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)

Exposure of phagocytic cells to asbestos in vitro results in an augmented production of reactive oxygen metabolites and increased peroxidation of lipids. The aim of this investigation was to assess the extent of lipid peroxidation both in cells and fluid obtained from bronchoalveolar lavage (BAL), and in lungs of rats exposed to crocidolite asbestos or titanium dioxide (TiO2), a nonfibrous particulate control. In comparison to sham and TiO2-exposed rats, the BAL fluid and cells of crocidolite-exposed animals contained significantly elevated levels of malondialdehyde (MDA), a breakdown product of lipid peroxidation detected using high-pressure liquid chromatography (HPLC). In contrast, no significant differences in MDA were detected in lavaged lung tissue from these animals. Inhalation of crocidolite caused an early inflammatory response characterized by elevated numbers of polymorphonuclear leukocytes and lymphocytes, as well as enhanced total protein in BAL. Pulmonary fibrosis and increased lung hydroxyproline also were observed after 20 days of exposure. Exposure to TiO2 did not cause inflammation, pulmonary fibrosis, or elevated amounts of hydroxyproline in the lung. Our results show that exposure to the fibrogenic and inflammatory mineral, crocidolite, results in an enhanced lipid peroxidation in BAL cells and fluid not observed after inhalation of the particulate TiO2. These novel observations suggest that MDA in BAL may be useful as a biomarker of exposure to inhaled asbestos or other oxidants.
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PMID:Enhanced lipid peroxidation in lung lavage of rats after inhalation of asbestos. 166 39

Studies comparing pulmonary responses to crystalline silica (SiO2) and titanium dioxide (0.3 microns diameter, TiO2-F) demonstrated a positive correlation between alveolar macrophage (AM) release of interleukin-1 (IL-1), tumor necrosis factor (TNF) and fibronectin and, pulmonary granuloma formation, inflammation and fibrosis, respectively. AM IL-1 release was associated with the development of pulmonary granulomas after SiO2 exposure. AM release of TNF positively correlated with the degree of neutrophil recruitment after SiO2 or TiO2-F exposure. A persistent increase in AM fibronectin release consistently correlated with the development of pulmonary fibrosis after SiO2 or TiO2-F exposure. Studies comparing pulmonary responses to ultrafine TiO2 (TiO2-D; particle diameter, 0.02 microns) with TiO2-F demonstrate that ultrafine particles have a relatively greater toxicity on a mass/lung basis. Exposure to TiO2-D resulted in a persistent increase in AM TNF and fibronectin release which was associated with neutrophil recruitment and fibrosis, respectively. TiO2-D did not stimulate AM IL-1 release and this was consistent with the absence of a granulomatous response to TiO2-D. In light of the known bioactivities of IL-1, TNF and fibronectin, these correlative findings suggest that these mediators play significant roles in pulmonary responses to mineral dust exposure and may serve as potential early biomarkers of pulmonary toxicity.
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PMID:Cytokine and growth factor release by alveolar macrophages: potential biomarkers of pulmonary toxicity. 166 54

Previous studies have shown that long thin asbestos fibres are more pathogenic in in vivo and more active in in vitro assays than short fibre samples. In the present study a long fibre amosite asbestos sample and a short fibre sample prepared from it were tested for ability to cause inflammation in the peritoneal cavity of the mouse; a UICC sample intermediate in fibre size and an inert compact dust, TiO2, were also tested. The ability of the dust samples to cause inflammation, as judged by macrophage and neutrophil recruitment, was ranked in the order long fibre greater than UICC greater than short fibre greater than TiO2. Ability of amosite samples to cause inflammation was therefore related to the proportion of long fibres. The enhanced ability of long fibres to cause inflammation and cause macrophage activation is probably a key factor in the ability of long fibres to cause pulmonary fibrosis and may also be important in fibre carcinogenesis.
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PMID:Inflammation generating potential of long and short fibre amosite asbestos samples. 254 Jul 93

The objective of this study was to determine whether workers exposed to titanium dioxide (TiO2) had significantly higher risks of lung cancer, chronic respiratory disease, pleural thickening/plaques, or pulmonary fibrosis than referent groups. A total of 1,576 employees exposed to TiO2 were observed from 1956 through 1985 for cancer and chronic respiratory disease incidence, and from 1935 through 1983 for mortality. A cross-sectional sample of 398 employees was evaluated for chest roentgenogram abnormalities. Cohort analyses suggested that the risks of developing lung cancer and other fatal respiratory diseases were no higher for TiO2-exposed employees than for the referent groups. Nested case-control analyses found no statistically significant associations between TiO2 exposure and risk of lung cancer, chronic respiratory disease, and chest roentgenogram abnormalities. No cases of pulmonary fibrosis were observed among TiO2-exposed employees.
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PMID:Epidemiologic study of workers exposed to titanium dioxide. 323 Apr 44

Recently published results in a NTP report of a 2-year inhalation study with talc in rats and mice seem to fit the category of being associated with particle overload quite well: Exposure concentrations of 6 and 18 mg/m3 induced pulmonary inflammation and fibrosis in male and female rats and induction of lung tumors (in female rats only) of the high exposure group; mice of either sex showed an inflammatory response but did not show pulmonary fibrosis or lung tumors. Analysis of the particle accumulation kinetics in lungs of both rats and mice indeed shows that lung overload had been reached at both exposure concentrations in both species resulting in increased talc accumulation of high lung burdens. This and the chronic inflammatory response indicate that the maximum tolerated dose (MTD) had been exceeded at both exposure levels. This result was predictable based on the outcome of a 4-week range-finding study prior to initiation of the chronic talc study; however, the short duration of the range-finding study may have been inadequate to give great confidence in the prediction and therefore may have accounted for the failure to include a concentration below the MTD in the chronic study. Further analysis of the results of the chronic talc study show that talc particles behave like other low-toxicity particles such as TiO2 and toner with respect to effects on lung clearance and chronic pulmonary inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The NTP talc inhalation study: a critical appraisal focused on lung particle overload. 764 11

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

Chronic rat inhalation studies have shown that a number of different particle types can induce significant adverse effects, including impaired lung clearance, chronic pulmonary inflammation, pulmonary fibrosis, and lung tumors. These effects occurred when highly insoluble particles of low solubility and low cytotoxicity were inhaled in long-term studies. Inhaled concentrations ranged from a few milligrams per cubic meter up to 250 mg/m3. This wide range of inhaled concentrations may indicate that the particulate compounds have differed largely in their toxicity. This view appears to be supported by the fact that cytotoxic crystalline SiO2 shows very similar effects after much lower inhaled concentrations. However, although administered doses are customarily expressed in units of mass, this may not be the appropriate dose-metric for a correlation with observed effects. For example, effects on alveolar macrophage (AM) mediated clearance of particles could best be correlated with the volumetric lung burden of different particle types, suggesting that the particle volume phagocytized by AM is an appropriate dose parameter for this endpoint. On the other hand, the inflammatory response induced by a number of different particle types could best be correlated with the surface area of the particles retained in the alveolar space. In addition, total surface area of retained particles was the best dose parameter (or a correlation when the endpoint was lung tumors. In all of these studies crystalline SiO2 did not fit into the overall exposure-response or dose-response relationship, clearly demonstrating that SiO2 is a very different (more cytotoxic) particle type. Particle size and surface area can play important roles in the response to inhaled particles, which is especially relevant for ultrafine particles. Inhalation studies with rats exposed to aggregated ultrafine TiO2 and carbon black showed that both compounds induced lung tumors in rats at considerably lower gravimetric lung burdens than larger sized TiO2. However, the different ultrafine particle types did also show differences in the strength of response that cannot be explained by differences in surface area only. Analyses of inhalation studies with ultra fine particles show that the movement of particles from alveolar spaces into interstitial sites appears to reflect the ability of inhaled ultrafine particle aggregates (TiO2; carbon black) to break down into smaller units, or even singlet particles. Further data are needed to evaluate the importance of interstitial cell-particle interactions for the long-term effects. The lung tumor response in rats after chronic high-dose particle inhalation has been suggested to be a rat-specific response that may not be relevant to humans. However, lacking an understanding about mechanistic events, the rat model should not be dismissed prematurely. What should be questioned instead is the relevance of using excessively high exposure concentrations of particles in a rat study. Exposure-response and dose-response relationships for different endpoints indicate the existence of a threshold below which no adverse effects may occur. Such a threshold could be explained by overwhelming specific defense mechanisms in the respiratory tract, such as particle loading of macrophages (prolongation of particle clearance), or limitations of pulmonary antioxidant capacities (inflammatory response). It appears, however, that duration of exposure plays a significant role that can result in a shift of exposure-dose-response relationships and a shift of a threshold when these relationships are compared at the end of a subchronic study versus the end of a chronic study. This shift will cause difficulties for defining a threshold as well as a maximum tolerated dose from results of a subchronic particle inhalation study.
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PMID:Significance of particle parameters in the evaluation of exposure-dose-response relationships of inhaled particles. 1154 96

Inhaled ultrafine titanium dioxide (UF-TiO2) particles cause pronounced pulmonary inflammation, in contrast to fine TiO2. Previous studies provide evidence for the production of reactive oxygen species by alveolar macrophages, after overloading with UF-TiO2 particles and cytotoxicity of UF-TiO2 in rat lung alveolar macrophages. UF-TiO2 also causes pulmonary fibrosis and lung tumors in rats. UF-TiO2 particles are photogenotoxic, but in general, information on the genotoxicity of UF-TiO2 is still limited. We studied the potential of UF-TiO2 (particle size less than or equal to 20 nm) and fine TiO2 (particle size > 200 nm) to induce chromosomal changes, which can be monitored by the formation of micronuclei (MN) in Syrian hamster embryo (SHE) cells. We also analyzed UF-TiO2-treated cells for apoptosis induction. The MN assay revealed a significant increase in MN induction (p less than or equal to 0.05) in SHE cells after treatment with UF-TiO2 (1.0 micro g/cm2) for 12 hr (mean, 24.5 MN/1,000 cells), 24 hr (mean, 31.13 MN/1,000 cells), 48 hr (mean, 30.8 MN/1,000 cells), 66 hr (mean, 31.2 MN/1,000 cells), and 72 hr (mean, 31.3 MN/1,000 cells). Bisbenzimide staining of the fixed cells revealed typical apoptotic structures (apoptotic bodies), and the apoptosis-specific "DNA ladder pattern" resulting from internucleosomal cleavage was identified by gel electrophoresis. Furthermore, transmission electron microscopy of the exposed cells revealed the typical chromatin compaction of apoptosis.
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PMID:Evidence that ultrafine titanium dioxide induces micronuclei and apoptosis in Syrian hamster embryo fibroblasts. 1215 61

The aim of this study was to evaluate the acute lung toxicity in rats of intratracheally instilled TiO2 particles that have been substantially encapsulated with pyrogenically deposited, amorphous silica. Groups of rats were intratracheally instilled either with doses of 1 or 5 mg/kg of hydrophilic Pigment A TiO2 particles or doses of 1 or 5 mg/kg of the following control or particle-types: 1) R-100 TiO2 particles (hydrophilic in nature); 2) quartz particles, 3) carbonyl iron particles. Phosphate-buffered saline (PBS) instilled rats served as additional controls. Following exposures, the lungs of PBS and particle-exposed rats were evaluated for bronchoalveolar lavage (BAL) fluid inflammatory markers, cell proliferation, and by histopathology at post-instillation time points of 24 hrs, 1 week, 1 month and 3 months. The bronchoalveolar lavage results demonstrated that lung exposures to quartz particles, at both concentrations but particularly at the higher dose, produced significant increases vs. controls in pulmonary inflammation and cytotoxicity indices. Exposures to Pigment A or R-100 TiO2 particles produced transient inflammatory and cell injury effects at 24 hours postexposure (pe), but these effects were not sustained when compared to quartz-related effects. Exposures to carbonyl iron particles or PBS resulted only in minor, short-term and reversible lung inflammation, likely related to the effects of the instillation procedure. Histopathological analyses of lung tissues revealed that pulmonary exposures to Pigment A TiO2 particles produced minor inflammation at 24 hours postexposure and these effects were not significantly different from exposures to R-100 or carbonyl iron particles. Pigment A-exposed lung tissue sections appeared normal at 1 and 3 months postexposure. In contrast, pulmonary exposures to quartz particles in rats produced a dose-dependent lung inflammatory response characterized by neutrophils and foamy (lipid-containing) alveolar macrophage accumulation as well as evidence of early lung tissue thickening consistent with the development of pulmonary fibrosis. Based on our results, we conclude the following: 1) Pulmonary instillation exposures to Pigment A TiO2 particles at 5 mg/kg produced a transient lung inflammatory response which was not different from the lung response to R-100 TiO2 particles or carbonyl iron particles; 2) the response to Pigment A was substantially less active in terms of inflammation, cytotoxicity, and fibrogenic effects than the positive control particle-type, quartz particles. Thus, based on the findings of this study, we would expect that inhaled Pigment A TiO2 particles would have a low risk potential for producing adverse pulmonary health effects.
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PMID:Pulmonary toxicity screening studies in male rats with TiO2 particulates substantially encapsulated with pyrogenically deposited, amorphous silica. 1643 14

Pulmonary toxicology studies in rats demonstrate that nanoparticles administered to the lung are more toxic than larger, fine-sized particles of similar chemistry at identical mass concentrations. The aim of this study was to evaluate the acute lung toxicity in rats of intratracheally instilled pigment-grade TiO2 particles (rutile-type particle size = approximately 300 nm) versus nanoscale TiO2 rods (anatase = 200 nm x 35 nm) or nanoscale TiO2 dots (anatase = approximately 10 nm) compared with a positive control particle type, quartz. Groups of rats were instilled with doses of 1 or 5 mg/kg of the various particle types in phosphate-buffered saline (PBS). Subsequently, the lungs of PBS- and particle-exposed rats were assessed using bronchoalveolar lavage fluid biomarkers, cell proliferation methods, and by the histopathological evaluation of lung tissue at 24 h, 1 week, 1 month, and 3 months postinstillation exposure. Exposures to nanoscale TiO2 rods or nanoscale TiO2 dots produced transient inflammatory and cell injury effects at 24 h postexposure (pe) and were not different from the pulmonary effects of larger sized TiO2 particle exposures. In contrast, pulmonary exposures to quartz particles in rats produced a dose-dependent lung inflammatory response characterized by neutrophils and foamy lipid-containing alveolar macrophage accumulation as well as evidence of early lung tissue thickening consistent with the development of pulmonary fibrosis. The results described herein provide the first example of nanoscale particle types which are not more cytotoxic or inflammogenic to the lung compared to larger sized particles of similar composition. Furthermore, these findings run counter to the postulation that surface area is a major factor associated with the pulmonary toxicity of nanoscale particle types.
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PMID:Pulmonary instillation studies with nanoscale TiO2 rods and dots in rats: toxicity is not dependent upon particle size and surface area. 1649 53


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