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Two subjects had silicosis complicated by tuberculosis. In both patients, there was a relapse of the tuberculosis after chemotherapy was discontinued, in one case after 13 years of therapy with isoniazid and p-aminosalicylic acid. It would appear that the risk of tuberculosis in subjects with silicosis persists for life, and the suggestion is made that chemotherapy should be continued indefinitely.
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 has 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.
A total of 764 autopsy cases with a pathological diagnosis of nonasbestos pneumoconiosis were investigated in a search for lung cancer: 146 patients bore 148 lung cancers (19.1%). The incidence of a lung cancer was associated positively with aging longer occupational exposures, and smoking habits. A reverse correlation was found between carcinogenesis and the severity of pneumoconiosis. A statistically significant increase in the incidence of certain types of lung cancer (squamous cell carcinoma + small cell carcinoma) was found in silicotic lungs with massive fibrosis as compared to lungs with mixed dust pneumoconiosis of comparable severity. Although there appears to be no dose-response relationship in general between silicosis and lung cancer, it is advisable to consider the possibility that a presumptive silica-induced carcinogenesis might be masked by the severe fibrosis of a silicotic type, which obliterates the lung tissue in a different way from asbestosis, which is associated with epithelial proliferation.
An epidemiological investigation was carried out to determine the relationship between silicosis in hardrock miners in Ontario and cumulative exposure to silica (free crystalline silica--alpha quartz) dust. This second report describes a side-by-side air-sampling program used to derive a konimeter/gravimetric silica conversion curve. A total of 2,360 filter samples and 90,000 konimeter samples were taken over 2 years in two mines representing the ore types gold and uranium, both in existing conditions as well as in an experimental stope in which dry drilling was used to simulate the high dust conditions of the past. The method of calculating cumulative respirable silica exposure indices for each miner is reported.
An epidemiological investigation was undertaken to determine the relationship between silicosis in hardrock miners in Ontario and cumulative exposure to silica (free crystalline silica--alpha quartz) dust. This report describes the analytic method and presents the risk estimates.
In the two decades following the First World War, American occupational medicine was consumed in cataloguing the pneumoconioses, and no physician was more prominent than Henry K. Pancoast of the University of Pennsylvania. In a landmark trial following the worst silicosis outbreak in the United States at Gauley Bridge, West Virginia, Pancoast testified for the defense, attributing the disease to tuberculosis. Pancoast was not an isolated commentator, as the prominence of the cases attracted some of the country's leading authorities on occupational medicine. Pancoast's error, as well as the accuracy of some of his colleagues, clarifies an important occupational disease in its epidemic period. There is also a less historically specific exposition of the impact of professional involvement in social policy, liability, and compensation.
Hepatic silicosis, cirrhosis, liver cell adenoma, and carcinomas developed in nude mice (NCr-Nu) given quartz by the subcutaneous and intraperitoneal routes. Syrian golden hamsters (15:16 EHS:cr) given quartz by both routes developed extensive fibrosis and cirrhosis and had higher morbidity and mortality rates after 3 months. Crystalline silica (quartz) induces fibrosis, adenomas, and carcinomas in the lungs of Fisher 344 rats, but certain strains of mice and hamsters are resistant to quartz-induced pulmonary carcinogenesis. Pulmonary fibrosis, however, is minimal in mice and absent in hamsters who received quartz intratracheally. To determine whether species differences are due to organ-specific rather than species-specific factors, susceptibility of the liver to quartz toxicity was investigated in nude mice and hamsters. The present study shows that the differential manifestations of quartz toxicity by these rodent species are dependent on factors that are organ-specific rather than host-specific. At 3 months, hepatocytes in mice were immunostained with intracellular transforming growth factor (TGF) beta 1 (LC 1-30) but not with TGF-beta 1 latency-associated peptide (LAP) protein (266-278); at 12 months, hepatocytes were immunostained with TGF-beta 1 LAP (266-278) but not with TGF-beta 1 (LC1-30). The hepatocytes of hamsters at 3 months showed immunoreactivities to TGF-beta 1 LAP (266-278) and TGF-beta 1 (LC1-30); immunostaining to TGF-beta 1 (LC1-30) was detected in nonparenchymal cells. Extracellular TGF-beta 1 (CC1-30) was detected in the silicotic granulomas and fibrous tissue in livers of both species. Quartz-induced liver carcinoma did not express TGF-beta 1 LAP (266-278) and LC (1-30) proteins, but these were detected in the cells of the adenoma in the same liver. Control animals showed no hepatic lesions nor immunoreactivity to TGF-beta 1. The spatial and temporal patterns of expression of TGF-beta 1, TGF-beta 2, TGF-beta receptor type II messenger RNAs (mRNAs), and TGF-beta 1 proteins in the different hepatic lesions suggests that TGF-beta isoforms may play a role in the pathogenesis of quartz-induced fibrosis, cirrhosis, liver cell adenoma, and carcinoma.
Levels of 9 different oncoproteins and growth factors were assayed by immunoblotting with monoclonal antibodies in 91 serum samples collected between March 1983 and August 1987 from 46 pneumoconiosis patients (36 asbestosis, 10 silicosis) at high risk for the development of cancer. Follow-up of these patients through June 1991 showed that 18 had developed cancer (11 lung, 2 pleural mesothelioma, 2 transitional-cell carcinomas of the urinary bladder, 1 osteosarcoma, 1 non-Hodgkin's lymphoma, 1 adenocarcinoma of the gallbladder). Increased serum levels of ras oncogene-related protein (p21) were found in 7 of the 18 patients who developed cancer (5 lung, 2 pleural mesothelioma) versus 2 of the 28 patients without cancer, a statistically significant difference (p = 0.012). In addition, 6 of the 7 p21-positive cancer cases had positive serum samples prior to clinical diagnosis of disease (average = 16.3 months, range = 3-26 months prior to diagnosis), suggesting that elevated serum p21 levels may be a useful marker for earlier detection in a significant percentage of respiratory malignancies. Finally, elevated serum levels of PDGF-related protein were detected significantly more frequently in advanced pneumoconiosis cases (ILO radiographic classification of 2/1 or greater) than in less advanced cases (80% vs. 41.9%; p = 0.016), and there was a tendency for these PDGF-positive patients to have progression of their disease (68.2% vs. 41.7%; p = 0.065), suggesting that elevated serum PDGF levels may be a marker for the development of severe and progressive pneumoconioses.
To evaluate the biological effects of aluminum lactate therapy on nodular silicosis, we exposed the tracheal lobe of three groups of sheep containing eight sheep per group to either 11 mg of Al lactate in 100 ml saline (Al group), 100 mg of Minusil-5 in 100 ml saline (Si group), or 100 mg of Minusil-5 in 100 ml saline followed by 11 mg of Al lactate at monthly intervals 4 months after exposure (Si Al-treated group). The lung biological processes were evaluated by sequential lung lavage analyses of cellularity and biochemistry of supernatant and by autopsy analyses of cellularity and biochemistry of supernatant and by autopsy analyses of lung tissue histopathology and quartz content. Al lactate alone did not have any significant effect. Silica exposure produced the silicotic nodules and significant increases on lung lavage of cellularity, enzyme release, surfactant, and glycosaminoglycan accumulations. Al lactate therapy at month 4 after exposure did not decrease the pathological score of disease, but it significantly reduced all markers of cellular hyperactivity. This therapy was associated with a 65% reduction of the quartz retention in lung tissue and might help to prevent long-term progression of the disease process.
Asbestosis and silicosis are fibrotic diseases initiated by the inhalation of silica-containing dusts, asbestos and quartz. There are various approaches for explaining the causes of these diseases. At present, our knowledge on the matter indicates that silicic acid dissolved from these minerals, contact between macrophages and minerals, highly reactive and oxidative species formed on the mineral surface, and lysosomal enzymes released upon engulfment of particulate mineral of appropriate size all contribute to various extents to the initiation of fibrosis. Among these mineral solubility seems to have a substantial contribution as a causative factor.
Experimental exposure to quartz dust for 100 days (= 700 h) induces in SPF rats histologic changes of the lungs, which have such striking similarities with human cases of pulmonary alveolar proteinosis that they may represent an animal model of human disease. Conventional stock rats, the standard model of experimental silicosis research, react upon the same dosage of quartz dust by the formation or an increase in size of perivascular lymphatic sheaths, in which epitheloid cell granulomas can arise. In SPF rats such granulomas can only be developed in the sparse pre-existent lymphatic tissue, mostly in hilar lymph nodes. The reaction of SPF rats opens an interesting aspect on the significance of the phenomenon of lymphatic "drainage," as comparable reactions are only known in conventional rats following extreme dosage and in human pathology as so-called acute silicoproteinosis.
Prolonged asbestos and silica inhalation is associated with pulmonary inflammation and fibrosis. Several studies suggest that TNF may play a role in the development of inflammation and fibrosis. We studied TNF production in a murine model of asbestosis and silicosis. Asbestos fibers caused a significant inflammatory response at two weeks and pulmonary fibrosis beginning at one month. Pulmonary inflammation was principally caused by an accumulation of neutrophils (0.88 x 10(5) neutrophils/compared to 0.05 x 10(5) in controls). TNF production by bronchoalveolar cells was higher in asbestos-instilled mice at two weeks, but was significantly diminished in older mice. Pulmonary inflammation was observed until six months in silica-instilled mice. Neutrophils were also the principal protagonists of the inflammation. In this group, severe fibrosis was observed at two weeks. TNF production in silica-instilled mice was similar to controls, possibly due to the presence of large numbers of neutrophils (3.3 x 10(5)/lavage) that could adsorb TNF. In vitro experiments showed an augmentation of TNF production by bronchoalveolar cells in the presence of silica. Taken together, our data suggest that asbestos and silica stimulate alveolar macrophages to produce TNF, which can be involved in pulmonary inflammation and fibrosis.
In spite of several studies, both in vivo and in vitro, the pathogenesis of silicosis remains unclear, mainly in those mechanisms related to fibrogenesis. In this study, we analyzed the concentration, biosynthesis, and degradation of collagen in silica-treated rats 7, 15, 30, 45, and 60 days after instillation. Our results showed a significant increase in collagen content and biosynthesis from the 15th day onward. However, our most remarkable finding was related to collagenolytic activity. In this sense, the silicotic rats presented a trimodal behavior: some animals showed an increased degradation, others had similar values to those of the controls, and others exhibited a decrease of collagenolytic activity. Altogether, these results suggest that collagen deposition in silicotic lungs is due to a rise in biosynthesis and, at least in some animals, to a decrease in degradation. Nevertheless, the steps of collagenolysis must be studied in more detail.
In the sheep tracheal lobe model of silicosis, we have recently reported that total phospholipid, lecithin, and phosphatidylglycerol levels were elevated in lung lavage. To investigate further this observation, we obtained complete phospholipid profiles of lung lavage in 10 sheep exposed to saline only (Sa group), 10 sheep exposed to aluminum lactate inhalation only (Al group), 10 sheep exposed to 100 mg Minusil-5 in saline followed by monthly saline inhalation (Si group), and 10 sheep exposed to 100 mg Minusil-5 in saline followed by monthly aluminum lactate inhalation (Si-Al group). The following phospholipid components were measured: total phospholipids, phosphatidylglycerol (PG), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylcholine, disaturated phosphatidylcholine, sphingomyelin, and lyso-phosphatidylcholine. All values were comparable in the Sa group, Al group, and Si-Al group. In the Si group, there was a significant increase in total phospholipid to approximately 200% of the control values. The phospholipid profile of this group demonstrated an increase in all of the phospholipid components with some enrichment of the fraction of PG, PE, and PI. We concluded that lung exposure to silica dust significantly increases the concentration of phospholipids in the alveoli. This increase is of a large spectrum of alveolar phospholipids and is completely suppressed by aluminum lactate inhalation.
Recent evidence confirms the fundamental involvement of the human immune system in the reaction to implantation of silicone-based medical devices. An as yet-to-be particularized epitope of many complex substances sharing siloxane structures is presented through the MHC-II apparatus with development and retention of T cell memory. This memory can be tested for in practical terms using one or more forms of silica, which links the immuno-histopathology and autoimmune attributes of "silicosis" with those of "siliconosis." The lesions of siliconosis are typical of those for persistent antigens and delayed, cell mediated hypersensitivity. The basic descriptive pathology of the reaction to silicone has been known since soon after introduction of silicones in medical procedures, with the exception of some details related to the more recent discoveries on the role of cytokines in the immunopathic process. The clinical consequences of siliconosis are common and can be severe in some individuals implanted with silicone devices.
It was proved in this experiment that tetrandrine, one of the bisbenzylisoquinoline alkaloids, may inhibit the development of experimental silicosis on rats whether the drug was given to the animal right after dusting or after the formation of silicotic nodules. As compared to the silicotic control rats, lowering of total weight and collagen content of the lungs were shown and some degradation of collagen fibers was also indicated from the histopathological examination.
The role of the complement system in the pathogenesis of crystal-induced pulmonary inflammation and fibrosis was evaluated using a mouse model of silicosis and congenitally complement-deficient mice. Mice lacking the fifth component of complement (B10.D2/o) were compared to C5-sufficient animals (B10.D2/n) for pulmonary changes following intratracheal instillation of silica crystals. Complement-deficient mice demonstrated a significant reduction compared to complement-sufficient mice in both cell number and protein content of lung lavage fluid throughout the 12 weeks following silica exposure. Lung hydroxyproline content (indicative of collagen deposition) was equivalent for both strains and significantly higher than controls at all time points following silica instillation. Moreover, studies in vitro have shown that silica crystals are capable of activating complement via the alternative pathway. These studies indicate that the complement system may be responsible for some of the pulmonary inflammation, but not fibrosis elicited by silica exposure.
Rat cytokine-induced neutrophil chemoattractants (CINCs), which belong to the interleukin-8 family, are known to be induced by treatment with lipopolysaccharide (LPS). Recently, CINCs were grouped into four subtypes-CINC-1, CINC-2alpha, CINC-2beta, and CINC-3-and CINC-1 was considered to be a major isoform among the four CINCs in LPS-induced acute lung inflammation in rats. The purpose of this study was to investigate the change in location of CINCs with chronic inflammation induced by experimental pulmonary silicosis. Administration of silica particles induced lung granulomas. Immunohistochemical staining for CINCs showed that the number of cells positive for CINC-2alpha, CINC-2beta, and CINC-3 was increased, peaking at 1 day after treatment with silica particles, whereas CINC-1 was almost undetectable. We suggest that CINC-2alpha, CINC-2beta, and CINC-3 are the most important chemoattractants in the formation of granulomas in chronic inflammation.