PubMed Health⌕ Search

Biomedical subjects

William MacNee

Publications and source records attributed to William MacNee.

At least 19 recordsLinked to original sources
PubMed2006

Permeability, inflammation and oxidant status in airspace epithelium exposed to ozone.

The aim of the study was to investigate possible mechanisms of epithelial injury in normal subjects exposed to environmentally relevant concentrations of ozone. Fifteen healthy non-smoking subjects (M:F 12:3) were studied. Five of the 15 subjects were exposed to filtered air, six were exposed to ozone 100 parts per billion (ppb) and seven were exposed to ozone 400 ppb with 99mtechnetium labelled diethylene-triamine-penta-acetate (99mTc-DTPA) or bronchoalveolar lavage (BAL) performed 1 or 6 h after exposure as indicated above. All the above studies were performed on different occasions at least 5 days apart. The subjects were exposed on each occasion for 1h during intermittent exercise at a ventilation of 40l min-1. 99mTc-DTPA lung clearance did not change after either level of ozone exposure, but neutrophils increased in BAL 6 h after exposure to 400 ppb. Superoxide anion release from mixed BAL leucocytes decreased 1 h after 100 ppb and 6 h after 400 ppb. Products of lipid peroxidation in epithelial lining fluid decreased both 1 and 6 h after 400 ppb. There was no change in anti-oxidant capacity or glutathione concentrations. Ozone exposure did not increase epithelial permeability, but was associated with neutrophil influx into the airspaces, without evidence of increased oxidative stress.

Adult↗
PubMed2006

Inflammatory lung secretions inhibit dendritic cell maturation and function via neutrophil elastase.

RATIONALE: Continuous episodes of infection are a feature of lung diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). Lung antigen-presenting dendritic cells (DCs) sample inhaled antigen to initiate immune responses. Therefore, we hypothesized that inflammatory mediators, such as neutrophil elastase (NE) released into the lung, may be able to modulate their activity. OBJECTIVE: To determine whether sputum (from patients with COPD and those with CF) or NE can alter DC phenotype and function. METHOD: NE and sputum samples were incubated with immature or mature murine DCs (mDCs). DC phenotype and function were studied by fluorescence-activated cell sorter and Western Blot analysis, assessing their expression of costimulatory molecules and their ability to induce T cell proliferation. RESULTS: COPD/CF sputum samples and human NE downregulated the expression of CD40, CD80, and CD86 (but not major histocompatibility complex II) on DCs and inhibited LPS-induced DC maturation. This effect was partially (sputa) to significantly (NE) reversed by addition of recombinant secretory leukocyte protease inhibitor. Western Blot analysis showed that purified NE degraded CD86 in mDC lysates in a time- and dose-dependent fashion, and caused shedding of CD86 into the supernatants of mDC cultures. NE treatment also inhibited the antigen-presenting ability of mDCs, as measured by their ability to induce ovalbumin-specific D011.10-transgenic T-cell proliferation. CONCLUSIONS: Our data indicate that NE in lung inflammatory secretions of patients with COPD/CF may disable DCs and prevent them from mounting an adequate immune response. This may have implications for the infection-driven generation of disease exacerbations in these two pathologies.

Adult↗
PubMed2006

The effect of smoking on the transcriptional regulation of lung inflammation in patients with chronic obstructive pulmonary disease.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is believed to result from an abnormal inflammatory response in the lungs to noxious particles and gases usually found in cigarette smoke. OBJECTIVES: In this study, the molecular mechanisms for the enhanced proinflammatory cytokine gene transcription in COPD were investigated. METHODS: Lung tissue was examined from 56 subjects undergoing resection for peripheral lung tumors as follows: current smokers with (n = 14) and without COPD (n = 17), ex-smokers with COPD (n = 13), and nonsmokers (n = 12). The levels of inhibitor kappaB-alpha (IkappaB-alpha), histone deacetylase 2 (HDAC2), acetylated (ac-) histone H3 and H4, the transcription factor nuclear factor-kappaB (NF-kappaB), proinflammatory cytokine messenger RNA, and 8-isoprostane were measured. MEASUREMENTS AND MAIN RESULTS: IkappaB-alpha levels were significantly decreased in healthy smokers and current and ex-smoking patients with COPD when compared with nonsmokers (p < 0.001), with an associated increase in NF-kappaB DNA binding in current smokers (p < 0.05). An increase in acetylated histone 4 (ac-H4; p < 0.01) was found in current smokers. Conversely, ex-smokers with COPD showed an increase in ac-H3 (p < 0.05). Decreased levels of cytoplasmic, but not nuclear, HDAC2 protein levels were detected. From the cytokine profiles, no significant differences were detected; however, interleukin-12p40 expression correlated with ac-H4 in current smokers with COPD (p < 0.01). CONCLUSION: These data propose a role for modification of nucleosomal structure in inflammatory cytokine gene transcription in response to smoking. The imbalance between histone deacetylation and acetylation in favor of acetylation may contribute to the enhanced inflammation in smokers susceptible to the development of COPD.

Aged↗
PubMed2006

Cryptic haplotypes of SERPINA1 confer susceptibility to chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a major cause of mortality and morbidity worldwide. While cigarette smoking is a major cause of COPD, only 15% of smokers develop the disease, indicating major genetic influences. The most widely recognized candidate gene in COPD is SERPINA1, although it has been suggested that SERPINA3 may also play a role. To detect cryptic genetic variants that might contribute to disease, we identified 15 SNP haplotype tags from high-density SNP maps of the two genes and evaluated these SNPs in the largest case-control genetic study of COPD conducted so far. For SERPINA1, six newly identified haplotypes with a common backbone of five SNPs were found to increase the risk of disease by six- to 50-fold, the highest risk of COPD reported to date. In contrast, no haplotype associations for SERPINA3 were identified.

Aged↗
PubMed2006

[Pathogenesis of chronic obstructive pulmonary disease. Cellular mechanisms (part I)].

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Smoking is considered the major cause of the disease. All smokers develop airway inflammation through oxidative stress with macrophages, neutrophiles, lymphocytes, eosinophils, NK-cells and mediators involved. Macrophages through the activation of Nuclear Factor kappa B (NF.-kappaB) release proinflammatory mediators, lymphocyte chemotactic agents and elastolytic enzymes, activate neutrophil driven serine proteases and GM-CSF. Neutrophiles release IL-8 which in turn recruits neutrophils to the airways. In response to cigarette smoke lung epithelium may release TNF-alpha, TGF-beta, IL-1beta, GM-CSF, IL-8 reactive oxygen species (ROS). Increased number of lymphocyte T CD8+ and CD4+ subpopulations may lead to lung epithelium cells apoptosis and necrosis through perphorines and granzyme-B and TNF-alpha activation. Moreover, increased expression of IL-6, IL-10, IL-12, IL-13, and INF-gamma is observed. Authors indicate the possibility of new treatment strategies such as: agents directed against adhesion molecules, chemokines, phosphodiesterase 4, p38 MAPK, NF.-kappaB phosphoinositide-3-kinase gamma, TGF-beta, NOS synthase, serine proteinases and matrix metalloproteinases.

Antigens, CD↗
PubMed2006

[Pathogenesis of chronic obstructive pulmonary disease. Molecular mechanisms (part II)].

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Smoking is considered the major cause of the disease. Relatively little is known about the molecular mechanisms underlying inflammatory response in smokers' lungs and how this relates to the susceptibility to the disease, particularly why only 10-15% of smokers develop COPD. Recent development in molecular biology techniques allowed the insight into the inner space of the cell, to the levels far beyond the reach of the traditional methods. We review recent hypotheses on cellular and molecular background of COPD with emphasis on the potential role of histone acetylation, as a key modulator of enhanced gene transcription responsible for proinflammatory cytokines production in COPD. Authors propose a role for modification of nucleosomal structure in inflammatory cytokine gene transcription in response to smoking. Cigarette smoke causes oxidative stress altering the balance between histone deacetylation and acetylation in favor of acetylation. This can contribute to the airflow obstruction in smokers susceptible to the development of COPD. Furthermore, histone acetylation seems to be a potential mechanism exclusive to smokers with susceptibility to COPD based on the transcription of specific pro- and anti-inflammatory cytokine combinations.

Cytokines↗
PubMed2005

Diesel exhaust inhalation causes vascular dysfunction and impaired endogenous fibrinolysis.

BACKGROUND: Although the mechanisms are unknown, it has been suggested that transient exposure to traffic-derived air pollution may be a trigger for acute myocardial infarction. The study aim was to investigate the effects of diesel exhaust inhalation on vascular and endothelial function in humans. METHODS AND RESULTS: In a double-blind, randomized, cross-over study, 30 healthy men were exposed to diluted diesel exhaust (300 microg/m3 particulate concentration) or air for 1 hour during intermittent exercise. Bilateral forearm blood flow and inflammatory factors were measured before and during unilateral intrabrachial bradykinin (100 to 1000 pmol/min), acetylcholine (5 to 20 microg/min), sodium nitroprusside (2 to 8 microg/min), and verapamil (10 to 100 microg/min) infusions 2 and 6 hours after exposure. There were no differences in resting forearm blood flow or inflammatory markers after exposure to diesel exhaust or air. Although there was a dose-dependent increase in blood flow with each vasodilator (P<0.0001 for all), this response was attenuated with bradykinin (P<0.05), acetylcholine (P<0.05), and sodium nitroprusside (P<0.001) infusions 2 hours after exposure to diesel exhaust, which persisted at 6 hours. Bradykinin caused a dose-dependent increase in plasma tissue plasminogen activator (P<0.0001) that was suppressed 6 hours after exposure to diesel (P<0.001; area under the curve decreased by 34%). CONCLUSIONS: At levels encountered in an urban environment, inhalation of dilute diesel exhaust impairs 2 important and complementary aspects of vascular function in humans: the regulation of vascular tone and endogenous fibrinolysis. These important findings provide a potential mechanism that links air pollution to the pathogenesis of atherothrombosis and acute myocardial infarction.

Adult↗
PubMed2005

Cigarette smoke disrupts VEGF165-VEGFR-2 receptor signaling complex in rat lungs and patients with COPD: morphological impact of VEGFR-2 inhibition.

VEGF is fundamental in the development and maintenance of the vasculature. VEGF(165) signaling through VEGF receptor (VEGFR)-2/kinase insert domain receptor (KDR) is a highly regulated process involving the formation of a tertiary complex with glypican (GYP)-1 and neuropilin (NRP)-1. Both VEGF and VEGFR-2 expression are reduced in emphysematous lungs; however, the mechanism of regulation of VEGF(165) signaling through the VEGFR-2 complex in response to cigarette smoke exposure in vivo, and in smokers with and without chronic obstructive pulmonary disease (COPD), is still unknown. We hypothesized that cigarette smoke exposure disrupts the VEGF(165)-VEGFR-2 complex, a potential mechanism in the pathogenesis of emphysema. We show that cigarette smoke exposure reduces NRP-1 and GYP-1 as well as VEGF and VEGFR-2 levels in rat lungs and that VEGF, VEGFR-2, GYP-1, and NRP-1 expression in the lungs of both smokers and patients with COPD are also reduced compared with nonsmokers. Moreover, our data suggest that specific inhibition of VEGFR-2 alone with NVP-AAD777 would appear not to result in emphysema in the adult rat lung. As both VEGF(165) and VEGFR-2 expression are reduced in emphysematous lungs, decreased GYP-1 and NRP-1 expression may yet further disrupt VEGF(165)-VEGFR-2 signaling. Whether or not this by itself is critical for inducing endothelial cell apoptosis and decreased vascularization of the lung seen in emphysema patients is still unclear at present. However, targeted therapies to restore VEGF(165)-VEGFR-2 complex may promote endothelial cell survival and help to ameliorate emphysema.

Animals↗
PubMed2005

High-dose acetylcysteine in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis is a chronic progressive disorder with a poor prognosis. METHODS: We conducted a double-blind, randomized, placebo-controlled multicenter study that assessed the effectiveness over one year of a high oral dose of acetylcysteine (600 mg three times daily) added to standard therapy with prednisone plus azathioprine. The primary end points were changes between baseline and month 12 in vital capacity and in single-breath carbon monoxide diffusing capacity (DL(CO)). RESULTS: A total of 182 patients were randomly assigned to treatment (92 to acetylcysteine and 90 to placebo). Of these patients, 155 (80 assigned to acetylcysteine and 75 to placebo) had usual interstitial pneumonia, as confirmed by high-resolution computed tomography and histologic findings reviewed by expert committees, and did not withdraw consent before the start of treatment. Fifty-seven of the 80 patients taking acetylcysteine (71 percent) and 51 of the 75 patients taking placebo (68 percent) completed one year of treatment. Acetylcysteine slowed the deterioration of vital capacity and DL(CO): at 12 months, the absolute differences in the change from baseline between patients taking acetylcysteine and those taking placebo were 0.18 liter (95 percent confidence interval, 0.03 to 0.32), or a relative difference of 9 percent, for vital capacity (P=0.02), and 0.75 mmol per minute per kilopascal (95 percent confidence interval, 0.27 to 1.23), or 24 percent, for DL(CO) (P=0.003). Mortality during the study was 9 percent among patients taking acetylcysteine and 11 percent among those taking placebo (P=0.69). There were no significant differences in the type or severity of adverse events between patients taking acetylcysteine and those taking placebo, except for a significantly lower rate of myelotoxic effects in the group taking acetylcysteine (P=0.03). CONCLUSIONS: Therapy with acetylcysteine at a dose of 600 mg three times daily, added to prednisone and azathioprine, preserves vital capacity and DL(CO) in patients with idiopathic pulmonary fibrosis better than does standard therapy alone.

Acetylcysteine↗
PubMed2005

Combustion-derived nanoparticles: a review of their toxicology following inhalation exposure.

This review considers the molecular toxicology of combustion-derived nanoparticles (CDNP) following inhalation exposure. CDNP originate from a number of sources and in this review we consider diesel soot, welding fume, carbon black and coal fly ash. A substantial literature demonstrates that these pose a hazard to the lungs through their potential to cause oxidative stress, inflammation and cancer; they also have the potential to redistribute to other organs following pulmonary deposition. These different CDNP show considerable heterogeneity in composition and solubility, meaning that oxidative stress may originate from different components depending on the particle under consideration. Key CDNP-associated properties of large surface area and the presence of metals and organics all have the potential to produce oxidative stress. CDNP may also exert genotoxic effects, depending on their composition. CDNP and their components also have the potential to translocate to the brain and also the blood, and thereby reach other targets such as the cardiovascular system, spleen and liver. CDNP therefore can be seen as a group of particulate toxins unified by a common mechanism of injury and properties of translocation which have the potential to mediate a range of adverse effects in the lungs and other organs and warrant further research.

Journal Article↗
PubMed2005

Role of inflammation in cardiopulmonary health effects of PM.

The relationship between increased exposure to PM and adverse cardiovascular effects is well documented in epidemiological studies. Inflammation in the lungs, caused by deposited particles, can be seen as a key process that could mediate adverse effects on the cardiovascular system. There are at least three potential pathways that could lead from pulmonary inflammation to adverse cardiovascular effects. Firstly, inflammation in the lung could lead to systemic inflammation, which is well known to be linked to sudden death from cardiovascular causes. Systemic inflammation can lead to destabilization by activation of inflammatory processes in atheromatous plaques. Secondly, inflammation can cause an imbalance in coagulation factors that favor propagation of thrombi if thrombosis is initiated. Thirdly, inflammation could affect the autonomic nervous system activity in ways that could lead to alterations in the control of heart rhythm which could culminate in fatal dysrhythmia.

Air Pollutants↗
PubMed2005

Pulmonary and systemic oxidant/antioxidant imbalance in chronic obstructive pulmonary disease.

An imbalance between oxidants and antioxidants is considered to play a role in the pathogenesis of chronic obstructive pulmonary disease (COPD). There is considerable evidence that an increased oxidative burden occurs in the lungs of patients with this disorder, and this may be involved in many of the pathogenic processes, such as direct injury to lung cells, mucus hypersecretion, inactivation of antiproteases, and enhancing lung inflammation through activation of redox-sensitive transcription factors. COPD is now recognized to have multiple systemic consequences, such as weight loss and skeletal muscle dysfunction. Moreover, it is appreciated that oxidative stress extends beyond the lung and may, through similar oxidative stress mechanisms as those in the lung, contribute to several of the systemic manifestations in COPD.

Airway Obstruction↗
PubMed2005

Pathogenesis of chronic obstructive pulmonary disease.

The current paradigm for the pathogenesis of chronic obstructive pulmonary disease is that chronic airflow limitation results from an abnormal inflammatory response to inhaled particles and gases in the lung. Airspace inflammation appears to be different in susceptible smokers and involves a predominance of CD8+ T lymphocytes, neutrophils, and macrophages. Studies have characterized inflammation in the peripheral airspaces in different stages of disease severity. Two other processes have received considerable research attention. The first is a protease-antiprotease imbalance, which has been linked to the pathogenesis of emphysema. However, the hypothesis of an increased protease burden associated with functional inhibition of antiproteases has been difficult to prove and is now considered an oversimplification. The second process, oxidative stress, has a role in many of the pathogenic processes of chronic obstructive pulmonary disease and may be one mechanism that enhances the inflammatory response. In addition, it has been proposed that the development of emphysema may involve alveolar cell loss through apoptosis. This mechanism may involve the vascular endothelial growth factor pathway and oxidative stress.

Animals↗
PubMed2004

Lack of systemic oxidative stress during PAF challenge in mild asthma.

To further establish the role of oxidative stress in the pathogenesis of acute bronchial asthma, we investigated the effects of platelet-activating factor (PAF) challenge on systemic oxidant-antioxidant balance in 12 asthmatic patients (age, 25+/-3[SEM] yr; FEV1, 95+/-10% predicted), using a double blinded, controlled with Lyso-PAF (L-PAF), cross-over design. Respiratory system resistance (Rrs), arterial blood gases, peripheral blood neutrophils and oxidant-antioxidant balance, including thiobarbituric acid (TBA)-malondialdehyde (MDA) adducts, protein sulphydryls and Trolox equivalent antioxidant capacity (TEAC), were assessed at baseline and 5, 15 and 45 min after PAF and L-PAF (18 microg each) bronchoprovocation. Urinary leukotriene E4 (uLTE4) elimination was measured 120 min after challenge. Compared with baseline, as expected, PAF increased significantly Rrs and AaPO2 and decreased PaO2 and peripheral blood neutrophils along with a rebound neutrophilia and increased uLTE4. By contrast, markers of systemic oxidative stress remained unaltered throughout the study. Unlike PAF, L-PAF-induced changes were negligible. We conclude that there is no systemic oxidant-antioxidant imbalance during acute bronchoconstriction induced by PAF in these patients with mild asthma.

Administration, Inhalation↗
PubMed2004

Soluble transition metals cause the pro-inflammatory effects of welding fumes in vitro.

Epidemiological studies have consistently reported a higher incidence of respiratory illnesses such as bronchitis, metal fume fever (MFF), and chronic pneumonitis among welders exposed to high concentrations of metal-enriched welding fumes. Here, we studied the molecular toxicology of three different metal-rich welding fumes: NIMROD 182, NIMROD c276, and COBSTEL 6. Fume toxicity in vitro was determined by exposing human type II alveolar epithelial cell line (A549) to whole welding fume, a soluble extract of fume or the "washed" particulate. All whole fumes were significantly toxic to A549 cells at doses >63 microg ml(-1) (TD 50; 42, 25, and 12 microg ml(-1), respectively). NIMROD c276 and COBSTEL 6 fumes increased levels of IL-8 mRNA and protein at 6 h and protein at 24 h, as did the soluble fraction alone, whereas metal chelation of the soluble fraction using chelex beads attenuated the effect. The soluble fraction of all three fumes caused a rapid depletion in intracellular glutathione following 2-h exposure with a rebound increase by 24 h. In addition, both nickel based fumes, NIMROD 182 and NIMROD c276, induced significant reactive oxygen species (ROS) production in A549 cells after 2 h as determined by DCFH fluorescence. ICP analysis confirmed that transition metal concentrations were similar in the whole and soluble fractions of each fume (dominated by Cr), but significantly less in both the washed particles and chelated fractions. These results support the hypothesis that the enhanced pro-inflammatory responses of welding fume particulates are mediated by soluble transition metal components via an oxidative stress mechanism.

Air Pollutants, Occupational↗
PubMed2004

Pulmonary and systemic effects of short-term inhalation exposure to ultrafine carbon black particles.

While environmental particles are associated with mortality and morbidity related to pulmonary and cardiovascular (CV) disease, the mechanisms involved in CV health effects are not known. Changes in systemic clotting factors have been associated with pulmonary inflammation. We hypothesized that inhaled ultrafine particles result in an inflammatory response which may stimulate systemic clotting factor release. Adult male Wistar rats were exposed to either fine or ultrafine carbon black (CB) for 7 h. The attained total suspended particle concentrations were 1.66 mg/m(3) for ultrafine CB and 1.40 mg/m(3) for fine CB. Particle concentration of ultrafine particles was more than 10 times greater than that of fine particles and the count median aerodynamic diameter averaged 114 nm for the ultrafine and 268 nm for the fine carbon particles. Data were collected immediately, 16 and 48 h following exposure. Only ultrafine CB caused an increase in total bronchoalveolar lavage (BAL) leukocytes, whereas both fine (2-fold) and ultrafine (4-fold) carbon particles caused an increase in BAL neutrophils at 16 h postexposure. Exposure to the ultrafine, but not fine, carbon was also associated with significant increases in the total numbers of blood leukocytes. Plasma fibrinogen, factor VII and von Willebrand factor (vWF) were unaffected by particle treatments as was plasma Trolox equivalent antioxidant status (TEAC). Macrophage inflammatory protein-2 mRNA was significantly increased in BAL cells 48 h following exposure to ultrafine CB. The data show that there is a small but consistent significant proinflammatory effect of this exposure to ultrafine particles that is greater than the effect of the same exposure to fine CB.

Administration, Inhalation↗