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Biomedical subjects

W MacNee

Publications and source records attributed to W MacNee.

At least 91 records · Page 5Linked to original sources
PubMed1996

Mechanisms of cigarette smoke induced increased airspace permeability.

BACKGROUND: Increased epithelial permeability of the airspaces occurs commonly in the lungs of cigarette smokers. It is likely to be important in augmenting the inflammatory response in the airspaces and hence may have a role in the pathogenesis of emphysema. It has previously been shown that intratracheal instillation of cigarette smoke condensate induces increased epithelial permeability in vivo in rats and in vitro in epithelial cell monolayers, associated with a disturbance in the lung antioxidant, glutathione (GSH). The aim of this study was to assess the role of neutrophils, GSH, and tumour necrosis factor (TNF) in the increased epithelial permeability following intratracheal instillation of cigarette smoke condensate. METHODS: Epithelial permeability of the airspaces was measured in rat lungs as the passage of intratracheally instilled 125-iodine labelled bovine serum albumin (BSA) into the blood. The permeability of a monolayer of human type II alveolar epithelial cells to 125I-BSA was also measured. RESULTS: Cigarette smoke condensate produced a 59.7% increase in epithelial permeability over control values peaking six hours after instillation and returning to control values by 24 hours. Depletion of neutrophils and, to a lesser extent, macrophages by an intraperitoneal injection of antineutrophil antibody did not influence the increased epithelial permeability induced by cigarette smoke condensate. Although instillation of human recombinant TNF alpha produced an increase in epithelial permeability in the rat lung from 0.62 (0.61)% to 1.27 (0.08)%, only a trivial amount of TNF alpha was detected in bronchoalveolar lavage (BAL) fluid in vivo or in culture medium from BAL leucocytes obtained from animals treated with cigarette smoke condensate (94.9 (28.8) units/ml). Furthermore, antiTNF antibody did not abolish the increased epithelial permeability produced by cigarette smoke condensate. The role of GSH was assessed by measuring the changes in both the reduced (GSH) and oxidised form (GSSG) in lung tissue and in BAL fluid. One hour after instillation of cigarette smoke condensate there was a marked fall in the GSH content in the lung (from 809.8 (31.8) to 501.7 (40.5) nmol/g) in association with increased GSSG levels (from 89.8 (2.7) to 148.7 (48.8) nmol/g). This was followed by a return of GSH levels to control values, with a concomitant decrease in GSSG levels six hours after instillation. GSH levels in BAL fluid fell dramatically following cigarette smoke condensate (from 2.56 (0.30) to 0.31 (0.21) nmol/ml) and this fall was sustained up to six hours after instillation of cigarette smoke condensate. CONCLUSIONS: These studies suggest that neutrophils and TNF do not have a major role in the increased epithelial permeability induced by cigarette smoke condensate. However, the data support a role for the depletion of the antioxidant glutathione in the increased epithelial permeability caused by cigarette smoke condensate.

Animals↗
PubMed1996

Salbutamol reduces pulmonary neutrophil sequestration of platelet-activating factor in humans.

To investigate whether salbutamol inhibits platelet-activating factor (PAF)-induced neutrophil sequestration in the lungs, we studied eight nonatopic, nonsmoking, healthy subjects (six men; aged 27.0 +/- 1.5 (SE) yr) with PAF-induced bronchial response. Prior to PAF challenge (24 micrograms), they inhaled either salbutamol (300 micrograms) or placebo in a randomized, double-blind, crossover manner two weeks apart. Respiratory system resistance (Rrs), arterial blood gases, and neutrophil counts were measured 4, 8, 12 and 30 min after PAF. Neutrophil kinetics in the lungs were assessed by tracking autologous 99mTc-erythrocytes and 111in-neutrophils. Compared with salbutamol, arterial blood neutrophil counts fell (p < 0.04) maximally at 4 min after PAF, followed by a mild rebound neutrophilia, whereas Rrs increased (p < 0.01) and Pao2 decreased (p < 0.05) at 4 min only. The intrapulmonary activity of 111in-neutrophils after pretreatment with placebo was higher compared with salbutamol (1.98 +/- 0.15 versus 1.33 +/- 0.23 cps/mCi/pixel) (p < 0.01) although both their initial sequestration (first-pass) and subsequent washout were not significantly different. Inhaled salbutamol blocks pulmonary neutrophil sequestration and lung function abnormalities following PAF challenge in humans.

Administration, Inhalation↗
PubMed1996

Systemic oxidative stress in asthma, COPD, and smokers.

An imbalance between oxidants and antioxidants is proposed in smokers and in patients with airways diseases. We tested this hypothesis by measuring the Trolox equivalent antioxidant capacity (TEAC) of plasma and the levels of products of lipid peroxidation as indices of overall oxidative stress. The plasma TEAC was markedly reduced (0.66 +/- 0.07 mmol/L; mean +/- SEM; n = 11), with increased levels of lipid peroxidation products, in healthy chronic smokers as compared with healthy nonsmokers (1.31 +/- 0.10 mmol/L, n = 14, p < 0.001), an effect that was exaggerated in those who had smoked 1 h before the study. Plasma TEAC was also low in patients presenting with acute exacerbations of chronic obstructive pulmonary disease (COPD) (0.46 +/- 0.10 mmol/L, n = 20, p < 0.001) or asthma (0.61 +/- 0.05 mmol/L, n = 9, p < 0.01) with increases in plasma lipid peroxidation products. There was a negative correlation between superoxide anion release by stimulated neutrophils and plasma antioxidant capacity (r = -0.73, p < 0.001) in patients with acute exacerbations of COPD. The profound decrease in TEAC was associated with a decreased plasma protein sulfhydryl concentrations in acute exacerbations of COPD but not in smokers or in asthmatic subjects. Therefore smoking, acute exacerbations of COPD, and asthma are associated with a marked oxidant/antioxidant imbalance in the blood, associated with evidence of increased oxidative stress. The decreased antioxidant capacity in plasma may result from different mechanisms in these conditions.

Adult↗
PubMed1996

[Evaluation of emphysema progression as measured by computed tomography in patients with chronic obstructive pulmonary disease].

It has been difficult to assess the progression of pulmonary emphysema since accurate quantification of the extent of this condition has only previously been possible on post mortem or resected lungs. Previously we have shown that measurements of CT lung density correlated with the degree of emphysema, measured morphometrically in resected lungs. We have therefore employed this technique to assess the progression of emphysema in 17 patients (12M, 5F) with wide range of chronic airflow limitation (FEV1 15-68% predicted). There was little change in the degree of airflow limitation, hyperinflation or arterial blood gas values over 30 +/- 4 months of follow up (p > 0.05). However during this period there was a significant decrease in the lowest 5th percentile of CT density, which fell from -920 +/- 32 to -940 +/- 36 Hounsfield units (p < 0.005) associated with significant fall in the diffusing capacity for carbon monoxide. We believe that these data show the ability of CT scanning to assess the progression of emphysema in patients with chronic obstructive pulmonary disease.

Aged↗
PubMed1996

[Levels of atrial natriuretic peptide in stable and exacerbated chronic obstructive pulmonary disease].

Plasma Atrial Natriuretic Peptide (ANP) levels are elevated in patients wish chronic obstructive pulmonary disease (COPD) and can play a role in oedema formation. Plasma ANP levels measured in 60 patients with COPD were compared with results of pulmonary haemodynamics, with therapeutic response to treatment in the time of exacerbation of COPD and with physiologic status of patients with stable COPD. Plasma ANP levels did not correlate with right atrial and pulmonary artery pressure, but were significantly related with right ventricular end diastolic volume and with right ventricular wall volume measured by magnetic resonance imaging. Oxygen breathing (2 l/min by nasal prongs in 30 min.) did not change either mean pulmonary artery pressure or ANP levels. Among patients studied during an acute exacerbation of COPD, plasma ANP levels were higher in patients with oedema (302 +/- 185 pg/ml) than in patients without oedema (87 +/- 43 pg/ml). Oxygen therapy applied in one hour did not influence plasma ANP levels. Plasma ANP levels decreased during first three days of treatment in patients with oedema. This decrease was related to the body weight. In the group of patients with hypoxemia in stable COPD, plasma ANP levels (120 +/- 50 pg/ml) were higher in patients with the history of hypercapnia and oedema than in others (54 +/- 15 pg/ml).

Aged↗
PubMed1995

Particulate air pollution and acute health effects.

Epidemiological studies have consistently shown an association between particulate air pollution and not only exacerbations of illness in people with respiratory disease but also rises in the numbers of deaths from cardiovascular and respiratory disease among older people. Meta-analyses of these studies indicate that the associations are unlikely to be explained by any confounder, and suggest that they represent cause and effect. We propose that the explanation lies in the nature of the urban particulate cloud, which may contain up to 100000 nanometer-sized particles per mL, in what may be a gravimetric concentration of only 100-200 micrograms/m3 of pollutant. We suggest that such ultra-fine particles are able to provoke alveolar inflammation, with release of mediators capable, in susceptible individuals, of causing exacerbations of lung disease and of increasing blood coagulability, thus also explaining the observed increases in cardiovascular deaths associated with urban pollution episodes. This hypothesis is testable both experimentally and epidemiologically.

Air Pollutants↗
PubMed1995

Review of the prescription of domiciliary long term oxygen therapy in Scotland.

BACKGROUND: Since 1989 long term oxygen therapy (LTOT) in Scotland has been prescribable only by respiratory physicians, whereas in England and Wales general practitioners can also prescribe this treatment. The effect of this policy has been audited. METHOD: Six hundred and thirty patients were prescribed LTOT in Scotland between 1 October 1989 and 30 September 1991, of which 519 case notes were reviewed. RESULTS: In 79% of patients the diagnosis was chronic obstructive pulmonary disease (COPD), with a near equal male to female ratio. The mean (SD) age was 65 (13) years (range 0.2-90). Sixty percent of patients died during the study period. Compliance with treatment was 14.9 (6.0) hours daily (range 1-24) and in 44% was less than 15 hours daily. Sixty one percent were clinically unstable when assessed and 14% were still smoking. Only 14% of those with COPD fulfilled all of the relative criteria for the prescription of LTOT. Only 56% had a repeated arterial blood gas measurement within 12 months of prescription and 51% of these were taken during a period of clinical instability. Expenditure on oxygen cylinders was six times greater than on oxygen concentrators over this period. CONCLUSIONS: Compliance with LTOT in Scotland, where prescription is the responsibility of respiratory physicians, is similar to other studies and ranges widely. The greatest problem concerning adherence to the guidelines is assessment during clinical instability. The number of deaths suggest that prescription occurs late in the course of the disease. This study highlights the areas where the prescription of LTOT needs to be improved.

Aged↗
PubMed1995

Neutrophil sequestration in rat lungs.

BACKGROUND: The transit of neutrophils through the pulmonary microvasculature is prolonged compared with red blood cells and is increased further during cigarette smoking and in exacerbations of chronic obstructive pulmonary disease. The increased residence time (sequestration) of neutrophils in the pulmonary capillaries in these conditions may be the first step leading to the accumulation of cells within the lung interstitium and in the bronchoalveolar space, so potentiating lung damage. A rat model has been developed to investigate the factors which may influence neutrophil transit through the lung microvasculature. METHODS: Intratracheal instillation of the heat killed organism Corynebacterium parvum was used to induce an acute neutrophil alveolitis. Neutrophils and red blood cells were isolated from donor rats, labelled with two distinct radioisotopes, and then reinjected into recipient rats to assess their transit through the pulmonary circulation. To ascertain whether peripheral blood neutrophils were minimally altered by the isolation procedure their functional status in vitro was compared with that of inflammatory neutrophils in a number of assays commonly used as descriptors of neutrophil activation. The influence of neutrophil activation on the accumulation of cells in the lungs was assessed by comparing the lung sequestration of control neutrophils, isolated from peripheral blood, with that of inflammatory neutrophils obtained from bronchoalveolar lavage of inflamed rat lungs. Lung sequestration of neutrophils was defined as the fold increase in the ratio of neutrophils labelled with chromium-51 to red blood cells labelled with technetium-99m in lung tissue compared with the same ratio in peripheral blood. RESULTS: Sequestration of peripheral blood neutrophils occurred in control rat lungs as shown by a 17.5 (2.1) fold increase in the ratio of neutrophils to red blood cells in the pulmonary circulation compared with the ratio of these cells in the peripheral circulation. When inflammatory neutrophils, obtained by bronchoalveolar lavage from C parvum-treated animals, were injected into control rats, the increase was 90.6 (11.0) fold. Induction of an inflammatory response in the lung tissue of the recipient rat also caused an increase in the sequestration of control neutrophils compared with the same cells in control rat lungs which was, however, less marked than when inflammatory neutrophils were used (34.7 (4.7) fold). The mean (SE) pressure developed on filtration of inflammatory neutrophils in vitro through a millipore filter (7.53 (0.2) cm H2O) was greater than that of peripheral blood neutrophils (1.18 (0.2) cm H2O). Increased filtration pressure indicates a decrease in cell deformability and suggests that this may be a contributory factor to the increased sequestration of inflammatory neutrophils in the pulmonary vasculature. CONCLUSIONS: This study shows that there is sequestration of neutrophils in the pulmonary vasculature in normal rat lungs which increases in acute lung inflammation and when inflammatory neutrophils are injected into control animals. In this model changes in the neutrophil, such as cell deformability, may have a more important role in inducing increased neutrophil sequestration than the inflammatory response in the lungs.

Animals↗
PubMed1995

Glutathione homeostasis in alveolar epithelial cells in vitro and lung in vivo under oxidative stress.

We studied the acute effects of cigarette smoke condensate (CSC), H2O2, and tumor necrosis factor (TNF)-alpha on the glutathione (GSH) redox system in a human type II epithelial cell line (A549) in vitro. CSC, in vitro and in vivo after intratracheal instillation of CSC in the rat, produced a depletion of intracellular soluble GSH, concomitant with GSH-conjugate formation, without significant elevation of oxidized GSH (GSSG), protein-GSH mixed disulfides (PrSSG), nor any GSH efflux from the cells. By contrast, H2O2 (500 microM) after 5-min exposure to A549 cells caused significant depletion of intracellular GSH associated with an efflux of GSSG and a significant increase in the formation of PrSSG. TNF-alpha, in concentrations of 100 U/ml and 1,000 U/ml, produced a significant depletion of GSH in A549 cells after 4- and 24-h exposure, with an associated elevation of GSSG. The activities of glutathione peroxidase, gamma-glutamylcysteine synthetase, and glucose-6-phosphate dehydrogenase were significantly decreased in epithelial cells and in rat lungs after CSC exposure, without change in glutathione S-transferase and glutathione reductase activities. By contrast, H2O2 and TNF-alpha did not alter these enzyme activities in epithelial cells. Thus GSH depletion and alteration in enzyme activities in alveolar epithelial cells by CSC, H2O2, and TNF-alpha occur by different mechanisms.

Animals↗
PubMed1995

The role of tumor necrosis factor in increased airspace epithelial permeability in acute lung inflammation.

Increased airspace epithelial permeability is an early event in lung inflammation and injury. In this study, we have developed a rat model to study the mechanisms of the epithelial permeability to 125iodine-labeled bovine serum albumin (125I-BSA), instilled intratracheally during acute lung inflammation. Epithelial permeability was measured as the percentage of instilled 125I-BSA appearing in the blood. The increase in epithelial permeability induced by intratracheal instillation of heat-killed Corynebacterium parvum produced a peak influx of neutrophils into the bronchoalveolar space at 16 h, which occurred after the peak increase in epithelial permeability (8 h). The increased epithelial permeability induced by C. parvum did not appear to be protease- or oxidant-mediated. Depletion of peripheral blood neutrophils was achieved by an intravenous injection of anti-neutrophil polyclonal antibody. The consequent profound reduction in neutrophil and macrophage influx into the airspaces 8 h after instillation of C. parvum reduced the epithelial permeability to control values. Bronchoalveolar lavage (BAL) leukocytes from rats 8 h, but not 16 h, after treatment with C. parvum caused a modest increase in epithelial permeability when re-instilled intratracheally into control rat lungs. Separation of the leukocytes before re-instillation indicated that macrophages rather than neutrophils were predominantly responsible for the increased epithelial permeability. The presence of dramatically increased levels of tumor necrosis factor (TNF) in BAL 8 h in contrast to a slight increase in BAL 16 h after C. parvum, the release of TNF from 8 h macrophages, the increased epithelial permeability induced by TNF in epithelial monolayers in vitro, and the inhibition of C. parvum-induced epithelial permeability by TNF antibody support the premise that TNF is a major player in the increased epithelial permeability that occurs during C. parvum-induced acute alveolitis.

Acute Disease↗
PubMed1995

Deformability and CD11/CD18 expression of sequestered neutrophils in normal and inflamed lungs.

Neutrophil (PMN) sequestration in the pulmonary microvasculature precedes the migration of these cells into the airspaces in inflamed lungs. Intratracheal instillation of the heat-killed organism Corynebacterium parvum in the rat induces an alveolitis in which PMN constitute 70 to 80% of the total cell count in the bronchoalveolar lavage (BAL). This acute alveolitis results in increased sequestration in the pulmonary microvasculature of 51Cr-labeled PMN when compared with control lungs. The aims of this study were to confirm this increased pulmonary PMN sequestration using unlabeled cells and to assess the function and adhesion molecule expression of such sequestered PMN. We counted the number of PMN and erythrocytes obtained by pulmonary vascular lavage (PVL) and compared the ratio of these two cell types in PVL and peripheral blood (PB) as a measure of the sequestration of PMN in the pulmonary vasculature. Compared with control animals, PVL in C. parvum-treated rats had higher PMN counts, which could not be accounted for by the PB leukocytosis. Sequestration of PMN in the pulmonary microvasculature depends on several factors, including the upregulation of adhesion molecules on both PMN and endothelial surfaces and the ability of the cells to deform when passing through the microcirculation. Cells obtained from the PVL were less deformable than PB cells in control but not in C. parvum-treated animals. The expression of the CD18 integrin on PMN obtained from the PVL of C. parvum-treated animals was increased compared with cells from control animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Effect of N-acetyl cysteine on the concentrations of thiols in plasma, bronchoalveolar lavage fluid, and lung tissue.

BACKGROUND: Oxidant/antioxidant imbalance may occur in the lungs of patients with chronic obstructive pulmonary disease (COPD). Glutathione is an important extracellular and intracellular thiol oxidant in the lungs. These studies were carried out to determine the effect of N-acetyl cysteine on thiol concentrations in plasma, bronchoalveolar lavage fluid, and lung tissue. METHODS: Studies were carried out on normal subjects, patients with COPD, and those undergoing lung resection. In the first study N-acetyl cysteine was given to three groups; healthy subjects (600 mg once daily by mouth) and two groups of patients with COPD. In the first group of patients with COPD the dose was 600 mg once daily and in the second 600 mg thrice daily, all for five days. The latter dosage regimen was also given to six patients before bronchoscopy and to 11 patients before lung resection. Lung glutathione (GSH) levels in bronchoalveolar lavage fluid or lung tissue were compared with the same numbers of patients who did not receive N-acetyl cysteine. RESULTS: N-acetyl cysteine was detected in plasma after a single 600 mg dose in normal subjects and patients with COPD up to 1.5 hours after the drug was given. Plasma cysteine concentrations increased in normal subjects on both days 1 and 5, and in patients with COPD on day 5. Glutathione concentrations in plasma increased on day 1 in normal subjects but not in patients with COPD given 600 mg N-acetyl cysteine daily. With the higher dose of 600 mg thrice daily, however, there was a sustained elevation of GSH concentrations in plasma in patients with COPD. In patients undergoing routine diagnostic bronchoscopy and bronchoalveolar lavage those who were given N-acetyl cysteine (600 mg) thrice daily for five days had higher concentrations of cysteine in the plasma, but no significant differences in cysteine concentrations in bronchoalveolar lavage or epithelial lining fluid compared with a control group; nor were there any differences in reduced glutathione concentrations in plasma, bronchoalveolar lavage or epithelial lining fluids between the control and treated groups. Moreover, in patients undergoing lung resection those treated with N-acetyl cysteine (600 mg thrice daily for five days) had similar concentrations of cysteine and glutathione in both plasma and lung tissue when compared with a control untreated group. CONCLUSIONS: These data suggest that, even when given in high oral doses, N-acetyl cysteine does not produce a sustained increase in glutathione levels sufficient to increase the antioxidant capacity of the lungs.

Acetylcysteine↗
PubMed1994

Effect of cigarette smoke and its condensates on alveolar epithelial cell injury in vitro.

The oxidant-antioxidant balance in the airspaces of the lungs may be critical in protecting the lungs from the effects of cigarette smoke. We studied the effect of cigarette smoke and its condensates on the detachment, attachment, and proliferation of the A549 human alveolar epithelial cell line, in an in vitro model of cell injury and regeneration and the protective effects of antioxidants. Whole and vapor phase cigarette smoke decreased 51Cr-labeled A549 cell attachment, increased cell detachment, and decreased cell proliferation, as assessed by [3H]thymidine uptake. Freshly isolated rat type II alveolar epithelial cells showed an enhanced susceptibility to smoke-induced cell lysis when compared with the A549 cell line. Reduced glutathione (GSH) (400 microM) protected against the effects of cigarette smoke exposure on cell attachment, proliferation, and detachment. Depletion of intracellular GSH with buthionine sulfoxamine enhanced the epithelial cell detachment injury produced by smoke condensates. We conclude that cigarette smoke and its condensates cause an oxidant-induced injury to A549 human type II alveolar epithelial cells. Both intra- and extracellular GSH have important roles in protecting epithelial cells from the injurious effects of cigarette smoke.

Animals↗