 1. Direct cytotoxicity of coal dust or silica, resulting in lung cell damage, release of lipases and proteases, and eventual lung scarring. 2. Activation of oxidant production by pulmonary phagocytes, such as alveolar macrophages. When oxidant production exceeds antioxidant defenses, lipid peroxidation and protein nitrosation occur, resulting in tissue injury and consequent scarring. 3. Activation of mediator release from alveolar macrophages and alveolar epithelial cells. Chemokines recruit polymorphonuclear leukocytes and macrophages from the pulmonary capillaries into the air spaces. Once within the air spaces, these leukocytes are activated by proinflammatory cytokines to produce reactive species, which increase oxidant injury and lung scarring. 4. Secretion of growth factors from alveolar macrophages and alveolar epithelial cells. Release of such mediators stimulates fibroblast proliferation and induces fibrosis. In conclusion, results of in vitro and animal studies have provided the basis for proposing mechanisms that may lead to the initiation and progression of CWP and silicosis. Data obtained from exposed workers has lent support to these proposals. The mechanistic understanding obtained for the development of CWP and silicosis should be useful in elucidating the possible pathogenicity of other inhaled particles.

From Coal Mine Dust To Quartz: Mechanisms of Pulmonary Pathogenicity

Exposure to coal mine dust or crystalline silica can result in the initiation and progression of interstitial lung disease. Pathogenesis is the consequence of damage to lung cells and resulting lung scarring associated with activation of fibrotic processes. This review presents the radiologic and histologic characteristics of simple and complicated coal workers’ pneumoconiosis (CWP) as well as pathological indices of acute and chronic silicosis. This presentation also reviews the results of in vitro, animal, and human investigations that elucidate mechanisms involved in the development of these pneumoconioses. Results support the involvement of four basic mechanisms in the etiology of CWP and silicosis:1. Direct cytotoxicity of coal dust or silica, resulting in lung cell damage, release of lipases and proteases, and eventual lung scarring.2. Activation of oxidant production by pulmonary phagocytes, such as alveolar macrophages. When oxidant production exceeds antioxidant defenses, lipid peroxidation and protein nitrosation occur, resulting in tissue injury and consequent scarring.3. Activation of mediator release from alveolar macrophages and alveolar epithelial cells. Chemokines recruit polymorphonuclear leukocytes and macrophages from the pulmonary capillaries into the air spaces. Once within the air spaces, these leukocytes are activated by proinflammatory cytokines to produce reactive species, which increase oxidant injury and lung scarring.4. Secretion of growth factors from alveolar macrophages and alveolar epithelial cells. Release of such mediators stimulates fibroblast proliferation and induces fibrosis.In conclusion, results of in vitro and animal studies have provided the basis for proposing mechanisms that may lead to the initiation and progression of CWP and silicosis. Data obtained from exposed workers has lent support to these proposals. The mechanistic understanding obtained for the development of CWP and silicosis should be useful in elucidating the possible pathogenicity of other inhaled particles.

Risk factors and early detection of lung cancer in a cohort of Chinese tin miners

PURPOSE: To examine risk factors and establish a biologic specimen and data bank for the study of early markers of lung cancer. METHODS: We designed a dynamic cohort using an ongoing lung cancer screening program among radon- and arsenic-exposed tin miners in Yunnan China. Through the first four years of the study, 8,346 miners aged 40 years and older with over 10 years of occupational exposure have been enrolled, risk factors have been assessed, annual sputum and chest radiographs have been obtained, and numerous biologic specimens have been collected. RESULTS: A total of 243 new lung cancer cases have been identified through 1995. Radon and arsenic exposures are the predominant risk factors, but lung cancer risk is also associated with chronic bronchitis and silicosis, as well as a number of measures of exposure to tobacco smoke, including early age of first use, duration, and cumulative exposure. Tumor and sputum samples are being examined for early markers of lung cancer. CONCLUSION: A cohort of occupationally-exposed tin miners with an extensive biologic specimen repository has been successfully established to simultaneously study the etiology and early detection of lung cancer.

Short course chemoprophylaxis with rifampicin, isoniazid and pyrazinamide for tuberculosis evaluated in gold miners with chronic silicosis: A double-blind placebo controlled trial

Setting: A medical facility for approximately 90 000 gold miners employed on 24 South African gold mines. Objective: To evaluate the effectiveness of rifampicin, isoniazid and pyrazinamide given for 3 months for the prevention of tuberculosis in men with silicosis. Design: A randomised double-blind placebo controlled trial with active 4-year follow up of subjects by routine radiographic screening. Results: A total of 382 gold miners with silicosis were randomised to receive rifampicin 600 mg, isoniazid 400 mg and pyrazinamide 1.25 g daily as Rifater® or a placebo. These men have been followed for 4 years since the end of the treatment period. Eleven men who received the combination tablet and 15 men who received the placebo tablet have developed tuberculosis ( χ 2 dfl = 0.66, P = 0.4). Conclusion: This multi-drug short course chemoprophylaxis regimen has failed to prevent tuberculosis in miners with silicosis. Even if a larger study had demonstrated a statistically significant effect of the regimen as compared with placebo, the rate of tuberculosis in the men who received the three-drug regimen was unacceptably high.

Institutional Control Measures for Tuberculosis in the Era of Multiple Drug Resistance: ACCP/ATS Consensus Conference

Institutional Control Measures for Tuberculosis in the Era of Multiple Drug Resistance: ACCP/ATS Consensus Conference

Pulmonary inflammation and fibrosis following subacute inhalational exposure to silica: determinants of progression

To evaluate components of the pulmonary cellular response to inhaled silica that might be determinants of progression to fibrosis, we developed a model of the early stages of chronic human silicosis. Groups of mice were subacutely exposed either to alpha-quartz or to nonfibrogenic titanium dioxide dust as a control. Induction of lesions by inhaled silica was dependent upon the size distribution and dose of the particles. A novel observation was that low intensity exposure to silica evoked reversible inflammatory lesions that were characterized by focal aggregation of particle-laden alveolar macrophages near terminal airways. In contrast, higher intensity exposure elicited progressive pulmonary inflammation, including a significant perivascular influx of T-lymphocytes early in the response. The airspace inflammatory lesions exhibited a statistically significant decline in numerical density over time. Meanwhile, deposition of collagen was observed at perivascular locations, which were anatomically distinct from the initial foci of inflammation, and the numerical density of fibrotic lesions increased significantly with time. We speculate that this pattern of response might be related to alveolar clearance mechanisms being overwhelmed, followed by translocation and sequestration of particles in the interstitium, subsequently leading to T-lymphocyte recruitment and ultimately to the development of fibrosis.

Lung function in relation to silicosis and silica exposure in granite workers

Lung function tests (forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and FEV1/FVC %) were related to silica exposure and the extent of radiological opacities in a study of 206 active and 132 previously employed granite workers from two quarries. The investigations included detailed personal interviews, spirometric testing and radiographic examination of the chest. The chest X-ray films were read randomly and independently by three readers, using International Labour Office (ILO) standard films. Cumulative exposure to respirable silica (mg.m-3-yr) and total granite dust (million particles per cubic foot (mppcf-yr)) were estimated for each subject based on his years of employment at various jobs and historical and current measurements of quarry-, period- and job-specific exposures. The results suggest that chronic simple silicosis, especially for profusion category 2 and 3, was associated with significant lung function loss. As expected, mixed dust fibrosis was associated with little or no functional disturbance. Massive fibrosis was associated with significant obstructive and restrictive impairment. No additional effect of exposure to respirable silica on lung function loss was found after allowing for the presence of "silicosis". However, exposure to total dust (mppcf-yr) appeared to be associated with some lung function loss independent of silicosis. Our results indicate that chronic simple silicosis is not a benign disease; silica exposure is the primary cause, but the lung function loss in silicotics is directly attributable to the fibrotic lung disease. However, exposure to total granite dust beyond the respirable size range may separately produce additional lung function loss.

Effect of Prednisolone Treatment in Chronic Silicosis

We evaluated the effects of daily oral prednisolone therapy on alveolitis parameters and pulmonary function tests over a 6-month period in patients with chronic silicosis. Pulmonary function tests were done in 34 patients, and bronchoalveolar lavage (BAL) was done in 21 of them. Pulmonary function tests showed a significant improvement in lung volumes, FEV1, PEFR, SGaw, DLCO, and PaO2. Analysis of BAL fluid revealed a significant decrease in total cell count. Mean fibronectin and immunoglobulin values in BAL fluid also were lower after treatment, but the change was not statistically significant. No serious side effects were encountered with prednisolone therapy. These results indicate that daily oral prednisolone therapy may suppress the alveolitis in certain patients with chronic silicosis and bring about a significant improvement in lung functions and gas exchange.

Mortality from lung cancer among Sardinian patients with silicosis.

The mortality of 724 subjects with silicosis, first diagnosed in 1964-70 in the Sardinia region of Italy, was followed up through to 31 December 1987. Smoking, occupational history, chest x ray films, and data on lung function were available from clinical records for each member of the cohort. The overall cohort accounted for 10,956.5 person-years. The standardised mortality ratios (SMRs) for selected causes of death (International Classification of Diseases (ICD) eighth revision) were based on the age specific regional death rates for each calendar year. An excess of deaths for all causes (SMR = 1.40) was found, mainly due to chronic obstructive lung disease, silicosis, and tuberculosis with an upward trend of the SMR with increasing severity of the International Labour Office (ILO) radiological categories. Twenty two subjects died from lung cancer (SMR = 1.29, 95% confidence interval (95% CI) = 0.8-2.0). The risk increased after a 10 and 15 year latency but the SMR never reached statistical significance. No correlation was found between lung cancer and severity of the radiological category, the type of silica (coal or metalliferous mines, quarries etc), or the degree of exposure to silica dust. A significant excess of deaths from lung cancer was found among heavy smokers (SMR = 4.11) and subjects with airflow obstruction (SMR = 2.83). A nested case-control study was planned to investigate whether the association between lung cancer and airway obstruction was due to confounding by smoking. No association was found with the ILO categories of silicosis or the estimated cumulative exposure to silica. The risk estimate for lung cancer by airflow obstruction after adjusting by cigarette consumption was 2.86 for a mild impairment and 7.23 for a severe obstruction. The results do not show any clear association between exposure to silica, severity of silicosis, and mortality from lung cancer. Other environmental or individual factors may act as confounders in the association between silicosis and lung cancer. Among them, attention should be given to chronic airways obstruction as an independent risk factor for lung cancer in patients with silicosis.

Pulmonary fibrosis: Bronchoalveolar cell types and impaired function of alveolar macrophages in experimental silicosis

To determine the impact of chronic silicosis on lung cell populations and macrophage function, we quantified the types of cells in lavage fluid (bronchoalveolar cells) from guinea pigs with chronic silicosis and tested in vitro the function of alveolar macrophages. The fractions of neutrophils and giant cells in bronchoalveolar cells of silicotic animals were increased while the fraction of macrophages was slightly decreased compared to those of controls (intratracheal saline). The fractions of both lymphocytes and eosinophils were similar in the two groups. The majority of macrophages from silicotic lungs did not adhere to a glass surface. In addition, the random and stimulated migration of the macrophages from the silicotic lung was subnormal. However, adherent macrophages from silicotic animals spread on glass in both the absence and presence of a potent stimulant, N-formylmethionyl phenylalanine, as did cells from controls. These results suggest that the types of cells recovered by lavage from the silicotic lung mirror the inflammatory reaction in the pulmonary parenchyma and that the function of some alveolar macrophages in the silicotic lung is impaired.

Relationship between hypoxic and hypercapnic ventilatory responses in man.

Ventilatory responses to hypoxia (A) and hypercapnia (S) were measured in 127 healthy men (105 males and 22 females) by a dual control system for regulating Pa O2 and Pa CO2 simultaneously and independently of each other. The subjects were classified into groups according to sex, age, family history, and genetics (twins). Mean values for A were 138 +/- SD 93 liters/min.mmHg in group I (subjects without family history of chronic lung diseases) and 80 +/- 56 liters/min.mmHg in group II (sons of patients with chronic obstructive pulmonary disease or silicosis). The difference was highly significant (P less than 0.001). Mean S were 1.11 +/- 0.39 liters/min.mmHg-1 in group I and 1.16 +/- 0.48 liters/min.mmHg-1 in group H. The difference was not significant. Mean values for A and S in the aged males (mean age = 71.3 years) did not differ from those in 15 adult males (mean age = 29.5 years) and 60 young twins (mean age = 16.4 years). In every respect of age, sex, familial factors, and genetics, A and S were not interrelated. Mouth occlusion pressure (P0.1) was measured during air breathing and it correlated neither with A nor S. These results indicate 1) hypoxic and hypercapnic responses are not strongly related to each other, and 2) the aging process does not alter ventilatory responses to hypoxia and hypercapnia.

Response of neonatal mouse lung in organ culture to silica

Short term organ cultures of lung fragments from neonatal mice maintain their normal architecture. Cultures exposed to silica flour in varying concentrations show effects resembling those seen in chronic silicosis produced by inoculation and inhalation methods.

The Radiographic Findings in Acute Silicosis

The radiological features of 4 cases of acute silicosis in sandblasters are described and correlated with the pathological findings. Alveolar involvement was more extensive than in chronic silicosis; in 2 cases an alveolar exudate similar to that found in alveolar proteinosis was present. The radiological changes in acute silicosis differ substantially from those in classical silicosis, mainly on the basis of the differing alveolar response.