PubMed Health⌕ Search

Biomedical subjects

K Donaldson

Publications and source records attributed to K Donaldson.

At least 37 records · Page 2Linked to original sources
PubMed2001

Oxidant-mediated lung epithelial cell tolerance: the role of intracellular glutathione and nuclear factor-kappaB.

The airway epithelium is injured by oxidants inhaled as atmospheric pollutants or produced during inflammatory responses. We studied the effect of modulating the antioxidant intracellular glutathione, both using thiol compounds and by the adaptive effect of hyperoxia, on oxidant-induced injury and activation of the nuclear factor-kappaB (NF-kappaB) in two cell lines: the human bronchial (16HBE) and type II alveolar epithelial cells (A549). The thiol antioxidants glutathione (GSH) and glutathione monoethyl ester (GSH-MEE) [2 mM] increased GSH levels (nmol/mg protein) in A549 cells (GSH 383 +/- 26 and GSH-MEE 336 +/- 23 vs control 171 +/- 13, P < 0.001) and in 16HBE cells (GSH 405 +/- 33, GSH-MEE 362 +/- 37 vs control 198 +/- 12, P < 0.001, N = 3). Treatment of hyperoxia (95% oxygen) also increased GSH levels between 4 and 24 hr exposure compared with control (P < 0.01). Hydrogen peroxide (H(2)O(2)) (0.01 mM) induced NF-kappaB activation, whereas hyperoxia exposure did not affect NF-kappaB activation in either cell line. Pretreatment with dl-buthionine (SR)-sulfoximine, which decreased intracellular glutathione, increased NF-kappaB binding induced by H(2)O(2) and increased lactate dehydrogenase (LDH) release (P < 0.001). Pretreatment with the thiol compounds and hyperoxia totally inhibited H(2)O(2)-induced NF-kappaB binding and cell injury as measured by LDH release. These data indicate the importance of intracellular glutathione and inhibition of NF-kappaB in both protection/tolerance against oxidant-induced epithelial cell injury, and NF-kappaB activation in response to oxidative stress which may be important in lung inflammation. Thus, increasing intracellular glutathione may be of therapeutic relevance if able to modulate NF-kappaB activation and hence attenuate inflammation.

Adaptation, Biological↗
PubMed2001

Impairment of alveolar macrophage phagocytosis by ultrafine particles.

We investigated whether slowed clearance after exposure to ultrafine particles was due to a failure in alveolar macrophage phagocytosis. This was achieved by measuring the ability of a macrophage cell line (J774.2 MPhi) to phagocytose 2-microg indicator latex beads following 8-h exposures to a number of test particles. Particles utilized were fine titanium dioxide (TiO2), ultrafine titanium dioxide (UTiO2), carbon black (CB), or ultrafine carbon black (UCB). Cytotoxicity of particles was measured by means of MTT activity. In a preliminary study, we assessed the effects of conditioned medium from particle-treated macrophages on the phagocytic ability of naive macrophages. Ultrafine and fine particles had no significant cytotoxic effects on J774.2 MPhi. A significant reduction in the ability of macrophages to phagocytose the indicator beads occurred after exposure to 0.39 microg/mm(2) (p < 0.001) of UCB and 0.78 microg/mm(2) (p < 0.001) of all particle types compared to the control. Furthermore, ultrafine particles were shown to significantly (p < 0.001) impair macrophage phagocytosis at a lower dose than their fine counterparts (0.39 and 0.78 microg/mm(2), respectively). At all doses, UCB resulted in a greater number (p < 0.001) of nonphagocytic macrophages compared to the other test particles. We tested whether a diffusable mediator being released from particle-exposed cells inhibited the phagocytic activity of adjacent macrophages. The conditioned medium from particle-exposed macrophages had no significant effect on the phagocytic ability of macrophages, suggesting that cell-cell contact is responsible for the pattern of failed phagocytosis (data not shown). We have demonstrated that ultrafine particles impair macrophage phagocytosis to a greater extent than fine particles compared on a mass basis. Therefore, we conclude that slowed clearance of particles, specifically the ultrafines, can in part be attributed to a particle-mediated impairment of macrophage phagocytosis.

Animals↗
PubMed2001

Potential mechanisms of adverse pulmonary and cardiovascular effects of particulate air pollution (PM10).

PM10 is the international convention for measuring environmental particulate air pollution. Increases in PM10 have been linked to exacerbations of airways disease and deaths from respiratory and cardiovascular causes. PM10 is a complex and variable mixture but toxicological data suggests that ultrafine particles, transition metals and endotoxins are the most likely components to mediate adverse health effects. Potential mechanisms for the local and systemic adverse effects of PM10 are discussed.

Air Pollutants↗
PubMed2001

Community hospitals and older people.

Recent health care policy has promoted the community hospital as one remedy for the contracted district general hospital. Unfortunately, a literature review reveals a weak evidence-base to support this policy. Although descriptive studies demonstrate the flexible, multi-purpose role of community hospitals, there is a worrying paucity of clinical outcome studies and no robust health economic evaluation. An important potential role for community hospitals is in the post-acute care of older people. However, evaluation by randomized trial is required to demonstrate effectiveness and cost effectiveness of community hospital transfer compared to alternatives such as remaining in a district general hospital.

Aged↗
PubMed2001

Inflammatory effects of respirable quartz collected in workplaces versus standard DQ12 quartz: particle surface correlates.

In 1997, the IARC (International Agency for Research on Cancer) reevaluated its quartz classification from a class 2 carcinogen, to that of a class 1, stating sufficient evidence for carcinogenicity in both humans and experimental animals. However, tumor development did not occur across all occupational settings. It is probable that this is due to the considerable differences in toxicity between workplace quartz in comparison to quartz used in experimental studies. We therefore hypothesized that workplace quartz samples differ in toxicity from standard experimental quartz samples at equal mass. To test this hypothesis we compared 2 workplace quartz samples (RH1 and OM) with standard experimental quartz (DQ12) in several assays commonly used in particle toxicology. The sizes of the quartz samples were as closely matched as possible. The endpoints of this study were inflammation in the rat lung following intratracheal instillation (1000 microg or 250 microg for 3 or 14 days), release of soluble iron, cytotoxicity to cells in culture, and surface reactivity as assessed by hemolysis and ESR. The workplace samples did not cause inflammation at any dose or time point. DQ12 quartz caused marked inflammatory responses, as measured by an increased number of neutrophils in the lungs of instilled animals for both time points and doses. Protein in the bronchoalveolar lavage also increased in animals exposed to DQ12 but not the workplace samples. In vitro, DQ12 had the greatest hemolytic activity but only RH1 released substantial amounts of soluble iron. The increased inflammogenicity of DQ12 was not wholly explained by a greater surface area, by diameter, or by releasable iron. The hemolytic activity of DQ12, while not being informative in terms of understanding the mechanism of carcinogenicity, was the best in vitro predictor for in vivo activity. Therefore the surface reactivity of DQ12 appears to drive its inflammogenicity.

Air Pollutants, Occupational↗
PubMed2001

Stimulation of IL-8 release from epithelial cells by gas cooker PM(10): a pilot study.

OBJECTIVE: To measure the effect of matter collected by a method that has a 50% efficiency for particles with an aerodynamic diameter of 10 microm (PM10), generated by gas and electric cooking, on A549 epithelial cells with and without nitrogen dioxide (NO2). METHOD: Multiple indoor PM10 samples were collected on Teflon filters during the use of gas or electric cookers. Interleukin-8 (IL-8) concentrations were measured with a sandwich enzyme linked immunosorbent assay (ELISA) system. RESULTS: Treatment of A549 cells with PM10 generated from gas cooking resulted in increased concentrations of IL-8 compared with untreated cells; particles from the electric cooker had no effect. NO2 did not alter the concentration of IL-8. CONCLUSION: PM10 generated by gas cooking has the potential to cause proinflammatory effects in lung cells. This may have implications for susceptible people.

Air Pollution, Indoor↗
PubMed2001

Ultrafine particles and nitrogen oxides generated by gas and electric cooking.

OBJECTIVES: To measure the concentrations of particles less than 100 nm diameter and of oxides of nitrogen generated by cooking with gas and electricity, to comment on possible hazards to health in poorly ventilated kitchens. METHODS: Experiments with gas and electric rings, grills, and ovens were used to compare different cooking procedures. Nitrogen oxides (NO(x)) were measured by a chemiluminescent ML9841A NO(x) analyser. A TSI 3934 scanning mobility particle sizer was used to measure average number concentration and size distribution of aerosols in the size range 10-500 nm. RESULTS: High concentrations of particles are generated by gas combustion, by frying, and by cooking of fatty foods. Electric rings and grills may also generate particles from their surfaces. In experiments where gas burning was the most important source of particles, most particles were in the size range 15-40 nm. When bacon was fried on the gas or electric rings the particles were of larger diameter, in the size range 50-100 nm. The smaller particles generated during experiments grew in size with time because of coagulation. Substantial concentrations of NO(X) were generated during cooking on gas; four rings for 15 minutes produced 5 minute peaks of about 1000 ppb nitrogen dioxide and about 2000 ppb nitric oxide. CONCLUSIONS: Cooking in a poorly ventilated kitchen may give rise to potentially toxic concentrations of numbers of particles. Very high concentrations of oxides of nitrogen may also be generated by gas cooking, and with no extraction and poor ventilation, may reach concentrations at which adverse health effects may be expected. Although respiratory effects of exposure to NO(x) might be anticipated, recent epidemiology suggests that cardiac effects cannot be excluded, and further investigation of this is desirable.

Air Pollution, Indoor↗
PubMed2001

Adenoviral E1A primes alveolar epithelial cells to PM(10)-induced transcription of interleukin-8.

The presence of the adenoviral early region 1A (E1A) protein in human lungs has been associated with an increased risk of chronic obstructive pulmonary disease (COPD), possibly by a mechanism involving amplification of proinflammatory responses. We hypothesize that enhanced inflammation results from increased transcription factor activation in E1A-carrying cells, which may afford susceptibility to environmental particulate matter < 10 microm (PM(10))-mediated oxidative stress. We measured interleukin (IL)-8 mRNA expression and protein release in human alveolar epithelial cells (A549) transfected with the E1A gene (E1A+ve). Both E1A+ve and -ve cells released IL-8 after incubation with TNF-alpha, but only E1A+ve cells were sensitive to LPS stimulation in IL-8 mRNA expression and protein release. E1A+ve cells showed an enhanced IL-8 mRNA and protein response after treatment with H(2)O(2) and PM(10). E1A-enhanced induction of IL-8 was accompanied by increases in activator protein-1 and nuclear factor-kappa B nuclear binding in E1A+ve cells, which also showed higher basal nuclear binding of these transcription factors. These data suggest that the presence of E1A primes the cell transcriptional machinery for oxidative stress signaling and therefore facilitates amplification of proinflammatory responses. By this mechanism, susceptibility to exacerbation of COPD in response to particulate air pollution may occur in individuals harboring E1A.

Adenovirus E1A Proteins↗
PubMed2001

Ambient particle inhalation and the cardiovascular system: potential mechanisms.

Well-documented air pollution episodes throughout recent history have led to deaths among individuals with cardiovascular and respiratory disease. Although the components of air pollution that cause the adverse health effects in these individuals are unknown, a small proportion by mass but a large proportion by number of the ambient air particles are ultrafine, i.e., less than 100 nm in diameter. This ultrafine component of particulate matter with a mass median aerodynamic diameter less than 10 microm (PM(10) may mediate some of the adverse health effects reported in epidemiologic studies and for which there is toxicologic evidence to support this contention. The exact mechanism by which ultrafine particles have adverse effects is unknown, but these particles have recently been shown to enhance calcium influx on contact with macrophages. Oxidative stress is also to be anticipated at the huge particle surface; this can be augmented by oxidants generated by recruited inflammatory leukocytes. Atheromatous plaques form in the coronary arteries and are major causes of morbidity and death associated epidemiologically with particulate air pollution. In populations exposed to air pollution episodes, blood viscosity, fibrinogen, and C-reactive protein (CRP) were higher. More recently, increases in heart rate in response to rising air pollution have been described and are most marked in individuals who have high blood viscosity. In our study of elderly individuals, there were significant rises in CRP, an index of inflammation. In this present review, we consider the likely interactions between the ultrafine particles the acute phase response and cardiovascular disease.

Acute Disease↗
PubMed2001

The quartz hazard: effects of surface and matrix on inflammogenic activity.

Modification of the quartz surface during the history of the particle is a powerful idea in understanding the variability of the quartz hazard. Interactions between quartz and other minerals are likely to occur in sediments, during industrial processing, or in matrix-bound quartz. We discuss new evidence regarding the basis of changes in the quartz surface that relate to changes in its ability to cause inflammation. Different samples of quartz were subjected to various biological assays. Endpoints included instillation of quartz into the tracheobronchial tree and measurement of PMN numbers in bronchoalveolar lavage (BAL) and in lung tissue, levels of the chemokine MIP-2 in BAL, and nuclear translocation of the transcription factor NF-kappaB in BAL cells. In vitro biological assays included cytotoxicity to epithelial cells, hemolytic activity, and radical activity of the particle surface as measured by electron spin resonance. Treatment of quartz with aluminium lactate impaired its ability to cause PMN recruitment, chemokine release, and NF-kappaB nuclear translocation in BAL. Workplace quartzes had no proinflammatory activity, which correlated with their ability to cause hemolysis but not their electron spin resonance (ESR) activity. Quartz in a matrix with coalmine dust or fly-ash showed different effects. In fly-ash, the toxicity was masked, but coalmine dusts were more toxic to epithelial cells than pure quartz in vitro; however, after instillation, the long-term inflammation was not related to the in vitro activity. Amelioration of quartz surface activity can occur in workplace samples of quartz and quartz samples whose surface is protected, to the extent that they have very little inflammogenic activity and display an inability to activate key subcellular pathways that lead to inflammation. Quartz from a workplace whose surface has been affected, or in a matrix such as coalmine dust or fly-ash, can have its toxicity modulated. These effects are due to minerals and organic compounds that can both decrease (e.g., aluminium salts) or enhance (e.g., coalmine dust matrix) biological activity and thus may contribute to toxicity in a complex way that is not easily predicted. Iron is a good example. There are reports that it can enhance quartz toxicity, or it may have little role to play in its toxicity, as shown here for almost pure quartz particles. A broad program of further research is needed before we have a sound understanding of the mechanisms of quartz toxicity.

Air Pollutants, Occupational↗
PubMed2001

The accessibility of computer-based health information for patients: kiosks and the web.

The Internet is a rich source of health information but it is not as accessible as many claim. This paper brings together three projects to illustrate technical and cost barriers and some options to overcome them. (1) A survey amongst a representative sample of 180 patients in rural Spain showed a marked age gradient in computer access. None over the age of 50 had, and less than 10% planned, access to the Internet whereas a quarter were prepared to use health centre based touchscreen kiosks. (2) Half the commonly used search engines did not include the two most relevant websites for Glasgow colorectal cancer patients in the first ten documents listed, showing the difficulty facing patients in finding relevant information. Selection of information would help patients avoid being overwhelmed with information. (3) One method to improve accessibility is to download websites to kiosks but two projects showed that considerable work is required to reformat the information. Public access computing, such as kiosks, could help make the Internet more accessible. We discuss whether Web sites which structure their information according to method of access, place and person provide a way forward.

Age Factors↗
PubMed2000

Persistent depletion of I kappa B alpha and interleukin-8 expression in human pulmonary epithelial cells exposed to quartz particles.

Chronic inflammation and fibrosis following quartz inhalation has been associated with persistent up-regulation of several "pro-inflammatory" genes, which are commonly regulated by nuclear factor kappa-B (NF-kappaB). Transcription of the NF-kappaB-inhibitor IkappaBalpha is also under NF-kappaB control, and its de novo synthesis is considered to comprise a negative feedback loop in transient inflammation. To investigate this mechanism in particle inflammation, we have studied IkappaBalpha degradation in A549 cells exposed to DQ12-quartz or TiO(2), in relation to the expression of IL-8. Although both quartz and TiO(2) were found to cause IkappaBalpha degradation, only quartz elicited a mild IkappaBalpha depletion, first appearing at 4 h. TiO(2) was found to cause a higher short-term increase in IkappaBalpha mRNA-expression compared to quartz, whereas the early enhancement of IL-8 expression and release was similar for both particles. Up-regulation of IL-8 expression was found to persist with quartz only. Cotreatment with PDTC and curcumin reduced particle-elicited IL-8 response, whereas cycloheximide caused enhancement of IL-8 mRNA expression in both the quartz- and TiO(2)-treated cells. Our results demonstrate that mineral dusts cause IkappaBalpha degradation, a transient increase in de novo synthesis of IkappaBalpha, and enhanced IL-8 expression in human pulmonary epithelial cells. While IkappaBalpha degradation and early IL-8 expression seem to be general particle phenomena, particle-specific characteristics impact on activation of IkappaBalpha gene transcription, apparently accounting for the different proinflammatory IL-8 responses seen with quartz and TiO(2) in the longer term. These observations may provide an explanation for the transient versus the persistent pulmonary inflammatory status and subsequent differences in pathogenic potency of TiO(2) and quartz.

Blotting, Western↗
PubMed2000

Activation of NF-kappaB by PM(10) occurs via an iron-mediated mechanism in the absence of IkappaB degradation.

Exposure to particulate air pollution (PM(10)) is associated with exacerbations of respiratory diseases and increased cardiopulmonary mortality. PM(10) induces lung inflammation in rats, which has been attributed to many factors, including the ultrafine components of PM(10), endotoxins, and transition metals. In this study, we investigated in alveolar epithelial (A549) cells whether PM(10) could activate nuclear factor-kappa B (NF-kappaB), a transcription factor stimulated in response to many proinflammatory agents. Our results show that PM(10) samples from various sites within the United Kingdom cause nuclear translocation, DNA-binding, and transcriptional activation of NF-kappaB in A549 cells. Furthermore, increased NF-kappaB activity was observed in the absence of IkappaB degradation. To evaluate the role of iron, A549 cells were exposed to PM(10) previously treated with phosphate-buffered saline (PBS), deferoxamine mesylate, or deferoxamine plus ferrozine. PBS-treated and, to a lesser extent, deferoxamine-treated PM(10) were able to activate NF-kappaB, whereas this response was completely abrogated in cells exposed to PM(10) treated with both deferoxamine and ferrozine. Moreover, we studied the effects of soluble components of PM(10) on NF-kappaB activation by exposing alveolar epithelial cells to soluble fractions from PM(10) treated with PBS or the metal chelators. We found that, compared with fractions from PBS-treated PM(10) which activated NF-kappaB, fractions from PM(10) treated with deferoxamine and ferrozine did not stimulate NF-kappaB activity above background levels. Coincubation of polymixin B, an endotoxin-binding compound, and PM(10) did not inhibit NF-kappaB. In summary, PM(10) activates NF-kappaB in A549 cells by an iron-mediated mechanism in the absence of IkappaB degradation.

Adenocarcinoma↗
PubMed2000

Asthma and PM10.

PM10 (the mass of particles present in the air having a 50% cutoff for particles with an aerodynamic diameter of 10 microm) is the standard measure of particulate air pollution used worldwide. Epidemiological studies suggest that asthma symptoms can be worsened by increases in the levels of PM10. Epidemiological evidence at present indicates that PM10 increases do not raise the chances of initial sensitisation and induction of disease, although further research is warranted. PM10 is a complex mixture of particle types and has many components and there is no general agreement regarding which component(s) could lead to exacerbations of asthma. However pro-inflammatory effects of transition metals, hydrocarbons, ultrafine particles and endotoxin, all present to varying degrees in PM10, could be important. An understanding of the role of the different components of PM10 in exacerbating asthma is essential before proper risk assessment can be undertaken leading to advice on risk management for the many asthmatics who are exposed to air pollution particles.

Air Pollution↗
PubMed2000

Effects of the aromatase inhibitor anastrozole on serum oestrogens in Japanese and Caucasian women.

PURPOSE: Substantial differences in plasma oestrogen disposition have been reported between Japanese and Caucasian women, but there are currently few data available on the relative endocrinological effects of aromatase inhibitors in these two groups. Hence, the effects of the nonsteroidal aromatase inhibitor anastrozole on serum oestrogen concentrations were compared in 24 healthy postmenopausal Japanese women and 24 healthy postmenopausal Caucasian women. METHODS: Anastrozole, 1 mg/day, was given once daily for 16 days. Serum oestradiol and oestrone sulphate levels were measured on three consecutive days beginning 2 days before the first dose, and on a further three consecutive days beginning on the penultimate day of dosing. Trough concentrations of anastrozole (measured 24 h after dosing) were also determined during the same periods. RESULTS: There were no substantial differences in plasma oestrogen concentrations between the Japanese and Caucasian women at baseline. On average, anastrozole suppressed serum oestradiol and oestrone sulphate levels by approximately 87% and 93%, respectively, for both Japanese and Caucasian women, and minimum plasma anastrozole concentrations at steady-state (anastrozole C(min)) were also similar in both groups. Statistical analysis of serum oestradiol and serum oestrone sulphate levels, and plasma anastrozole C(min) showed that there were no statistically significant differences between the Japanese and Caucasian women. CONCLUSION: Neither the pharmacodynamic effects of anastrozole on serum oestrogens nor the pharmacokinetics of anastrozole differ between postmenopausal Japanese and Caucasian women. Hence, these findings suggest that the therapeutic benefits of anastrozole in Caucasians will be predictive of the drug's effect in Japanese women and support the use of anastrozole in postmenopausal Japanese women with breast cancer.

Aged↗
PubMed2000

Release of TNFalpha in response to SiC fibres: differential effects in rodent and human primary macrophages, and in macrophage-like cell lines.

Asbestos has been implicated in the pathogenesis of several lung diseases, but its mechanism of action is not fully understood. However, asbestos-induced oxidative stress and production of inflammatory cytokines may play a significant role. TNFalpha is an inflammatory cytokine which has a central role in inflammation and fibrosis due to its ability to stimulate fibroblasts and collagen deposition. In this study, a panel of fibres designated either pathogenic or non-pathogenic in recent animal studies, were utilized. The amount of TNFalpha released after a 16-hour exposure to the panel of fibres was compared in four different cell types; two primary macrophage cell types and two cell lines. TNFalpha release by cells exposed to the panel did not equate to pathogenicity, although the most pathogenic fibre caused three out of the four cell types tested, to produce the greatest amount of TNFalpha. Primary rat cells and primary human cells behaved in a similar manner as regards to TNFalpha production; the cell lines behaved quite differently to their primary counterparts with regards to TNFalpha production in this study.

Animals↗