Serum Concentration of Prostaglandin E2 as a Diagnostic Biomarker in Patients With Silicosis: A Case-Control Study.

OBJECTIVE: Silicosis is a prevalent incurable pneumoconiosis caused by inhalation of silica dust. Study aimed to investigate inflammatory, hematological, and biochemical parameters as additional biomarkers for diagnosing or monitoring silicosis. METHODS: Research enrolled 14 workers with silicosis and 7 healthy controls (without exposure and silicosis). The serum level of prostaglandin E2, C-reactive protein, fibrinogen, biochemical, and hematological parameters were measured. The receiver operating characteristic curve was used to determine diagnostic sensitivity of each biomarker. RESULTS: Patients with silicosis have a significantly higher level of prostaglandin E2, erythrocyte, hemoglobin, and hematocrit than patients without silicosis. Prostaglandin E2, hemoglobin, and the erythrocyte count are significant in separating the silicosis cases from healthy controls. CONCLUSIONS: Prostaglandin E2 might be an adjuvant peripheral diagnostic biomarker for silicosis, while hematological parameters (erythrocytes, hemoglobin, and hematocrit) might be prognostic biomarkers.

Nonmalignant respiratory disease mortality in male Colorado Plateau uranium miners, 1960-2016.

BACKGROUND: To evaluate trends of nonmalignant respiratory disease (NMRD) mortality among US underground uranium miners on the Colorado Plateau, and to estimate the exposure-response association between cumulative radon progeny exposure and NMRD subtype mortality. METHODS: Standardized mortality ratios (SMRs) and excess relative rates per 100 working level months (excess relative rate [ERR]/100 WLM) were estimated in a cohort of 4021 male underground uranium miners who were followed from 1960 through 2016. RESULTS: We observed elevated SMRs for all NMRD subtypes. Silicosis had the largest SMR (n = 52, SMR = 41.4; 95% confidence interval [CI]: 30.9, 54.3), followed by other pneumoconiosis (n = 49, SMR = 39.6; 95% CI: 29.6, 52.3) and idiopathic pulmonary fibrosis (IPF) (n = 64, SMR = 4.77; 95% CI 3.67, 6.09). SMRs for silicosis increased with duration of employment; SMRs for IPF increased with duration of employment and calendar period. There was a positive association between cumulative radon exposure and silicosis with evidence of modification by smoking (ERR/100 WLM≥10 pack-years = 0.78; 95% CI: 0.05, 24.6 and ERR/100 WLM<10 pack-years = 0.01; 95% CI: -0.03, 0.52), as well as a small positive association between radon and IPF (ERR/100 WLM = 0.06, 95% CI: 0.00, 0.24); these associations were driven by workers with prior employment in hard rock mining. CONCLUSIONS: Uranium mining workers had excess NMRD mortality compared with the general population; this excess persisted throughout follow-up. Exposure-response analyses indicated a positive association between radon exposure and IPF and silicosis, but these analyses have limitations due to outcome misclassification and missing information on occupational co-exposures such as silica dust.

Biological effects of inhaled hydraulic fracturing sand dust. II. Particle characterization and pulmonary effects 30 d following intratracheal instillation.

Hydraulic fracturing ("fracking") is used in unconventional gas drilling to allow for the free flow of natural gas from rock. Sand in fracking fluid is pumped into the well bore under high pressure to enter and stabilize fissures in the rock. In the process of manipulating the sand on site, respirable dust (fracking sand dust, FSD) is generated. Inhalation of FSD is a potential hazard to workers inasmuch as respirable crystalline silica causes silicosis, and levels of FSD at drilling work sites have exceeded occupational exposure limits set by OSHA. In the absence of any information about its potential toxicity, a comprehensive rat animal model was designed to investigate the bioactivities of several FSDs in comparison to MIN-U-SIL® 5, a respirable α-quartz reference dust used in previous animal models of silicosis, in several organ systems (Fedan, J.S., Toxicol Appl Pharmacol. 00, 000-000, 2020). The present report, part of the larger investigation, describes: 1) a comparison of the physico-chemical properties of nine FSDs, collected at drilling sites, and MIN-U-SIL® 5, a reference silica dust, and 2) a comparison of the pulmonary inflammatory responses to intratracheal instillation of the nine FSDs and MIN-U-SIL® 5. Our findings indicate that, in many respects, the physico-chemical characteristics, and the biological effects of the FSDs and MIN-U-SIL® 5 after intratracheal instillation, have distinct differences.

Influence of quartz exposure on lung cancer types in cases of lymph node-only silicosis and lung silicosis in German uranium miners.

Inhaled crystalline quartz is a carcinogen. Analyses show differences in the distribution of lung cancer types depending on the status of silicosis. Using 2,524 lung tumor cases from the WISMUT autopsy repository database, silicosis was differentiated into cases without silicosis in lung parenchyma and its lymph nodes, with lymph node-only silicosis, or with lung silicosis including lymph node silicosis. The proportions of adenocarcinoma, squamous cell carcinoma, and small-cell lung carcinoma mortality for increasing quartz exposures were estimated in a multinomial logistic regression model. The relative proportions of the lung cancer subtypes in lymph node-only silicosis were more similar to lung silicosis than without any silicosis. The results support the hypothesis that quartz-related carcinogenesis in case of lymph node-only silicosis is more similar to that in lung silicosis than in without silicosis.

The social costs of uranium mining in the US Colorado Plateau cohort, 1960-2005.

OBJECTIVES: Long-term social costs associated with underground uranium mining are largely unknown. This study estimated health costs of Native American and white (Hispanic and non-Hispanic origin) uranium miners in the US Public Health Service Colorado Plateau cohort study. METHODS: Elevated uranium miner person-years of life lost (PYLL) were calculated from the most recent study of the Colorado Plateau cohort over 1960-2005. Nine causes of death categories were included. Costs to society of miner PYLL were monetized using the value of a statistical life-year approach. RESULTS: Costs over 1960-2005 totaled $2 billion USD [95% CI: $1.8, $2.2], or $2.9 million per elevated miner death. This corresponds to $43.1 million [95%: $38.7, $48.7] in annual costs. Lung cancer was the most costly cause of death at $1.4 billion [95%: $1.3, $1.5]. Absolute health costs were largest for white miners, but Native Americans had larger costs per elevated death. Annual excess mortality over 1960-2005 averaged 366.4 per 100,000 miners; 404.6 (white) and 201.5 per 100,000 (Native American). CONCLUSIONS: This research advances our understanding of uranium extraction legacy impacts, particularly among indigenous populations.

Traumatic Inhalation due to Merapi Volcanic Ash.

Pneumonoultramicroscopicsilicovolcanoconiosis is fibrotic lung diseases of the pulmonary parenchyma following chronic inhalation of inorganic dusts containing crystalline silicon dioxide. The acute manifestations observed after heavy ashfalls include attacks of asthma and bronchitis, with an increased reporting of cough, breathlessness, chest tightness, and wheezing due to irritation of the lining of the airways. The chronic health condition of most concern is silicosis, a diffuse nodular fibrosis of the lungs, develops slowly, usually appearing 10 to 30 years after first exposure. A 35 years old male was admitted to Sardjito Hospital, Yogyakarta with complaints of progressive dyspnoea, right side chest pain since last 3 month and periodic episodes of dry cough. He had history of exposure to volcanic ash at the location around volcano eruption for about 10 month. Examination revealed hyperresonant note, diminished vesicular breath sounds in lower right side of the chest. The chest X-ray presence leads to bleb. Based on the clinical and radiological suspicion of pneumoconiosis the patient was submitted to computed tomography of the chest and revealed bilateral multiple bullae mainly at the right lung field. The biopsy specimen verified the diagnosis of anthrocosilicosis. There is no proven specific therapy for any form of silicosis. Symptomatic therapy should include treatment of airflow limitation with bronchodilators, aggressive management of respiratory tract infection with antibiotics, and use of supplemental oxygen (if indicated) to prevent complications of chronic hypoxemia.

La silicosis: ¿un problema de salud pública prioritario para Chile? / Silicosis: a relevant public health issue in Chile?

Work related diseases and common diseases are covered by separated health systems in Chile. Chilean Ministry of Health focuses on common diseases, making work related diseases almost absent from public health policies. In this article current national and international information about the magnitude and impact of silicosis is reviewed. Although the quality of the national information is suboptimal, it is possible to estimate in several hundreds of thousands the number of workers exposed to silica dust, tens of thousands those under medical surveillance and thousands those currently affected by the disease. Albeit, additional efforts need to be made to estimate the burden of this disease on the Chilean population, information gathered in this article suggests that it is a relevant public health issue, deserving more importance among public policies in our country.

Las enfermedades comunes y laborales son atendidas en distintos sistemas de aseguramiento de la salud en Chile. Las políticas públicas emanadas del Ministerio de Salud se enfocan en las enfermedades comunes, relegando a un rol secundario a aquellas ocasionadas por la actividad laboral de las personas. En este artículo, los autores revisan información actualizada tanto nacional como internacional con el fin de determinar si la silicosis constituye un problema de salud relevante. Aunque la calidad de la información nacional no es óptima, su revisión permite estimar que son cientos de miles los trabajadores expuestos a sílice cristalina, que hay varias decenas de miles bajo vigilancia médica y que son más de mil los portadores de la enfermedad. Si bien es necesario hacer mayores esfuerzos para estimar la carga que esta patología representa para la sociedad chilena, la información recopilada indica que constituye un problema de salud pública relevante que debiera tener mayor protagonismo en las políticas públicas de nuestro país.

Silica dust, radon and death from non-malignant respiratory diseases in German uranium miners.

OBJECTIVE: To quantify the relationship between death from non-malignant respiratory diseases (NMRD) and exposure to silica dust or radon in a cohort of 58,690 former German uranium miners. METHODS: In the follow-up period from 1946 to 2008, a total of 2336 underlying deaths from NMRDs occurred, including 715 deaths from chronic obstructive pulmonary diseases (COPD) and 975 deaths from silicosis or other pneumoconiosis. Exposure to respirable crystalline silica and radon was individually assessed by means of a comprehensive job-exposure matrix. Risk analyses were based on a linear Poisson regression model with the baseline stratified by age, calendar year and duration of employment. RESULTS: There was no increase in risk of death from COPDs or any other NMRDs in relation to cumulative exposure to silica (mean=5.9, max=56 mg/m(3)-years), except in the group of deaths from silicosis or other pneumoconiosis. Here, a strong non-linear increase in risk was observed. Cumulative radon exposure (mean=280; max=3224 Working Level Months) was not related to death from COPDs or any other NMRDs. CONCLUSIONS: The present findings do not indicate a relationship between mortality from COPD with silica dust or radon. However, validity of cause of death and lack of control for smoking remain potential sources of bias.

Granuloma formation induced by low-dose chronic silica inhalation is associated with an anti-apoptotic response in Lewis rats.

Chronic human silicosis results primarily from continued occupational exposure to silica and exhibits a long asymptomatic latency. Similarly, continued exposure of Lewis rats to low doses of silica is known to cause delayed granuloma formation with limited lung inflammation and injury. On the other hand, intratracheal exposure to large doses of silica induces acute silicosis characterized by granuloma-like formations in the lung associated with apoptosis, severe alveolitis, and alveolar lipoproteinosis. To ascertain similarities/differences between acute and chronic silicosis, in this communication, we compared cellular and molecular changes in established rat models of acute and chronic silicosis. In Lewis rats, acute silicosis was induced by intratracheal instillation of 35 mg silica, and chronic silicosis through inhalation of aerosolized silica (6.2 mg/m(3), 5 d/wk for 6 wk). Animals exposed to acute high-dose silica were sacrificed at 14 d after silica instillation while chronically silica-treated animals were sacrificed between 4 d and 28 wk after silica exposure. The lung granulomas formation in acute silicosis was associated with strong inflammation, presence of TUNEL-positive cells, and increases in caspase-3 activity and other molecular markers of apoptosis. On the other hand, lungs from chronically silica-exposed animals exhibited limited inflammation and increased expression of anti-apoptotic markers, including dramatic increases in Bcl-2 and procaspase-3, and lower caspase-3 activity. Moreover, chronic silicotic lungs were TUNEL-negative and overexpressed Bcl-3 and NF-kappaB-p50 but not NF-kappaB-p65 subunits. These results suggest that, unlike acute silicosis, chronic exposures to occupationally relevant doses of silica cause significantly lower lung inflammation and elevated expression of anti-apoptotic rather than proapoptotic markers in the lung that might result from interaction between NF-kappaB-p50 and Bcl-3.

Silicosis in lymph nodes: the canary in the miner?

OBJECTIVES: To investigate evidence that lymph node silicosis can precede parenchymal silicosis. METHODS: The study population was comprised of 264 deceased male uranium miners for whom two or more of four pathologists agreed on the presence or absence of silicosis in lymph nodes and lung parenchyma. We had work histories and silica exposure estimates. RESULTS: Twenty percent of the miners had lymph node silicosis only, 4% had parenchymal silicosis only, and 39% had both. Silica exposure was lower for miners with lymph node silicosis only than for those with both lymph node and parenchymal silicosis. Lymph node silicosis was associated with parenchymal silicosis after adjustment for silica exposure. CONCLUSIONS: Our results are consistent with silicosis potentially occurring in lymph nodes before the parenchyma. Lymph node damage could impair silica clearance and increase the risk for parenchymal silicosis.

Major histopathological patterns of lung cancer related to arsenic exposure in German uranium miners.

OBJECTIVE: The mechanisms of action of arsenic in the development of lung cancer are still not yet elucidated. Considering the relationship between arsenic and squamous cell carcinomas of the skin, we hypothesized that arsenic exposure may be more closely associated with squamous cell carcinoma of the lung. METHODS: A comprehensive histopathological database and a detailed job-exposure matrix developed for former German uranium miners with exposure to arsenic, radon, and quartz were analyzed to quantitatively assess the effect of arsenic regarding cell type of lung cancer. The distributions of major lung cancer cell types in 1,786 German uranium miners were associated with levels of arsenic exposure under control for the other lung carcinogens. To evaluate the arsenic effects in association with a frequent occupational lung disease in miners stratification by silicosis was performed. RESULTS: There was an arsenic-related increase of the proportion of squamous cell carcinoma of the lung but restricted to miners without silicosis. The increase was found at all levels of co-exposure to radon and quartz dust. In miners with silicosis, the proportion of adenocarcinoma increased with rising arsenic exposure. Arsenic exposure was associated with non-small cell lung cancer. Silicosis turned out as major determinant of the cell type related with arsenic. CONCLUSION: These results indicate a cell type characteristic effect of arsenic in the development of lung cancer.

Sputum screening for lung cancer in radon exposed uranium miners: a comparison of semi-automated sputum cytometry and conventional cytology.

Preparing for a prospective study on early lung cancer, correlation between semi-automated sputum cytometry (ASC) and conventional cytology (CY) was examined in 1517 former uranium miners with posterior-anterior and lateral chest roentgenograms. A hundred and twenty sputum specimens were classified as suspicious (grade II) and another 18 as highly suspicious (grade III) by ASC. Within grade III group, 9 samples were classified by CY as tumor cell positive, 7 severe, and 1 mild and 1 moderate dysplasias. In the group of grade II ASC, 7 were tumor cell positive, 27 classified as severe dysplasia or CIS, 20 as moderate and 19 as mild dysplasia. Twenty seven contained metaplasias and 18 were normal or inflammatory. Of the 1358 samples classified as benign (grade I) by ASC, only 5 samples were classified by CY as severe dysplasia, 6 as moderate and 34 as mild dysplasia, 173 as metaplasia, the others were normal or inflammatory. Twenty one samples were judged as inadequate for ASC and CY. At present, 23 tumors were found in final diagnosis. Sensitivity of ASC was 87% at a specificity of 92%, while CY, at high grade alterations as a threshold, had a sensitivity of 83% at 97% specificity. We conclude that, along with modern radiological procedures and molecular biological markers, ASC and CY should be included in a controlled prospective randomized study on early lung cancer.

Role of exposure to radon and silicosis on the cell type of lung carcinoma in German uranium miners.

BACKGROUND: In East Germany, uranium mining was undertaken on a large scale from 1946 to 1990. Poor working conditions led to a high level of exposure to ionizing radiation and quartz dust. This analysis evaluates the histopathology of lung carcinoma in uranium miners in relation to radon exposure and silicosis. METHODS: A database developed for autopsy cases ascertained in a pathological tissue repository of German uranium miners was used to estimate odds ratios for developing lung carcinoma by major cell type with regard to radon exposure and silicosis. Silicosis information was extracted from autopsy protocols. Working level months (WLM) were calculated with a job-exposure matrix to assess lifetime radon exposure. Risk estimates were based on 3414 male miners who died from small cell lung carcinoma (SCLC, n = 1446), squamous cell carcinoma (SqCC, n = 1006), or adenocarcinoma (AC, n = 962) between 1957 and 1990. RESULTS: SCLC and SqCC seem more likely to be associated with high radon exposure than AC. Mean cumulative radon exposure was 868 (SD 631) WLM in SCLC, 871 (SD 652) WLM in SqCC, and 743 (SD 598) WLM in AC. Silicosis prevalence was 26% in SCLC, 38% in SqCC, and 30% in AC. In silicotics, AC and SqCC had a relatively higher frequency at the expense of SCLC. SCLC occurred earlier than AC and SqCC. CONCLUSION: High radon exposure was associated with a higher relative frequency of SCLC and SqCC than AC. Silicosis tended to increase the appearance of SqCC and AC.

Shenjincao (Palhinhaea cernua) injection for treatment of experimental silicosis of rats.

Shenjincao injection is a traditional Chinese medicine prepared from Palhinhaea cernua (L.) A. Franco et Vasc. by ultrafiltration. Its anti-silicosis action has been investigated both as a prophylactic and for treatment of the disease. Wistar rats were injected intra-tracheally with quartz dust and then divided randomly into groups-treatment and control prophylactic groups and treatment and control disease groups. After five days or eight weeks, respectively, the silica-exposed rats of the two treatment groups were injected intraperitoneally three times a week with shenjincao injection, dose 2.0 mL, for five weeks or 11 weeks, respectively. The rats were then dissected, and the ceruloplasmin content of the serum and the fresh weight, dry weight, collagen content and pathological grade of the lungs were measured. Compared with the corresponding exposed control groups for the same treatment periods the values of these parameters were reduced by 62.8% to 30.7% for rats in the prophylactic treatment group (P < 0.01 for all) and by 50.8% to 30.2% for the diseased group (P < 0.01 for all). The values for the disease-treatment group were also reduced by 37.9% to 25.9% compared with values for the exposed control group before treatment (P < 0.01 or P < 0.05). The effective coefficients for prophylactic treatment were 82.6% to 56.0%; for disease treatment they were 68.8% to 39.8%. These results show that shenjincao injection is efficacious against experimental silicosis not only when used prophylactically but also when used to treat the disease.

Lung cancer in relation to exposure to silica dust, silicosis and uranium production in South African gold miners.

BACKGROUND: A nested case-control study for lung cancer was performed on a cohort of 2260 South African gold miners in whom an association between exposure to silica dust and risk of lung cancer was previously reported. The objective was to investigate an expanded set of risk factors and also cancer cell type. METHODS: The 78 cases of lung cancer found during the follow up period from 1970 to 1986 were matched with 386 controls. Risk of lung cancer was related to smoking, exposure to silica dust, incidence of silicosis, and uranium production and the uranium content of the mine ore. RESULTS: The risk of lung cancer was associated with tobacco smoking, cumulative dust exposure, duration of underground mining, and with silicosis. The best predictive model included pack years of cigarette consumption (adjusted relative risk (RR) = 1.0 for < 6.5 pack years, 3.5 (95% confidence interval (CI) 0.7 to 16.8) for 6.5-20 pack years, 5.7 (95% CI 1.3 to 25.8) for 21-30 pack years, and 13.2 (95% CI 3.1 to 56.2) for more than 30 pack years) and silicosis (RR = 2.45 (95% CI 1.2 to 5.2)). No association was found with uranium production. The lung tumour cell type distribution was 40.3% small cell carcinoma, 38.8% squamous cell, 16.4% adenocarcinoma, and 4.5% large cell carcinoma. Small and large cell cancer combined were associated with exposure to dust. CONCLUSIONS: The results cannot be interpreted definitively in terms of causal association. Possible interpretations are: (1) subjects with high dust exposure who develop silicosis are at increased risk of lung cancer; (2) high levels of exposure to silica dust on its own is important in the pathogenesis of lung cancer and silicosis is coincidental; and (3) high levels of silica dust exposure may be a surrogate for the exposure to radon daughters.

Al Eskan disease: Persian Gulf syndrome.

This article examines the potential relationship between Al Eskan disease and the Persian Gulf syndrome. Al Eskan disease, reported in Military Medicine in 1992, is a novel and previously unreported condition triggered by the exceptionally fine sand dust of the Central and Eastern Saudi Arabian peninsula. We repeat our study of the pathogenesis of Al Eskan disease to include the ultrastructural and microanalytical study of the sand, aerobiological studies of the Kingdom of Saudi Arabia, and the etiology, symptoms, and prevalence of the disease. We conclude that immunodepression resulting from the continued presence of sand particles less than 1 micron in diameter in the lungs and bodies of Persian Gulf veterans explains not only the symptoms of the hyperegic lung condition of phase I and the symptoms of phase II of Al Eskan disease, but also provides an important clue to a common factor in most cases of Persian Gulf illnesses. We include a discussion of most of the commonly suspected agents in the Persian Gulf syndrome. In this case, we conclude that each of these factors, such as oil well fires, old-world diseases, or depleted uranium, are probably adjuvant or contributing causes. The only common exposure that would lead to recognition of the Persian Gulf syndrome as a single medical condition, rather than a catch-all phrase for unrelated conditions, appears to be exposure to the ubiquitous, fine sand of the area, and a resulting immunosuppression that is aggravated by opportunistic infections and other nonmicrobial ailments.

Clinical measures, smoking, radon exposure, and risk of lung cancer in uranium miners.

OBJECTIVES: Exposure to the radioactive daughters of radon is associated with increased risk of lung cancer in mining populations. An investigation of incidence of lung cancer following a clinical survey of Ontario uranium miners was undertaken to explore whether risk associated with radon is modified by factors including smoking, radiographic silicosis, clinical symptoms, the results of lung function testing, and the temporal pattern of radon exposure. METHODS: Miners were examined in 1974 by a respiratory questionnaire, tests of lung function, and chest radiography. A random selection of 733 (75%) of the original 973 participants was followed up by linkage to the Ontario Mortality and Cancer Registries. RESULTS: Incidence of lung cancer was increased threefold. Risk of lung cancer among miners who had stopped smoking was half that of men who continued to smoke. There was no interaction between smoking and radon exposure. Men with lung function test results consistent with airways obstruction had an increased risk of lung cancer, even after adjustment for cigarette smoking. There was no association between radiographic silicosis and risk of lung cancer. Lung cancer was associated with exposures to radon daughters accumulated in a time window four to 14 years before diagnosis, but there was little association with exposures incurred earlier than 14 years before diagnosis. Among the men diagnosed with lung cancer, the mean and median dose rates were 2.6 working level months (WLM) a year and 1.8 WLM/year in the four to 14 year exposure window. CONCLUSIONS: Risk of lung cancer associated with radon is modified by dose and time from exposure. Risk can be substantially decreased by stopping smoking.

Does the human cornea contain silicon?

BACKGROUND: Our study investigated the presence, type and quantity of silicon in the human cornea. We report the results of silicon measurements in the corneas of silicotic individuals, bricklayers and apparently normal human individuals and offer a hypothesis for the mechanism of silicon deposition in the human cornea. METHODS: We examined corneas from 13 decreased subjects who suffered from silicosis, 2 bricklayers and 6 apparently healthy subjects. Cornea samples were examined by energy-dispersive x-ray analysis (EDXA) under calibrated conditions in a scanning electron microscope (SEM). The EDXA detector was a silicon-free germanium crystal. Five distinct layers (epithelium, Bowman's membrane, central stroma. Descemet's membrane and endothelium) were analyzed in each cornea. The method allows simultaneous semiquantitative analysis of, among other elements, silicon, calcium and oxygen. We measured amorphous silicon and visible particles of silicon. RESULTS: We found amorphous silicon in low concentrations in 38% of the silicotic corneas and in very low concentrations in 29% of the healthy corneas. Bricklayers showed high concentrations of amorphous silicon. These accumulations of silicon were predominantly located in Descemet's membrane. Silicotic corneas showed significantly more silicon-containing particles than corneas of healthy controls (chi 2-test, P < 0.01). CONCLUSION: Normal corneas contain very low amounts of silicon. Longterm exposure to inhalative silicon dusts results in only very slightly increased levels of amorphous silicon in the cornea. However, silicon-containing particles accumulate in the cornea of silicotic individuals. Bricklayers incorporate more amorphous silicon into the cornea.

Isolation of nine gene sequences induced by silica in murine macrophages.

Macrophage activation by silica is the initial step in the development of silicosis. To identify genes that might be involved in silica-mediated activation, RAW 264.7 mouse macrophages were treated with silica for 48 h, and a subtracted cDNA library enriched for silica-induced genes (SIG) was constructed and differentially screened. Nine cDNA clones (designated SIG-12, -14, -20, -41, -61, -81, -91, -92, and -111) were partially sequenced and compared with sequences in GenBank/EMBL databases. SIG-12, -14, and -20 corresponded to the genes for ribosomal proteins L13a, L32, and L26, respectively. SIG-61 is the mouse homologue of p21 RhoC. SIG-91 is identical to the 67-kDa high-affinity laminin receptor. Four genes were not identified and are novel. All of the mRNAs corresponding to the nine cloned cDNAs were inducible by silica. Steady-state levels of mRNAs in RAW 264.7 cells treated with various macrophage activators and inducers of signal transduction pathways were determined. A complex pattern of induction and repression was found, indicating that upon phagocytosis of silica particles, many regulatory mechanisms of gene expression are simultaneously triggered.