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Query: UMLS:C0034069 (pulmonary fibrosis)
 7,050 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Silica-induced pulmonary fibrosis usually follows exposure to increased levels of this particulate and its retention in interstitial macrophages of the lung. It is suggested that accelerated clearance of particles from the pulmonary interstitium may ameliorate subsequent fibrosis. To test this hypothesis, one group of mice received 2-mg intratracheal (IT) silica; some particles were phagocytized and cleared during the subsequent inflammatory response, other particles were translocated across the epithelium to reach interstitial macrophages by 2 weeks. These mice later showed increased fibroblast growth, a doubling of lung collagen levels and large silicotic nodules by 16 weeks when much of the silica was still present in the lung. A second group of mice received IT silica, then 2 and 3 weeks later received IT injections of N-formyl-L-methionyl-leucyl-phenylalanine (FMLP), a leukocyte chemoattractant. Subsequently, a significant increase in inflammatory cells was seen and silica was observed mostly in phagocytes within the alveolar spaces. Few interstitial particles were found at 4 weeks, and extensive fibrosis did not develop by 16 weeks; only a few small nodules were seen and little silica was present in the lung. The results indicate that clearance of interstitial particles by a controlled inflammatory response is possible, and that removal of silica from the interstitium decreases the fibrotic response.
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PMID:Instillation of chemotactic factor to silica-injected lungs lowers interstitial particle content and reduces pulmonary fibrosis. 132 17

A single intratracheal injection of 50 mg crystalline silica (quartz) into rats produces silicosis. This animal model may be used to study collagen metabolism during the early, middle, and late phases of lung injury, corresponding respectively to the stages of lung injury, development of discrete granulomas, and development of mature silicotic nodules. The early phase is characterized by a rapid increase in the rate of synthesis of lung collagen (within one week of instillation) and increased deposition of excess lung collagen (significant increases within two weeks of instillation). Later phases are characterized by a continuing increase in deposition of excess lung collagen for at least one year after instillation. Silica-induced fibrosis is unique among all the animal models (and in most human fibrotic diseases) thus far examined, in that the excess collagen deposited in the lung contains normal ratios of the two major collagen types of the lung: types I and III. This collagen is nonetheless biochemically different from normal lung collagen. There are reproducible and characteristic differences in the intermolecular cross-links of the collagen in lungs from rats injected with silica. Within one month of silica instillation (the earliest time point examined thus far), an increased hydroxylysine content of collagen can be appreciated. The reducible dysfunctional cross-links are also more likely to be derived from hydroxylysine (i.e. the ratio of dihydroxylated to monohydroxylated cross-links increases). Within four months of silica instillation (and increasingly thereafter), increased amounts of the mature trifunctional cross-link hydroxypyridinium (derived from three residues of hydroxylysine) can also be appreciated, seemingly paralleling the evolution of mature silicotic nodules in these lungs. These changes in cross-linking of lung collagen seem to be common to all the animal models of pulmonary fibrosis examined, and are also consistent with changes occurring in human fibrotic lungs. Preliminary observations suggest that the locus of cross-linking remains the same: hydroxylysine replaces lysine in the primary structure of a specific collagen alpha chain to form the altered cross-links. Thus, there may be molecular markers for the collagen of fibrosis in diseased lungs.
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PMID:Effects of silica on lung collagen. 242 84

Foamy alveolar macrophages (FAM) are observed in lungs injured by Bleomycin (BLM), but their relation to pulmonary fibrosis is not clearly understood. We purified FAM from BLM-instilled rat lungs by density gradient centrifugation on Percoll, and studied the effect of FAM on pulmonary fibrosis. The cells lavaged from the rat lungs 14 days after the administration of BLM (B) or saline (S), were applied on Percoll. After centrifugation, the cells layered on each interface were collected and named as SI, SII, SIII, and BI, BII, BIII in order of gravity. The BI layer included 8.5% of unfractionated cells (U). These BI cells were viable (88%), significantly larger than the others, nonspecific esterase positive cells, and included much ferritin and lysozyme, and were morphologically identified as alveolar macrophages (AM). Therefore, we called the BI cells FAM. We estimated the capacity of FAM (2.5 X 10(5] to synthesize DNA (3H-thymidine uptake) and RNA (3H-uridine uptake), and the activities of silica-stimulated FAM to cause proliferation of mouse thymocytes (IL-1 activity) and rat lung fibroblasts (FP activity), and to produce PGE2. FAM has a lower mitogenic activity but did not have been protein synthetic activity as compared with the others. Silica-stimulated FAM released less IL-1 than BII or BIII, and induced less fibroblast growth than BII, but induced as much as BIII, possibly because of the increased capacity of BIII cells to produce PGE2, which is known to inhibit fibroblast growth. In this way, FAM were considered to be "already activated" rather than "highly activated" cells, but the presence of FAM suggested that smaller or denser AM might receive bleomycin stimulation and release fibrogenic mediators (IL-1 or MDGF) into the alveolar spaces during FAM formation, and that AM might participate in the fibrogenic responses.
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PMID:[The effect of foamy alveolar macrophages presented in bleomycin-injured rat lungs in pulmonary fibrosis]. 247 35

Several inhaled substances, from occupational or other environmental exposure, produce significant pulmonary disease and abnormalities demonstrated by pulmonary imaging. Areas of controversy and misconception relate principally to the extent and nature of both the clinical disease and the imaging abnormalities specific to each substance. The size and shape of the inhaled particles is an important determinant of the nature and severity of the disease produced, with fibrous shapes usually being the most pathogenetic. Fibrogenicity is another important pathogenetic characteristic of talc and kaolin, as well as asbestos. Talc produces four distinct forms of pulmonary disease, depending not only on the other substances with which it is inhaled, but also whether it is inhaled or injected intravenously. When inhaled alone, talc does not appear to produce significant pulmonary fibrosis or malignancy. Kaolin, mica, fuller's earth, zeolite, and fiberglass all vary in disease production according to their shape and fibrogenicity. Silica, diatomaceous earth, and other forms of silica are all highly fibrogenic and thus produce clinically obvious disease with sufficient inhalation. The largest particles usually produce nodular patterns in the upper pulmonary fields, as is typical of silicosis. The fibrous particles are more likely to manifest themselves as interstitial patterns in the lower pulmonary fields.
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PMID:Misconceptions regarding the pathogenicity of silicas and silicates. 253 43

The dynamics of the biological response of pulmonary tissue to silica dust (silica earth from Piotrowice, Poland, recommended as a domestic reference fibrogenic standard) was studied in rats after single-shot intratracheal instillation of a suspension of 20 mg of the dust for one, three, and seven months. Silica dust provoked pronounced pulmonary fibrosis as inferred from increased collagen content together with pathomorphological alteration (silicotic nodules). The lung burden of silica dust affected the lysosomal subfraction as manifested by an increase in its protein content with concomitant stimulation (release and presumably induction) of beta-glucuronidase and cathepsin D and a transient (up to three months) stimulation of lipid peroxidation. Stimulation of activity of lysosomal enzymes and lipid peroxidation mediated by silica dust may reflect destructive metabolic processes resulting in the development of pulmonary fibrosis as the sign of a pathological repair mechanism. The extent of the effects brought about by silica earth testify that it may be recommended as a reference standard for evaluating the potential health hazard from industrial exposure to dusts containing SiO2.
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PMID:Silica earth provoked lung fibrosis with stimulation of lysosomal enzymes and lipid peroxidation in rats. 283 69

Silica-induced pulmonary fibrosis is thought to involve fibroblast stimulation by a product of alveolar macrophages (AM) but various cell culture systems have given conflicting results. Macrophage-fibroblast interactions are now studied using an homologous system in which supernatants of rat AM after incubation with silica, are tested on fibroblasts isolated from the same animals to assess the effects on cell proliferation and collagen production. Fibroblast growth varied with initial seeding density and changes induced by AM supernatants varied depending on the proliferative rate. Normal AM supernatants inhibited [3H]-thymidine incorporation into fibroblasts, especially in more rapidly dividing cells. Supernatants of silica-treated AMs also inhibited division of rapidly growing fibroblasts, whereas the same material stimulated growth of slowly dividing cells. Collagen synthesis increased with the length of time that fibroblasts were confluent and was inhibited by control AM supernatants. Silica-treated AM supernatants increased collagen production by fibroblasts confluent for 3 days, whereas the same supernatants inhibited collagen synthesis by cells confluent for at least 8 days. The observation that a factor derived from silica-exposed AM first stimulates them inhibits fibrogenesis, indicates a modulation of the normal macrophage-fibroblast control system. This suggests that other factors may be required in vivo to shift this cellular balance towards the fibrotic process.
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PMID:Modulation of fibroblast activity by normal and silica-exposed alveolar macrophages. 300 67

We tested the efficacy of 2 antifibrotic agents, the proline analogue cis-4-hydroxy-L-proline (cHyp) and the lathyrogen beta-aminopropionitrile (BAPN), on experimental silicosis in hamsters. Silica (75 mg) was instilled intratracheally, and 3 months later lung hydroxyproline content, the volume density of silicotic nodules in lung parenchyma, fluid-filled lung pressure-volume curves, body weight and survival were measured. Animals were injected with cHyp, 200 mg/kg body weight, or BAPN, 150 mg/kg body weight, twice daily for 3 months. Hydroxyproline contents (mg/lung) at 3 months were: control, 0.8 +/- 0.1; silica, 1.4 +/- 0.1 (P less than 0.05 compared to control); silica-cHyp, 1.2 +/- 0.2; silica-BAPN, 1.4 +/- 0.1 (both NS compared to silica). The volume density of granuloma (% of surface area) was: silica, 0.7 +/- 0.1; silica-cHyp, 5.9 +/- 1.0; silica-BAPN, 9.7 +/- 1.5 (both P less than 0.5 compared to silica). There was no difference among the groups as assessed by lung pressure-volume curves. No toxic effects were produced on the skeletal system as assessed by bone hydroxyproline content and skeletal roentgenograms. Final body weights (g) were: silica, 114 +/- 5; silica-BAPN, 108 +/- 6; silica-cHyp, 88 +/- 7 (the latter P less than 0.05 compared to silica). Survival (%) was: silica, 62%; silica-BAPN, 34%, silica-cHyp, 28% (both P less than 0.05 compared to silica). These data show that cHyp and BAPN treatment did not prevent silica-induced pulmonary fibrosis, led to more extensive silicotic nodules, and were toxic. Both cHyp and BAPN have some efficacy in other models of fibrosis, and the observations in the present study could be specific to silicosis in the hamster.
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PMID:Treatment of experimental silicosis with antifibrotic agents. 321 91

A review was made on the recent advances in the study on the pathogenesis of silica-induced pulmonary fibrosis. Alveolar macrophages which ingest silica particles liberate a fibrogenic factor, which stimulates the production of collagen of cultured fibroblasts. Silica deposited in the alveoli augments the demand of macrophages, the supply of which is maintained by monocytes recruited from the bone marrow. Attempts to demonstrate in vitro the presence of a fibrogenic factor in the supernatant of macrophages have been made in many laboratories, and an in vivo model utilizing diffusion chambers implanted in mice has been used by some investigators. A fibrogenic factor has been isolated and purified from the medium of silica-treated macrophages. Recent advances in immunological studies have demonstrated that silica stimulates macrophages to release monokines such as interleukin 1 (IL-1) and that IL-1 has chemical properties identical to the fibrogenic factor, which enhances the level of collagen production by modulating the proliferation of fibroblasts. Silica inhibits the suppressive effects of macrophages on fibroblasts. The increased protein synthesis in the fibroblasts is due partly to increase in mRNA. Collagen synthesis is stimulated not only by the fibrogenic factor released from silica-treated macrophages but also by the inhibition of macrophage ribonuclease activity. Information on the number of cells, collagen content and protease activity in the lung as well as in the bronchopulmonary lavage fluid has provided us a better understanding of the mechanisms involved in silica-induced pulmonary fibrosis.
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PMID:[Recent advances in the study of the mechanisms of silica-induced pulmonary fibrosis]. 391 86

The question whether silica is carcinogenic is not new, but there has been a resurgence of research over the last two decades with the use of more powerful epidemiological methodologies. There is sufficient evidence for the carcinogenicity of crystalline silica in animals. A large number of cohort and case-control studies consistently suggest a modest excess of lung cancer in workers with occupational silica exposure (relative risk less than 2). However, in many studies, the association is confounded by exposures to cigarette smoke, and environmental cocarcinogens like radon daughters, polyaromatic hydrocarbons and asbestos. The excess risk of lung cancer is more pronounced in workers with silicosis (relative risk of 2 to 4). Silica may act as a direct carcinogen or indirectly by the adsorption of cocarcinogens such as polyaromatic hydrocarbons from cigarette smoke or industrial pyrolysis products, and/or by impairing pulmonary clearance, thereby increasing the effective dose and duration of exposure to these carcinogens. Pulmonary fibrosis itself may be a precursor to the development of lung cancer.
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PMID:Silica and lung cancer: a continuing controversy. 784 60

Silica is a well-known occupational fibrogenic agent and its primary target cell is alveolar macrophage. Particle-stimulated macrophages are believed to release various mediator which can regulate the inflammation as well as pulmonary fibrosis. Even though oxygen radicals play the major role among these mediators, the mechanisms concerning the stimulation of alveolar macrophages are not clear yet. The present study was carried out to investigate the signal transduction pathway on oxygen radical generation in silica-stimulated alveolar macrophages. Silica induced oxygen radical generation in a dose-response pattern. Extracellular calcium depletion, calcium channel blockers, and calcium release blocker decreased the effect of silica on oxygen radical generation. Silica increased intracellular calcium through the influx of calcium through the calcium channel and the calcium release from the intracellular calcium store. To know the role of protein kinase C (PKC), phospholipase C (PLC), and protein tyrosine kinase (PTK) in silica-induced oxygen radical generation, we pretreated alveolar macrophages with inhibitors of these enzymes. Inhibitors of PKC (sphingosine and staurosporine), PLC (neomycin and U-73122), and PTK (genistein and erbstatin) suppressed the silica-induced oxygen radical generation. Silica increased the PLC activity at the concentration of 5 mg/ml. The inhibitors of PTK and PLC suppressed the action of silica on the PLC activity. From these results, we suggest that silica induces oxygen radical generation through PTK, PLC, and PKC in alveolar macrophages.
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PMID:Silica-induced oxygen radical generation in alveolar macrophage. 924 22


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