[show abstract][hide abstract] ABSTRACT: Lung exposure to metal oxide nanoparticles (NPs) comprising soluble metal haptens may produce T-helper cell type 1 (Th1)- and Th17-associated delayed-type hypersensitivity (DTH) responses and pulmonary alveolar proteinosis (PAP). In order to study this, haptenic metal oxide NPs (NiO, Co(3)O(4), Cr(2)O(3) and CuO) were instilled into the lungs of female Wistar rats, and the immunoinflammatory responses were assessed at 24 h and 4 weeks post-instillation. Primary culture of alveolar macrophages from Wistar rats was used to evaluate the effect of the NPs on the ability to clear surfactant. NiO NPs induced chronic interstitial inflammation and pro-inflammatory Th1 and Th17 immune responses characterised by increases in the cytokines monocyte chemotactic protein (MCP)-1/CCL2, interleukin (IL)-12 p40, interferon-γ and IL-17A, whilst similar pathological responses induced by Co(3)O(4) NPs were associated with increases in MCP-1/CCL2 and IL-12 p40. However, neither Cr(2)O(3) nor CuO NPs elicited immunoinflammatory reactions. PAP was induced by both NiO and Co(3)O(4) NPs during the chronic phase. PAP was associated with over-production of surfactant by proliferation of type II cells and impaired clearance of surfactant by macrophages. These findings have implications for the risk management of occupational NP exposure and provide evidence that haptenic metal oxide NPs can induce chronic progressive lung immune responses via a DTH-like mechanism.
European Respiratory Journal 08/2011; 39(3):546-57. · 6.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: Simultaneous monitoring of respiratory function and activity level would be of benefit in the monitoring of chronic conditions such as chronic obstructive pulmonary disorder (COPD), but is ill-addressed by existing methods. Current solutions for monitoring respiratory function are obtrusive and not suitable for pervasive monitoring in the home, while existing activity monitors, not equipped to measure parameters of respiration, do not differentiate between causes of sedentary behaviour. Previous work has validated a method for obtaining angular rates of breathing motion of the chest wall using a tri-axial accelerometer against nasal pressure. We have used this method to perform respiratory monitoring during periods of low activity while simultaneously monitoring activity using a single wireless device. We observe that the optimal placement for respiratory monitoring does not preclude successful activity monitoring. We propose an activity monitoring algorithm based on direct estimation of motion energy observed by the device. We show favourable comparison against three commercial activity monitors validated against indirect calorimetry during a programme of exercise activities in healthy subjects.
Body Sensor Networks (BSN), 2011 International Conference on; 06/2011
[show abstract][hide abstract] ABSTRACT: Lung exposure to metal oxide nanoparticles (NP) comprising soluble metal haptens may produce Type 1 helper T cells (Th1) and Type 17 helper T cells (Th17) associated delayed-type hypersensitivity (DTH) responses and pulmonary alveolar proteinosis (PAP). In order to study this, haptenic metal oxide NP (NiO, Co3O4, Cr2O3, and CuO) were instilled into the lungs of female Wistar rats and the immuno-inflammatory responses were assessed at 24 hours and 4 weeks post-instillation. Primary culture of alveolar macrophages from Wistar rats was used to evaluate the effect of the NP on the ability to clear surfactant. NiONP induced chronic interstitial inflammation and pro-inflammatory Th1 and Th17 immune responses characterized by increases in the cytokines MCP-1/CCL2, IL-12+p40, IFN-gamma, and IL-17A, whilst similar pathological responses induced by Co3O4NP were associated with increases in MCP-1/CCL2 and IL-12+p40. However, neither Cr2O3NP nor CuONP elicited immuno-inflammatory reactions. PAP was induced by both NiONP and Co3O4NP at the chronic phase. PAP was associated with over-production of surfactant by proliferation of type II cells and impaired clearance of surfactant by macrophages. These findings have implications for the risk management of occupational NP exposure and provide evidence that haptenic metal oxide NP can induce chronic progressive lung immune responses via a DTH-like mechanism
[show abstract][hide abstract] ABSTRACT: Computed tomography (CT) scanning allows precise assessment of both the extent and distribution of emphysema. There has been little work on the relationship between the distribution of emphysema and clinical features of the disease. The current study investigated the association between clinical features and distribution of emphysema. A total of 129 patients with smoking-related chronic obstructive pulmonary disease underwent CT assessment of the extent and distribution of their emphysema (core/rind and upper/lower zone predominance). Emphysema was found predominantly in the upper/core zone and this distribution was related to the extent of disease. Core predominance was associated with lower forced expiratory volume in one second (FEV(1)), FEV(1)/forced vital capacity ratio and body mass index (BMI); and with higher BODE (BMI, airflow obstruction, dyspnoea and exercise capacity) index and Medical Research Council dyspnoea score. Upper-zone predominance was associated with female sex and an increased total St George's Respiratory Questionnaire score. Using multiple linear regression age, sex and whole lung emphysema severity were independently associated with core/rind distribution, while sex and whole lung emphysema severity were independently related to upper/lower distribution. Distribution of emphysema related best to clinical features when divided into core/rind predominance. However, the effects were not independent of the extent of emphysema. Increased age and female sex were related to disease distribution independent of emphysema severity. These findings may be related to differences in development of emphysema.
European Respiratory Journal 11/2008; 33(3):536-42. · 6.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: The genetic factors that contribute to the development of chronic obstructive pulmonary disease (COPD) are poorly understood. Many candidate genes have been proposed, including enzymes that protect the lung against oxidative stress, such as microsomal epoxide hydrolase (EPHX1) and glutamate-cysteine ligase (GCL). To date, most reported findings have been for EPHX1, particularly in relation to functional variants associated with fast and slow metabolism of epoxide intermediates. The present study aimed to identify any association of variation in these genes with COPD susceptibility or severity. In total, 1,017 white COPD patients and 912 nondiseased age and sex matched smoking controls were genotyped for six single nucleotide polymorphisms (SNPs) in EPHX1 (including the fast and slow variants and associated haplotypes), and eight SNPs in the two genes encoding GCL. GCL is a rate-limiting enzyme in the synthesis of glutathione, a major contributor to anti-oxidant protection in the lung. No association of variation was found in EPHX1 or GCL with susceptibility to COPD or disease severity. This is the largest reported study to date and is well powered to detect associations that have been previously suggested. The current data indicate that these genetic variants are unlikely to be related to susceptibility or disease severity in white chronic obstructive pulmonary disease patients.
European Respiratory Journal 08/2008; 32(4):931-7. · 6.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: Chronic obstructive pulmonary disease (COPD) is associated with a 2-3-fold increase in the risk of ischaemic heart disease, stroke and sudden death. The mechanisms responsible for this association are not clear and appear to be independent of smoking history.
We test the hypothesis that patients with COPD have increased arterial stiffness and blood pressure in comparison with age and smoking matched controls.
In a prospective case control study, we recruited 102 patients with COPD and 103 healthy controls matched for age and smoking status. Patients were assessed by clinical history and spirometry, with arterial stiffness and blood pressure determined using radial artery applanation tonometry and sphygmomanometry.
Patients with COPD had increased arterial stiffness compared with matched controls, with elevated augmentation pressure (17 (1) vs 14 (1) mm Hg; p = 0.005) and a reduced time to wave reflection (131 (1) vs 137 (2) ms; p = 0.004). These differences were associated with increases in both diastolic (82 (1) vs 78 (1) mm Hg; p = 0.005) and systolic blood pressure (147 (2) vs 132 (2) mm Hg; p<0.001). Serum C reactive protein concentrations were threefold higher in patients (6.1 (0.9) vs 2.3 (0.4) mg/l; p = 0.001). Data are presented as mean (SEM).
Patients with COPD have increased arterial stiffness and blood pressure in comparison with controls matched for age and smoking status. We speculate that increased systemic inflammation and vascular dysfunction could potentially explain the excess cardiovascular morbidity and mortality associated with COPD.
[show abstract][hide abstract] ABSTRACT: The epidemiological association between cancer and exposure to ambient air pollution particles (particles with a 50% cut-off aerodynamic diameter of 10 microm (PM(10))) has been related to the ability of PM(10) and its constituent nanoparticles (NPs) to cause reactive oxidative species (ROS)-driven DNA damage. However, there are no data on the molecular response to these genotoxic effects. In order to assess whether PM(10), NP and ROS-driven DNA damage induce carcinogenesis pathways, A549 cells were treated with tert-butyl-hyperperoxide (Tbh), urban dust (UD), carbon black (CB), nanoparticulate CB (NPCB), benzo(a)pyrene (BaP) and NPCB coated with BaP for <or=24 h. Single- and double-strand breakage of DNA was determined by comet assay; cell cycle status was analysed using flow cytometry. Nuclear extracts or acid-extracted histones were used for Western blot analysis of p-ser15-p53 (p53 phosphorylated at ser15), p53 binding protein (53BP) 1, phospho-histone H2A.X (p-H2A.X) and phospho-BRCA1 (p-BRCA1). UD caused both single- and double-strand DNA breaks, while other tested NPs caused only single-strand DNA breaks. NPs significantly altered cell cycle kinetics. Tbh enhanced p-H2A.X after 1 and 6 h (2.1- and 2.2-fold, respectively). NP increased 53BP1 expression at 1 h (2.4-8.7-fold) and p-BRCA1 at 1-6 h. N-acetylcysteine blocked NP-driven p-ser15-p53 response. In conclusion, nanoparticles and reactive oxidative species induce DNA damage, activating p53 and proteins related to DNA repair, mimicking irradiation-related carcinogenesis pathways.
European Respiratory Journal 02/2008; 31(2):241-51. · 6.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: To assess whether nanoparticle (NP) driven DNA damage induces the expression of proinflammatory transcription factors such as NFB and AP-1 A549, lung epithelial cells were treated with Carbon Black (CB), nanoparticulate CB (NPCB), NPCB coated with BaP (BaP-NPCB) for various times ranging from 30 min to 24 h. DNA strand break was determined by the comet assay and cell cycle status was analyzed using flow cytometry. Nuclear extracts were used for WB analysis of P approximately Ser15-p53. EMSA was used to detect DNA binding. Tested NP caused single strand breaks and significantly altered cell cycle kinetics. NF-kappaB and AP-1 DNA binding were increased at early time points (2.3 and 2.6 fold at 1 hour, respectively). Effects were also found on Ser15-p53 phosphorylation. N-acetylcysteine blocked NP driven effects. In conclusion, NPCB and BaP-NPCB induce DNA damage, activating p53, proteins related to DNA repair and proinflammatory transcription factors.
Journal of physiology and pharmacology: an official journal of the Polish Physiological Society 12/2007; 58 Suppl 5(Pt 2):461-70. · 2.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: cAMP responsive element binding protein (CREB) plays an important role in transcriptional machinery. CREB signaling is altered in patients with asthma. However, the role of CREB in chronic obstructive pulmonary disease (COPD) is less clear. In the present study we assessed changes in subcellular CREB distribution and activation (CREB-P) in 35 stable COPD patients treated with formoterol (F), formoterol+budesonide (F/ICS), and formoterol+budesonide+theophylline (F/ICS/Th) b.i.d. for 4 weeks, using SDS-PAGE/WB in cytosol and nuclear extracts of induced sputum cells. The expression of CREB was increased after F/ICS in both cytosolic and nuclear fractions by about 40% and 24%, respectively (P<0.001, P<0.01), while CREB-P increased after F/ICS by about 50% (P<0.01) in both compartments. These changes were not affected by theophylline. In F/ICS-treated patients, relative accumulation of CREB in cytosol was observed. These findings indicate, that poor response to ICS therapy may be related to increased CREB-associated signaling.
Journal of physiology and pharmacology: an official journal of the Polish Physiological Society 12/2007; 58 Suppl 5(Pt 2):437-44. · 2.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: Telomeres are complex DNA-protein structures located at the end of eukaryotic chromosomes. Telomere length shortens with age in all replicating somatic cells. It has been shown that tobacco smoking enhances telomere shortening in circulating lymphocytes. The present study investigated whether this effect was further amplified in smokers who develop chronic obstructive pulmonary disease. Telomere length was determined by fluorescence in situ hybridisation in circulating lymphocytes harvested from 26 never-smokers, 24 smokers with normal lung function and 26 smokers with moderate-to-severe airflow obstruction (forced expiratory flow in one second 48+/-4% predicted). In contrast to never-smokers, telomere length significantly decreased with age in smokers. There was also a dose-effect relationship between the cumulative long-life exposure to tobacco smoking (pack-yrs) and telomere length. The presence and/or severity of chronic airflow obstruction did not modify this relationship. The results of the current study confirm that smoking exposure enhances telomere shortening in circulating lymphocytes. It also demonstrates a dose-effect relationship between exposure to tobacco smoking and telomere length, but failed to show that this effect is amplified in smokers who develop chronic obstructive pulmonary disease.
European Respiratory Journal 04/2006; 27(3):525-8. · 6.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: We previously reported that the molecular pro-inflammatory effects of welding fumes in vitro were caused by soluble transition metals via an oxidative stress-mediated mechanism. Herein, we tested the hypothesis that transition metals in welding fume drive the in vivo inflammatory response caused by welding fume. Rats were instilled with either whole, soluble extract or washed welding fume particulates or soluble extracts pre-treated with a transition metal chelator. Markers of pulmonary inflammation were measured in the bronchoalveolar lavage fluid (BALF) and nuclear translocation of transcription factor was assessed in BAL cells by electrophoretic mobility shift assay. Instillation of either whole or soluble fractions of welding fume caused a significant influx of inflammatory cells and other markers of inflammation in the BALF 24 h later. MIP-2 protein in BALF and nuclear translocation of NF-kappaB and AP-1 were significantly greater following instillation of whole and soluble fractions than in saline-instilled lungs. Chelation of the soluble fraction, to remove transition metals, abolished the ability to cause inflammation, MIP-2 increase or transcription factor translocation to the nucleus. Instillation of washed particulates alone caused no significant change in any end-point compared to saline. This study demonstrates that soluble transition metals present in welding fumes cause inflammation via activation of the redox-sensitive transcription factors NF-kappaB and AP-1 and confirms the validity of utilising in vitro models to assess inflammatory responses to such particles.
[show abstract][hide abstract] ABSTRACT: Epidemiology studies have shown that cardiovascular (CV) disease is primarily responsible for the mortality associated with increased pulmonary environmental particle (PM10) exposure. The mechanisms involved in PM10 mediated CV effects are unknown although changes in plasma viscosity and in the homoeostasis of blood coagulation have been implicated. It was hypothesised that PM10 exposure would result in an inflammatory response and enhance the activation of the extrinsic coagulation mechanisms in pulmonary and vascular cells in culture.
Primary human monocyte derived macrophages and human umbilical cord vein endothelial, human alveolar type II epithelial (A549), and human bronchial epithelial (16HBE) cells were tested for their inflammatory and procoagulant response to PM10 exposure. IL-8, tissue factor (TF), and tissue plasminogen activator (tPA) gene expression and protein release, and coagulation enhancing ability of culture media were determined 6 and 24 hours following exposure.
The culture media from macrophages and 16HBE bronchial epithelial cells, but not A549 cells, exposed to PM10 had an enhanced ability to cause clotting. Furthermore, H2O2 also increased the clotting activity. Apoptosis was significantly increased in macrophages exposed to PM10 and LPS as shown by annexin V binding. TF gene expression was enhanced in macrophages exposed to PM10, and HUVEC tissue factor and tPA gene and protein expression were inhibited.
These data indicate that PM10 has the ability to alter macrophage, epithelial, and endothelial cell function to favour blood coagulation via activation of the extrinsic pathway and inhibition of fibrinolysis pathways.
Occupational and environmental medicine 04/2005; 62(3):164-71. · 3.64 Impact Factor
[show abstract][hide abstract] ABSTRACT: A study was undertaken to assess both oxidative stress and inflammation in the lungs of patients with chronic obstructive pulmonary disease (COPD) during severe and very severe exacerbations compared with those with stable COPD, healthy smokers, and non-smokers. Two sites within the lungs were compared: the large airways (in sputum) and the peripheral airways (by bronchoalveolar lavage (BAL)).
BAL fluid cell numbers and levels of tumour necrosis factor (TNFalpha) and interleukin (IL)-8 were measured as markers of airway inflammation and glutathione (GSH) levels as a marker of antioxidant status. Nuclear translocation of the pro-inflammatory transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) were also measured by electromobility shift assay in BAL fluid leucocytes and lung biopsy samples.
Influx of inflammatory cells into the peripheral airways during exacerbations of COPD was confirmed. Increased IL-8 levels were detected in BAL fluid from patients with stable COPD compared with non-smokers and healthy smokers, with no further increase during exacerbations. In contrast, IL-8 levels in the large airways increased during exacerbations. GSH levels were increased in the BAL fluid of smokers (444%) and patients with stable COPD (235%) compared with non-smokers and were reduced during exacerbations (severe 89.2%; very severe 52.3% compared with stable COPD). NF-kappaB DNA binding in BAL leucocytes was decreased in healthy smokers compared with non-smokers (41.3%, n = 9, p<0.001) but did not differ in COPD patients, whereas AP-1 DNA binding was significantly decreased during exacerbations of COPD.
There is evidence of increased oxidative stress in the airways of patients with COPD that is increased further in severe and very severe exacerbations of the disease. This is associated with increased neutrophil influx and IL-8 levels during exacerbations.
[show abstract][hide abstract] ABSTRACT: Particulate air pollution (particles with a 50% cut-off aerodynamic diameter of 10 microm (PM10)) has strong associations with the adverse health events detected by epidemiological studies in chronic obstructive pulmonary disease patients in diverse geographical locations. Transition metals may determine the toxic effects of PM10 through oxidative stress which may be injurious as shown by an increase in airspace epithelial permeability and may lead to inflammation through the activation of transcription factors for pro-inflammatory genes in both macrophages and epithelial cells. Recently, the present authors have shown that particulate air pollution may cause further molecular events that enhance transcription factor activation by causing acetylation of histones leading to unwinding of deoxyribonucleic acid (DNA) enhancing transcription factor DNA binding and increasing transcription for pro-inflammatory genes. Further, ultrafine particles (< 100 nm diameter), which have marked toxicity, may be responsible for some of the PM10 adverse effects. The current authors have demonstrated that ultrafine carbon black (ufCB) does not have its effects via transition metal-mediated mechanisms. However, ufCB and other ultrafines generate free radicals at their surface as measured by a number of chemical assays and are able to cause oxidative stress to cells and this is likely to be a factor in their ability to cause inflammation. Changes in calcium resulting from oxidative stress within cells may be an additional factor leading to transcription of pro-inflammatory genes. Understanding the mechanisms of the harmful effects of particulate air pollution in chronic obstructive pulmonary disease may help in risk strategy for individuals who are susceptible to the effects of air pollution.
The European respiratory journal. Supplement 06/2003; 40:47s-51s.
[show abstract][hide abstract] ABSTRACT: A review of the management of COPD is presented, with particular emphasis on the effect on the approach to management of new information which has become available in the 5 years since the BTS guidelines on COPD were published. A major problem is the effective implementation of what is already known, and allocation of the resources necessary to make this available to all who might benefit.