Toxicity of fibers and particles. Report of the workshop held in Munich, Germany, 26-27 October 2000.
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Air Pollutants↗
Biomedical subjects
K Driscoll
Publications and source records attributed to K Driscoll.
High-level multiplex DNA amplification.
We present data on efficient amplification of large number of DNA targets using a single-tube polymerase chain reaction (PCR). This is a further enhancement of our approach to multiplexed PCR based on PCR suppression, which allows multiple DNA amplification using only one sequence-specific primer per amplicon while the second primer is common for all targets (Broude, N.E., et al., Proc. Natl. Acad. Sci. USA 98, 206-211, 2001). The reaction conditions have been optimized for simultaneous synthesis of 30 DNA targets, mostly consisting of fragments containing single nucleotide polymorphisms (SNP). The size of the amplified fragments, derived from many different human chromosomes, varies from 100 to 600 bp. We conclude that this method has potential for highly multiplexed DNA amplification useful for SNP analyses, DNA diagnostics, and forensics.
Base Sequence↗
Inhaled particulate matter causes expression of nuclear factor (NF)-kappaB-related genes and oxidant-dependent NF-kappaB activation in vitro.
High levels of ambient air pollution are associated with exacerbation of asthma and respiratory morbidity, yet little is known concerning the mechanisms of inflammation and toxicity by components of inhaled particulate matter (PM). Brief inhalation of PM(2.5) (particles of an aerodynamic diameter of < 2.5 microns) (300 microg/m(3) air for 6 h followed by a period of 24 h in clean air) by either C3H/HeJ or C57/BL6 mice caused significant (P </= 0.05) increases in steady-state messenger RNA (mRNA) levels of a number of nuclear factor (NF)-kappaB-associated and/ or -regulated genes, including tumor necrosis factor-alpha and -beta, interleukin-6, interferon-gamma, and transforming growth factor-beta. Lung mRNA levels of lymphotoxin-beta and macrophage migration inhibitory factor were unchanged. In murine C10 alveolar cells and an NF-kappaB-luciferase reporter cell line, exposure to PM(2.5) at noncytotoxic concentrations resulted in increases in transcriptional activation of NF-kappaB-dependent gene expression which were inhibited in the presence of catalase. Early and persistent increases in intracellular oxidants, as measured by flow cytometry and cell imaging using the oxidant probe 2'-7'-dichlorofluoroscin diacetate, were observed in epithelial cells exposed to PM(2.5) and ultrafine carbon black particles. Studies here are the first to show NF-kappaB-related inflammatory and cytokine gene expression after inhalation of PM(2.5) and oxidant-dependent induction of NF-kappaB activity by PM(2.5) in pulmonary epithelial cells.
Air Pollutants↗
Ambient particulate matter causes activation of the c-jun kinase/stress-activated protein kinase cascade and DNA synthesis in lung epithelial cells.
Numerous epidemiological studies have demonstrated a positive association between ambient air pollution and adverse health effects including respiratory morbidity, asthma, and lung cancer. It has been suggested in some experimental studies that airborne particulate matter (PM) can produce inflammatory effects, but nothing is known about the possible proliferative and carcinogenic effects of these particles on cells of the lung. We show here that exposure of pulmonary epithelial cells, a cell type affected in acute lung injury, asthma, and lung carcinomas, to nontoxic concentrations of PM in vitro results in increases in c-jun kinase activity, levels of phosphorylated cJun immunoreactive protein, and transcriptional activation of activator protein-1-dependent gene expression. These changes are accompanied by elevations in numbers of cells incorporating 5'-bromodeoxyuridine, a marker of unscheduled DNA synthesis and/or cell proliferation. Data here are the first to demonstrate that interaction of ambient PM with target cells of the lung initiates a cell signaling cascade related causally to aberrant cell proliferation and carcinogenesis.
Air Pollution↗
Cell signaling pathways elicited by asbestos.
In recent years, it has become apparent that minerals can trigger alterations in gene expression by initiating signaling events upstream of gene transactivation. These cascades may be initiated at the cell surface after interaction of minerals with the plasma membrane either through receptorlike mechanisms or integrins. Alternatively, signaling pathways may be stimulated by active oxygen species generated both during phagocytosis of minerals and by redox reactions on the mineral surface. At least two signaling cascades linked to activation of transcription factors, i.e., DNA-binding proteins involved in modulating gene expression and DNA replication, are stimulated after exposure of lung cells to asbestos fibers in vitro. These include nuclear factor kappa B (NF kappa B) and the mitogen-activated protein kinase (MAPK) cascade important in regulation of the transcription factor, activator protein-1 (AP-1). Both NF kappa B and AP-1 bind to specific DNA sequences within the regulatory or promoter regions of genes that are critical to cell proliferation and inflammation. Unraveling the cell signaling cascades initiated by mineral dusts and pharmacologic inhibition of these events may be important for the control and treatment of mineral-associated occupational diseases.
Animals↗
Particles, inflammation and respiratory tract carcinogenesis.
Particle-induced carcinogenesis is a non-specific outcome of many different particles. It was the purpose of this study, (i) to comprehensively review some of the mechanisms through which particles and particle-associated carcinogens can cause mutagenic/carcinogenic effects, and (ii) to indicate how this affects risk assessment studies. Data are presented that demonstrate the crucial role of a chronic inflammatory response in mutagenic effects of both silica and carbon black particles on the HPRT gene in lung target cells. The concept of inflammation in particle-induced genotoxicity is put into the context of other mechanisms, such as the release of cytokines and reactive oxygen species. It is concluded that interpretation of rat inhalation studies should certainly include this concept.
Air Pollutants↗
Adenoviral gene transfer of macrophage inflammatory protein-2 in rat lung.
Replication-defective adenoviral vectors are capable of localized transfer and expression of incorporated gene product in lung tissue. We have constructed an adenoviral vector that expresses rat macrophage inflammatory protein (MIP)-2, a C-X-C chemokine specifically chemotactic for neutrophils, Supernatants from 293 cells, infected with the adenoviral MIP-2 (ADMIP-2) construct, showed potent chemotactic activity and the ability of the ADMIP-2 vector to transcribe and make functional protein was confirmed. In vivo analysis of bronchoalveolar lavage fluid from rats after intratracheal instillation of ADMIP-2 (10(9) plaque-forming units) showed a 10-fold increase in the absolute number of neutrophils in bronchoalveolar lavage fluid as opposed to rats treated with an equal titer of an E1-disabled control virus expressing firefly luciferase (ADCA-18). Neutrophils constituted 65% of total BAL cells with alveolar macrophages being the other major cell type recovered. Rat MIP-2 protein was increased (nanograms per milliliter) in bronchoalveolar lavage fluid over a period of 7 days in ADMIP-2-treated animals. MIP-2 mRNA was demonstrated by Northern blot analysis in lung tissue, and histological analysis confirmed the presence of massive localized tissue neutrophilia. Evidence of chronic tissue injury and repair (ie, fibrosis) was not detected up to 2 weeks after the neutrophil infiltrate had resolved, subsequent to decreased chemokine presence. Adenoviral gene transfer proved an effective tool for the assessment of lung tissue expression of this chemokine in vivo and is useful in developing rodent models of tissue neutrophilia.
Adenoviridae↗
Oxidant stress responses in human pleural mesothelial cells exposed to asbestos.
The generation of oxidants is a proposed mechanism of cell injury by asbestos fibers. To determine whether human pleural mesothelial cells (HMC) respond to asbestos and active oxygen species (AOS) by induction of antioxidant enzymes, cells obtained from pleural effusion were exposed to crocidolite or chrysotile asbestos or xanthine/xanthine oxidase (X/XO), a chemical-generating system of AOS. Gene expression of manganese-containing superoxide dismutase (MnSOD) and heme oxygenase (HO), endogenous enzymes involved in cell defense against oxidant stresses, was then determined. Dosage-dependent increases in steady-state mRNA levels of MnSOD and HO were observed in HMC exposed to asbestos or X/XO. However, increases in gene expression of MnSOD or HO did not occur in HMC after exposure to particulates such as polystyrene beads or riebeckite, the nonfibrous analog of crocidolite asbestos. Comparative experiments with human adult lung fibroblasts (HAL) showed less striking increases in mRNA levels of MnSOD and HO in response to asbestos, but steady-state mRNA levels for HO were increased more than fivefold in response to X/XO. To determine whether increases in mRNA levels of MnSOD were translated into protein, Western blot analyses were performed on HMC and HAL cells exposed to asbestos or X/XO. Slight increases in MnSOD immunoreactive protein were observed in HMC in response to both agents. In contrast, X/XO caused striking elevations in MnSOD protein levels in HAL cells. These results suggest that certain antioxidant enzymes are inducible in HMC after exposure to asbestos and other oxidants.
Asbestos, Crocidolite↗
Modulation of eicosanoid production by human alveolar macrophages exposed to silica in vitro.
Repeated inhalation of silica dust can lead to inflammation and fibrosis in human lung and in experimental animal models. The alveolar macrophage is believed to play a pivotal role in this process. Numerous macrophage-derived growth factors, cytokines, and arachidonic acid metabolites have been shown to contribute to inflammation and fibrosis. The objective of this study was to determine the eicosanoid production by human alveolar macrophages in response to silica exposure in vitro and to assess the contribution of alveolar macrophages to silica-induced fibrosis and inflammation. Macrophages were obtained from healthy volunteers and were incubated for 3 or 24 hr in the presence of silica (100, 60, and 0 micrograms/mL). Supernatants were removed for eicosanoid analysis. Eicosanoids were analyzed by both high performance liquid chromatography and radioimmunoassay. The data suggest that silica causes an increased release of leukotriene B4, leukotrienes C4/D4/E4, and 5-hydroxyeicosatetraenoic acid (5-HETE) after 3 hr and decreases in prostaglandin E2 and thromboxane B2 production after 24 hr of exposure to 100 micrograms/mL silica. In addition, 12-HETE and 15-HETE production remained unchanged at either time point. These opposing effects seen with the metabolites of lipoxygenase and cyclooxygenase pathways could contribute to silica-induced fibrosis. The pattern of eicosanoid production after exposure to silica was different from that obtained when macrophages were stimulated with lipopolysaccharide for 3 or 24 hr, indicating that the response to the particles was not just due to general cellular activation.
Adult↗
Staff members' compliance with their facility's antineoplastic drug handling policy.
This study examined use of protective garments and equipment by staff when handling antineoplastic drugs. Nurses, pharmacists, and physicians were compared on protection used, reasons for nonuse, compliance with policy, correspondence of staff beliefs about policy with actual policy, and the relationship between what protection staff believes is required and what protection is used. Pharmacists were the best protected group. There was little correspondence among staff beliefs about policy content and actual content. Beliefs about what protection was required had a stronger correlation with actual use than did policy content.
Antineoplastic Agents↗
Comparison of antineoplastic drug handling policies of hospitals with OSHA guidelines: a pilot study.
Hospital antineoplastic drug handling policies of 24 hospitals in eight Southwestern Ohio counties were compared with recommendations of the 1986 Occupational Safety and Health Administration (OSHA) guidelines. Although most study facilities where antineoplastics are handled have policies, content varies and is generally less complete than OSHA guidelines, particularly regarding storing, transporting, and disposing of drugs; managing equipment; informing personnel of risk; and surveillance. Recommendations for personal protection concur more closely with OSHA guidelines than do other content areas.
Antineoplastic Agents↗
Dose- and time-response relationships of triethylenemelamine-induced chromosomal aberrations in rat bone marrow cells.
Groups of 18 male Sprague-Dawley rats were administered single i.p. doses of 0.00, 0.125, 0.25 or 0.50 mg/kg of triethylenemelamine (TEM). 6 rats per treatment group were killed 6, 24 or 48 h after dosing, and bone marrow cells were collected and prepared for cytogenetic analysis. Under the present conditions, 0.25 mg/kg with sampling of bone marrow cells 24 h after treatment appeared to represent optimal conditions for using TEM as a positive control agent in the rat in vivo cytogenetic assay as described.
Animals↗
Search and seizure in the emergency department.
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Adult↗