Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034069 (pulmonary fibrosis)
 7,050 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The type of lung disease caused by metal compounds depends on the nature of the offending agent, its physicochemical form, the dose, exposure conditions and host factors. The fumes or gaseous forms of several metals, e.g. cadmium (Cd), manganese (Mn), mercury (Hg), nickel carbonyl (Nl(CO)4, zinc chloride (ZnCl2), vanadium pentoxide (V2O5), may lead to acute chemical pneumonitis and pulmonary oedema or to acute tracheobronchitis. Metal fume fever, which may follow the inhalation of metal fumes e.g. zinc (Zn), copper (Cu) and many others, is a poorly understood influenza-like reaction, accompanied by an acute self-limiting neutrophil alveolitis. Chronic obstructive lung disease may result from occupational exposure to mineral dusts, including probably some metallic dusts, or from jobs involving the working of metal compounds, such as welding. Exposure to cadmium may lead to emphysema. Bronchial asthma may be caused by complex platinum salts, nickel, chromium or cobalt, presumably on the basis of allergic sensitization. The cause of asthma in aluminium workers is unknown. It is remarkable that asthma induced by nickel (Ni) or chromium (Cr) is apparently infrequent, considering their potency and frequent involvement as dermal sensitizers. Metallic dusts deposited in the lung may give rise to pulmonary fibrosis and functional impairment, depending on the fibrogenic potential of the agent and on poorly understood host factors. Inhalation of iron compounds causes siderosis, a pneumoconiosis with little or no fibrosis. Hard metal lung disease is a fibrosis characterized by desquamative and giant cell interstitial pneumonitis and is probably caused by cobalt, since a similar disease has been observed in workers exposed to cobalt in the absence of tungsten carbide. Chronic beryllium disease is a fibrosis with sarcoid-like epitheloid granulomas and is presumably due to a cell-mediated immune response to beryllium. Such a mechanism may be responsible for the pulmonary fibrosis occasionally found in subjects exposed to other metals e.g. aluminium (Al), titanium (Ti), rare earths. The proportion of lung cancer attributable to occupation is around 15%, with exposure to metals being frequently incriminated. Underground mining of e.g. uranium or iron is associated with a high incidence of lung cancer, as a result of exposure to radon. At least some forms of arsenic, chromium and nickel are well established lung carcinogens in humans. There is also evidence for increased lung cancer mortality in cadmium workers and in iron or steel workers.
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PMID:Metal toxicity and the respiratory tract. 217 66

Serum copper (Cu) concentration was evaluated as an index of lung injury in two rat models of pneumotoxicity: hemithoracic irradiation and monocrotaline ingestion. In both models there was a dose- and time-dependent increase in serum Cu concentration. This hypercupremia paralleled the development of pulmonary endothelial dysfunction (decreased lung plasminogen activator activity and increased prostacyclin production) and pulmonary fibrosis (hydroxyproline accumulation). In the radiation model, lung injury and hypercupremia persisted for at least 6 months, and were spared similarly when the total dose was delivered in multiple daily fractions as compared to single doses. In irradiated rats, the elevated serum Cu concentration was accompanied by increases in plasma ceruloplasmin, lung Cu concentration, and lung Cu/Zn superoxide dismutase (SOD) activity. In monocrotaline-treated rats, lung damage and hypercupremia also were accompanied by a reduction in liver Cu concentration, and by a direct correlation between the concentrations of Cu and SGOT in the serum. In both models, some but not all modifiers of lung damage (penicillamine, angiotensin converting enzyme inhibitors, pentoxifylline) also partially prevented the insult-induced hypercupremia. In contrast, serum iron concentration was largely independent of treatment in all experiments. These data suggest that elevated serum copper concentration is an accurate and minimally invasive index of lung injury in irradiated and monocrotaline-treated rats.
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PMID:Serum copper concentration as an index of experimental lung injury. 251 9

The fibrogenic potentials of coal and copper slags used as substitutes for silica sand in abrasive blasting operations were assessed in rats. The test animals were given a single pulmonary intralobar instillation of 20 mg of test material and were sacrificed 10 months after dosing. Pulmonary fibrosis was seen in the coal slag-treated rats while no fibrosis was seen in the copper slag-treated animals. Granulomas were seen in the lungs from all treatment groups. The results of the study emphasize the need for bioassay of silica sand replacements for fibrogenic potential in spite of the low free silica contents of these materials.
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PMID:Fibrogenic potential of slags used as substitutes for sand in abrasive blasting operations. 745 75

Studies have implicated active oxygen species (AOS) in the pathogenesis of various lung diseases. Many chemical and physical agents in the environment are potent generators of AOS, including ozone, hyperoxia, mineral dusts, paraquat, etc. These agents produce AOS by different mechanisms, but frequently the lung is the primary target of toxicity, and exposure results in damage to lung tissue to varying degrees. The lung has developed defenses to AOS-mediated damage, which include antioxidant enzymes, the superoxide dismutases [copper-zinc (CuZnSOD) and manganese-containing (MnSOD)], catalase, and glutathione peroxidase (GPX). In this review, antioxidant defenses to environmental stresses in the lung as well as in isolated pulmonary cells following exposure to a number of different oxidants, are summarized. Each oxidant appears to induce a different pattern of antioxidant enzyme response in the lung, although some common trends, i.e., induction of MnSOD following oxidants inducing inflammation or pulmonary fibrosis, in responses to oxidants occur. Responses may vary between the different cell types in the lung as a function of cell-cycle or other factors. Increases in MnSOD mRNA or immunoreactive protein in response to certain oxidants may serve as a biomarker of AOS-mediated damage in the lung.
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PMID:Regulation of antioxidant enzymes in lung after oxidant injury. 752 4

Biochemical and molecular markers of inflammation, cell proliferation, and pulmonary fibrosis were studied in lungs and bronchoalveolar lavage preparations from Fischer 344 rats at time periods from 3 to 20 days after inhalation of two airborne concentrations (0.18 and 8.2 mg/m3 air) of chrysotile asbestos. Additional groups of animals were examined for lung histopathology and cell proliferation with an antibody to 5-bromo-2'-deoxyuridine after exposure to asbestos for 5 and 20 days and after 20 days of exposure followed by an additional 20 days in room air. Exposure to chrysotile at the higher concentration caused protracted increases in steady-state mRNA levels of manganese-containing superoxide dismutase and elevation in glyceraldehyde-3-phosphate dehydrogenase mRNA at 3 days, but levels of mRNAs encoding copper-zinc-containing superoxide dismutase, ornithine decarboxylase, and the proto-oncogene, c-jun were not statistically elevated from levels occurring in lung homogenates from sham control rats. Differential cell counts in bronchoalveolar lavage revealed an early infiltration of neutrophils that correlated with focal areas of increased cellularity and fibrosis in rat lungs at the higher concentrations of asbestos. However, elevations in lung hydroxyproline were not observed. Significant increases in epithelial cells of the bronchi, the interstitial compartment of the lung, and mesothelial cells incorporating 5-bromo-2'-deoxyuridine, an indication of DNA synthesis, were noted in the higher chrysotile group at 5 days, but labeling in all cell compartments was comparable with that occurring in sham controls at later time points. Indicators of inflammation, increased cell proliferation, and pulmonary fibrosis were not observed in the lungs of rats exposed to the lower concentration of chrysotile. Thus, results indicate that cellular and molecular markers of inflammation and proliferation in lung are dose-related and indicative of the histopathological development of asbestosis.
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PMID:Patterns of inflammation, cell proliferation, and related gene expression in lung after inhalation of chrysotile asbestos. 767 84

Steady-state mRNA levels and immunoreactive protein for manganese-containing superoxide dismutase (MnSOD) were assayed in rat lungs after subchronic inhalation of the fibrogenic silicon dioxide, cristobalite, or preparations of titanium dioxide (TiO2) of different inflammatory and fibrogenic potential. Total and differential cell counts recoverable by bronchoalveolar lavage (BAL) were also measured to ascertain whether induction of certain antioxidant enzymes (AOE) correlated with inflammatory responses. Inhalation of cristobalite and ultra-fine TiO2, a particle causing pulmonary inflammation and fibrosis, caused dramatic increases in MnSOD mRNA levels in rat lung which correlated with increases in MnSOD immunoreactive protein. Increases in gene expression of other AOE [catalase, glutathione peroxidase (GPX), copper-zinc containing superoxide dismutase (CuZnSOD)] were less striking and did not correlate precisely with inflammatory potential of minerals. Inflammatory changes in BAL correlated directly with steady-state MnSOD mRNA levels in lung. Inhalation of TiO2-F, a noninflammatory, nonfibrogenic mineral, failed to induce MnSOD or mRNAs for other AOE. Our data suggest that particles causing inflammation and pulmonary fibrosis increase expression of AOE in lung, most notably MnSOD. Thus, elevations of MnSOD mRNA levels in lung or BAL may be predictive of lung disease.
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PMID:Increased expression of manganese-containing superoxide dismutase in rat lungs after inhalation of inflammatory and fibrogenic minerals. 806 94

Blasting sand is used for abrasive blasting, but its inhalation is associated with pulmonary inflammation and fibrosis. Consequently, safer substitute materials for blasting sand are needed. In a previous study from this laboratory, the comparative pulmonary toxicity of five abrasive blasting substitutes and blasting sand was reported. In this study, the pulmonary toxicity of blasting sand was compared to five additional abrasive blasting substitutes: steel grit, copper slag, nickel slag, crushed glass, and olivine. Exposed rats received by intratracheal instillation 10 mg of respirable-size particles of blasting sand or an abrasive blasting substitute, while controls were instilled with vehicle. Pulmonary inflammation, damage, and fibrosis were examined 28 d postexposure. Pulmonary inflammation was monitored by determining bronchoalveolar lavage polymorphonuclear cell counts and alveolar macrophage activation by chemiluminescence. Pulmonary damage was assessed by acellular bronchoalveolar (BAL) fluid serum albumin concentrations and lactate dehydrogenase activities. Histological examination of lung tissue samples was made to assess the severity and distribution of pulmonary fibrosis, alveolitis, and alveolar epithelial cell hypertrophy and hyperplasia. In comparison to blasting sand, olivine exposed rats had higher levels of pulmonary inflammation and damage with a similar level of fibrosis. Steel grit-exposed rats had lower levels of pulmonary inflammation and damage, and did not develop fibrosis. However, steel grit-exposed rats had a level of epithelial cell hypertrophy and hyperplasia similar to blasting sand. The other abrasive blasting substitutes gave a mixed profile of toxicity. The data demonstrate that steel grit produced less acute pulmonary toxicity than blasting sand or any of the other abrasive blasting substitutes. Notwithstanding, the data also suggest that chronic exposure to steel grit may pose a health risk due to its effects on epithelial cell proliferation in the lung.
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PMID:Comparative pulmonary toxicity of blasting sand and five substitute abrasive blasting agents. 1216 12

Tetrathiomolybdate (TM), a drug developed for the treatment of Wilson's disease, produces an antiangiogenic effect by reducing systemic copper levels. Several angiogenic cytokines appear to depend on normal levels of copper for activity. In both animal tumor models and in cancer patients, TM therapy has proved effective in inhibiting the growth of tumors. We have hypothesized that the activities of fibrotic and inflammatory cytokines are also subject to modulation by the availability of copper in a manner similar to angiogenic cytokines. As a first step in evaluating whether TM plays a therapeutic role in diseases of inflammation and fibrosis, we studied the effects of TM on a murine model of bleomycin-induced pulmonary fibrosis. Oral TM therapy resulted in dose-dependent reduction in serum ceruloplasmin, a surrogate marker of systemic copper levels. Significant decreases in systemic copper levels were associated with marked reduction in lung fibrosis as determined on the basis of histopathologic findings and a biochemical measure of fibrosis. The protection afforded by TM was also reflected in significantly reduced bleomycin-induced body-weight loss. In the next phase of this work, we will seek to determine the mechanisms by which TM brings about this therapeutic benefit.
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PMID:Tetrathiomolybdate therapy protects against bleomycin-induced pulmonary fibrosis in mice. 1262 2

The study was undertaken to investigate the influence of alpha-tocopherol on zinc, copper, iron, calcium, magnesium, and potassium concentrations in serum of rats with bleomycin-induced pulmonary fibrosis. Fourteen Wistar albino rats were randomly divided into two groups of seven animals each. The first group was treated intratracheally with bleomycin hydrochloride (BM group); the second group was also instilled with BM but received injections of alpha-tocopherol twice a week (BM+E group). The third group was treated in the same manner with saline solution only, acting as controls (C). The zinc concentrations of the BM and BM+E groups were significantly decreased compared to the controls (p<0.05). The iron concentration of the controls was significantly higher than the other two groups. The magnesium concentration in the controls and the BM+E group was significantly higher than that of the BM group. The serum copper, calcium, and potassium concentrations were not found to be statistically different among the three groups. Distinct histopathologic changes were found in the BM group compared to the untreated rats. Less severe fibrotic lesions were also observed in the BM+E group. The results of this study show that lungs of rats treated with bleomycin were seriously damaged and that vitamin E seemed to counteract some of the damage, as indicated by differences in the serum concentrations of major elements.
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PMID:Effects of alpha-tocopherol on serum trace and major elements in rats with bleomycin-induced pulmonary fibrosis. 1720

Pulmonary fibrosis (PF) is characterized by an increase in the number of fibroblasts and an accumulation of collagen fibers in the extracellular matrix (ECM). The members of the copper-dependent lysyl oxidase (LOX) enzyme family regulate the collagen accumulation in the ECM. Tetrathiomolybdate (TM) is a copper chelator. The present study reported the effect of TM on the expression of LOX proteins (LOX, LOXL1, and LOXL2), collagen digestion enzymes (MMP2 and MMP8), and TIMP1 (a collagenase inhibitor) in PF. The PF in mice was induced by intratracheal bleomycin instillation. Adult mice were divided into four groups: mice dissected after 21 days of the first bleomycin (0.08 mg/kg, single dose) treatment (I) and their controls (II), and mice treated with TM for 1 week (1.2 mg/day/mice for the first 4 days and 0.9 mg/day/mice for the last 3 days) after 14 days of the first bleomycin instillation and dissected in the 21st day of the experiment (III) and their controls (IV). Mice in groups III and IV were fed a low-copper (2 mg/kg) diet during the last 7 days of the experiment. The fibrosis score in the lung was determined under a microscope. The expressions of collagen-I, LOX, MMP, and TIMP1 proteins were analyzed by Western blotting in the lung. Mice lungs with fibrosis were characterized by an overexpression of collagen-I, LOX, MMP, and TIMP1 proteins in addition to an accumulation of collagen fibers. TM treatments significantly regressed the overexpression of these proteins in the fibrotic mice lung. In conclusion, TM treatments can be used for the regression of PF, by decreasing collagen-I protein expression and accumulation.
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PMID:The copper chelator tetrathiomolybdate regressed bleomycin-induced pulmonary fibrosis in mice, by reducing lysyl oxidase expressions. 2534 39


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