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Collagen crosslinking in lungs of rats with experimental silicosis.

Rats were intratracheally instilled with 50 mg of size-fractionated crystalline quartz to induce silicosis. Lungs were analyzed 1, 4, 6, and 9 months after instillation for their content of the reduced difunctional collagen crosslinks dihydroxylysinonorleucine (DHLNL) and hydroxylysinonorleucine (HLNL), of the nonreducible trifunctional (mature) crosslink, hydroxypyridinium (OHP), and of hydroxylysine. Ratios of DHLNL: HLNL were elevated in silicotic lung collagen at all times sampled, due both to increased levels of DHLNL and decreased amounts of HLNL. Hydroxylysine content of collagen in the silicotic lungs was also increased as compared with age-matched control rats. Hydroxypyridinium content of silicotic lung collagen was less than control values at 1 month, but was significantly increased to about 120%, 150%, and 175% of the age-matched control values at 4, 6, and 9 months after silica instillation, respectively. The increased levels of OHP in lung collagen were temporally correlated with the appearance of mature silicotic nodules in these lungs. We conclude that the large amounts of excess collagen deposited in silicotic lungs differs biochemically from normal lung collagen despite maintenance of the normal ratio of major collagen types in silicotic lungs.

Amino Acids↗

Resistance to acute silicosis in senescent rats: role of alveolar macrophages.

We have previously demonstrated in alveolar macrophages that aging is associated with a decline in lipopolysaccharide-induced tumor necrosis factor-alpha production. The purpose of the present study was to investigate the immunotoxicological consequences of this defective activation in an experimental model of acute silicosis. Young (3 months old) and old (>18 months old) rats were intratracheally instilled with silica or saline as control. In young animals, as expected, silica induced a significant increase in bronchoalveolar lavage fluid of tumor necrosis factor-alpha, lactate dehydrogenase, and cell numbers, which correlated with increased collagen deposition and silicotic nodule formations. On the contrary, in old rats, no changes in bronchoalveolar lavage fluid or lung parameters were observed, indicating that senescent rats are resistant to the acute effects of silica. These in vivo results were confirmed in vitro, where silica-induced tumor necrosis factor-alpha release was drastically reduced in alveolar macrophages obtained from old animals. This could be explained with a defective protein kinase C betaII translocation in aged macrophages, due to decreased expression of its anchoring protein RACK-1. Furthermore, a decrease in FAS-L expression and silica-induced apoptosis in old macrophages was observed, supporting the idea that age-associated alterations in signal transduction pathways contribute to decreased sensitivity to silica-induced acute lung fibrosis in old animals.

Acute Disease↗

Immunocytochemical characterization of lung macrophage surface phenotypes and expression of cytokines in acute experimental silicosis in mice.

The expression of the surface phenotypical profile and the cytokines TNF-alpha and IL-1beta from murine lung macrophages was studied in parenchymal lung tissue and bronchoalveolar fluid of mice, over a 2-week period, following a single intratracheal instillation of silica. The acute inflammatory reaction, confirmed by a significant augmentation of four times the control values of the number of macrophages recovered by lavage from experimental animals, was followed by organized granulomas in the interstitium. The immunohistochemical analysis of lung tissue sections after silica instillation demonstrated the increased alveolar and interstitial tissue expression of all surface antigens and cytokines studied, mainly Mac-1, F4/80 antigens, TNF-alpha and IL-1beta, which were occasionally observed in normal uninjected and saline-treated mice. These findings show that, after silica instillation, the expression of surface phenotypical markers of lung macrophages increased, and this change was concomitantly associated with an increased expression of the cytokines TNF-alpha and IL-1beta. These changes support the conclusion that an influx of the newly recruited and activated macrophage population, with a different phenotype, is induced by treatment during inflammation. The populational changes involve difference in functional activity and enhance TNF-alpha and IL-1beta expression. These cytokines, produced in the silicosis-induced inflammatory process, are associated with the development of fibrosis and may contribute to disease severity.

Acute Disease↗

Left recurrent laryngeal nerve palsy associated with silicosis.

Left recurrent laryngeal nerve palsy usually results from invasion or compression of the nerve caused by diseases localized within the aortopulmonary window. This study reports the case of a 76-yr-old male with vocal cord paralysis due to lymph node involvement by silicosis. This rare entity was identified by video-mediastinoscopy, which revealed a granulomatous and fibrosed recurrent lymph node encasing the nerve. The nerve was dissected and released from scar tissues. Progressive clinical improvement was observed followed by total and durable recovery of the voice after 15 weeks follow-up.

Aged↗

Lymphopenia in occupational pulmonary silicosis with or without autoimmune disease.

An increased prevalence of autoimmune diseases such as rheumatoid arthritis has been demonstrated in silica-exposed patients. The aim of this study was to determine the peripheral blood lymphocyte phenotype in a population of silicotic workers employed in the slate mines of the district. Silicosis was assessed in 58 patients according to the International Labor Office's criteria. Clinical and biological data including flow cytometric evaluation of the lymphocyte subsets were compared with those from 41 healthy volunteers. The silicotic patients had a higher prevalence of autoimmune diseases (6/58 versus 0/41: P < 0.05) and of elevated antinuclear antibody titres compared to the control group. A very significant decrease of total lymphocyte count (P < 0.001) involving B, T and Natural Killer cells was found in silicotic patients as compared with matched healthy volunteers. A significant increase in the percentage of activated T cells (12.3%) was observed in the silicotic group as compared to 6.5% in the control group (P = 5 x 10(-5)). Our results show that in silicotic patients, the absolute number of circulating lymphocytes is diminished with an increased proportion of activated T cells. Whether these findings could predispose to the development of autoimmune disorders is discussed.

Adult↗

[Systemic lupus erythematosus and silicosis].

A 60-year-old stonemason, suffering for many years from joint pains and exertional dyspnoea, developed a high fever with weight loss. Physical examination revealed reddening of light-exposed skin areas, fine rales and overly warm and reddened hand and knee joints. Abnormal laboratory findings were increased erythrocyte sedimentation rate of 66 mm/h, C-reactive protein concentration of 1 mg/dl, haemoglobin of 9.4 g/dl and white cell count of 3300/microliters. Urine contained albumin (100 mg/dl) and cylinders. Titres of both antinuclear and anti-ds-DNA antibodies were elevated (1:2560 and > 97 U/ml, respectively). The chest radiography showed enlarged hili, as well as reticular and nodular shadows which histologically showed silicosis. Systemic lupus erythematodes was diagnosed and the patient was treated with prednisone (2 mg/kg daily), the dosage being reduced to 12 mg daily within 3 months. When the joint pains recurred, azathioprine (50 mg daily) was added for 24 months. At present he is receiving prednisone (12 mg daily) and there has been no recurrence for 4 years.

Diagnosis, Differential↗

A chemoattractant cytokine associated with granulomas in tuberculosis and silicosis.

Chronic inflammation and granuloma formation are associated with mononuclear cell infiltrates and are characteristic pathologic responses in tuberculosis. To identify host cell genes involved in tuberculous pathology, we screened macrophage cDNA libraries for genes induced by mycobacterial infection. One gene isolated in this screen, osteopontin (also known as early T lymphocyte activation protein 1 or Eta-1), was of particular interest because it is a cytokine and macrophage chemoattractant. Further study revealed that Mycobacterium tuberculosis infection of primary human alveolar macrophages causes a substantial increase in osteopontin gene expression. Osteopontin protein was identified by immunohistochemistry in macrophages, lymphocytes, and the extracellular matrix of pathologic tissue sections of patients with tuberculosis. Increased osteopontin expression also was found to be associated with silicosis, another granulomatous disease. The association of osteopontin with granulomatous pathology, together with the known properties of the protein, suggest that osteopontin may participate in granuloma formation. The strategy of identifying host genes whose expression is altered by infection thus can provide valuable clues to disease mechanisms and will be increasingly valuable as additional human genome sequences become available.

Bronchopneumonia↗

Silicosis and lung cancer in U.S. metal miners.

The association between silicosis and lung cancer mortality was estimated in 9,912 (369 silicotics and 9,543 nonsilicotics) white male metal miners. These miners were examined by the U.S. Public Health Service during 1959-1961 and were followed through 1975. Miners were excluded from this study if they were employed in a mine during 1959-1961 that used diesel equipment underground. The ores that were mined consisted of copper, lead-zinc, iron, mercury, lead silver, gold and gold-silver, tungsten, and molybenum. The standardized mortality ratio (SMR, U.S. white male rates) for lung cancer was 1.73 (95% CI: .94-2.90) in silicotics and 1.18 (95% CI: .98-1.42) in nonsilicotics. Additionally, SMRs were higher in silicotics than in nonsilicotics, even in most subgroups stratified by cigarette smoking habit, type of ore mined, years of service in an underground job, radon exposure group, or year of hire. When lung cancer mortality between silicotics and nonsilicotics was compared, the age-adjusted rate ratio (95% CI) was 1.56 (.91-2.68), and the age- and smoking-adjusted rate ratio was 1.96 (.98-3.67). Corresponding figures for miners who were employed in mines with low levels of radon exposure were 1.90 (.98-3.67) and 2.59 (1.44-4.68), respectively. These findings indicate that lung cancer mortality risk was increased in silicotics, and this probably did not result from chance or bias. However, confounding from radon exposure could not be ruled out. The findings indicate that further follow-up of this cohort is needed.

Bias↗

Quantitative image analysis of lung connective tissue in murine silicosis.

Pulmonary fibrosis is a disabling consequence of many lung diseases but is difficult to quantify. Lucifer yellow CH fluorescent dye (LY) appears to stain connective tissue matrix macromolecules selectively. Laser scanning confocal microscopy can quantify the intensity of fluorescence and determine the area of fluorescent material. We hypothesized that the abundance of lucifer yellow-stained matrix macromolecules in lung tissue sections could be measured by laser scanning confocal microscopy, would reflect differences between varying degrees of pulmonary fibrosis, and could be compared directly to biochemical measurements of lung collagen. We exposed C57B1/6 and 129 strains of mice by aerosol to cristobalite silica (70 mg/m3, 12 days, 5 hours/day) or sham-air and examined them 2 and 16 weeks after exposure. The area of LY-stained matrix in tissue sections was quantitated by laser scanning confocal microscopy, and total lung collagen was measured biochemically as hydroxyproline (OH-proline). The LY-stained connective tissue matrix appeared as bright linear bands in the alveolar septae, and was increased significantly by image analysis in C57B1/6 and 129 mice with silicosis 16 weeks after exposure. Total lung OH-proline was significantly increased in silica-exposed mice from both stains at both time points. Comparing all 8 groups, there was a significant linear correlation between the average area of connective tissue measured by LY stain and the total OH-proline per lung measured by chemical analysis (r = .72, P = .042). LY staining and confocal microscopy with image analysis offers a rapid technique for quantitative measurements of the extent of pulmonary fibrosis.

Animals↗

ESR evidence for the hydroxyl radical formation in aqueous suspension of quartz particles and its possible significance to lipid peroxidation in silicosis.

Electron spin resonance (ESR) spectrum of the hydroxyl (.OH) radical spin adduct with the spin trap 5,5-dimethyl-1-pyrroline-N-oxide has been obtained in suspensions of freshly ground quartz particles. The concentration of the spin adduct (and hence of the .OH radicals) increases with the amount of grinding. The dust's potential for the generation of the .OH radicals is maximum when fresh (i.e., immediately after grinding) and decreases to 50% in about a day on storage in air. Studies involving metal chelates indicate that the .OH radical formation involves mainly the silica surface and H2O rather than the Fenton reaction. The results suggest that hydroxyl radical reaction(s) could be important in the lipid peroxidation and fibrogenicity by quartz dust, particularly in acute silicosis.

Electron Spin Resonance Spectroscopy↗

Coming up for air: experts, employers, and workers in campaigns to compensate silicosis sufferers in Britain, 1918-1939.

Government regulation of dangerous trades and the compensation of those injured by their work remains a matter of considerable debate among medical historians. Trade unions have frequently been criticized for pursuing financial awards for their members rather than demanding improvements in health and safety at the workplace. This article examines the neglected subject of silicosis injuries in Britain from the time when the first legislation was passed for compensation of those suffering from the harmful affects of silica dust in 1918 to the outbreak of war in 1939, when a major new study was under way which would transform the scientific understanding and the legal compensation of those who were diagnosed as being ill with pneumoconiosis. It is argued that in framing legislation from compensation, politicians and their civil servants sought to retain the legal framework created in 1897-1906 and developed a model of industrial insurance which depended to a large extent on a co-operative relationship with leading employers. Medical scientists identified silica as a uniquely hazardous agent in workers' lung disease, which emphasizing the specialist knowledge required for its diagnosis. One remarkable feature of the selective compensation schemes devised after 1918 was the reliance on geological rather than pathological evidence to prove compensation rights as well as strict employment limits on those eligible to claim. only the campaigning of labour organizations and persistent evidence of lung disease among anthracite coal miners led to a significant relaxation of compensation rules in 1934 and the fresh scientific investigation which transformed the medical understanding of respiratory illness among industrial workers.

Coal Mining↗

Accelerated silicosis with mixed-dust pneumoconiosis in a hard-metal grinder.

We describe a fatal case of accelerated silicosis with a component of mixed-dust pneumoconiosis in a young hard-metal grinder that we believe is the first case of its kind in Israel and one of the rare cases reported worldwide. The patient's diagnosis was based on typical features: restrictive lung function, abnormal chest roentgenogram suggesting lung fibrosis, a history of exposure to silica and hard metals, bronchoalveolar lavage (BAL) fluid findings, and mineralogical studies. BAL cells showed an abundance of giant multinucleated macrophages. The CD4/CD8 ratio of T lymphocytes was 1.1, with a high percentage of CD8 and CD8/38 positive cells (37% suppressor/cytotoxic and 12% cytotoxic T lymphocytes, respectively). mRNA transcripts isolated from BAL cells were positive for interleukin-1 (IL-1) and transforming growth factor (TGF) Il-5, IL-2, and IL-10 but not for IL-6, IL-4, and interferon. Polarizing light microscopic studies of BAL and induced sputum cells showed polarizing particles, which are typical for silica. Mineralogical studies of electron microscopy performed on BAL fluid and on dust collected at the patient's workstation revealed silica particles as well as aluminum-titanium and other particles. The latter might have contributed to the patient's lung disease.

Adult↗

Silica, silicosis, and lung cancer: a response to a recent working group report.

The relationship between crystalline silica and lung cancer has been the subject of many recent publications, conferences, and regulatory considerations. An influential, international body has determined that there was sufficient evidence to conclude that quartz and cristobalite are carcinogenic in humans. The present authors believe that the results of these studies are inconsistent and, when positive, only weakly positive. Other, methodologically strong, negative studies have not been considered, and several studies viewed as providing evidence supporting the carcinogenicity of silica have significant methodological weaknesses. Silica is not directly genotoxic and is a pulmonary carcinogen only in the rat, a species that seems to be inappropriate for assessing particulate carcinogenesis in humans. Data on humans demonstrate a lack of association between lung cancer and exposure to crystalline silica. Exposure-response relationships have generally not been found. Studies in which silicotic patients were not identified from compensation registries and in which enumeration was complete did not support a causal association between silicosis and lung cancer, which further argues against the carcinogenicity of crystalline silica.

Animals↗

A silicosis patient presenting with an enlarged supraclavicular lymph node.

A stone splitter was discovered to have an enlarged supraclavicular lymph node which showed nodules with bi-refringent crystals on histological examination. He had worked in a dusty environment for more than 10 years with ineffective respiratory protection. He gave a history of occasional cough with blood-stained sputum for 10 years for which no definite diagnosis was made. Silicosis (classified as type s/s with profusion 1/1) was confirmed after his chest radiographs were reviewed. The presentation was unusual and illustrated the importance of an occupational history in clinical practice.

Clavicle↗

Silicosis in surface coalmine drillers.

Surface coalminers are generally thought to be at minimal risk of developing pneumoconiosis. Biopsy-proved silicoproteinosis was found in a 34-year-old surface coalmine driller, and two of nine other drill crew members who worked for the same company had chest radiographic findings compatible with simple silicosis. Reanalysis of data from a previous United States Public Health Service survey of surface coalminers, after exclusion of those with underground mining experience, showed that 38% of the cases of pneumoconiosis occurred in drill crew members, a group comprising only 11% of the study population. On the basis of these data surface coalmine drillers appear to have an increased risk of developing occupational lung disease.

Adult↗

Factors associated with massive fibrosis in silicosis.

Data on 1432 patients with silicosis on a register in Hong Kong were analysed to examine the association of massive fibrosis with possible predisposing factors. Detailed occupational and clinical histories, clinical records, radiographic readings according to the International Standard Classification of Radiographs of Pneumoconioses, and environmental dust measurements from hygiene surveys were used to obtain information for several variables--namely, age at first exposure, relative dust exposure level, duration of exposure, smoking, previous recorded history of tuberculosis, and background profusion of small opacities. The most significant risk factors associated with massive fibrosis were high relative dust exposure level, a history of tuberculosis, and increased background profusion of small opacities.

Adult↗

Pulmonary alveolar proteinosis: relationship to silicosis and pulmonary infection.

Pulmonary alveolar proteinosis is a rare disease with varied radiographic and clinical manifestations. Thirteen patients are presented and the role of pulmonary lavage in management is illustrated. Six patients had associated diseases such as nocardiosis, leukemia, and silicosis. The broad spectrum of relationships found in alveolar proteinosis suggests that it represents one mechanism by which the lung responds to a variety of insults.

Adolescent↗