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

Potential Role of Ultrafine Particles in Associations between Airborne Particle Mass and Cardiovascular Health

Numerous epidemiologic time-series studies have shown generally consistent associations of cardiovascular hospital admissions and mortality with outdoor air pollution, particularly mass concentrations of particulate matter (PM) ≤2.5 or ≤10 μm in diameter (PM(2.5), PM(10)). Panel studies with repeated measures have supported the time-series results showing associations between PM and risk of cardiac ischemia and arrhythmias, increased blood pressure, decreased heart rate variability, and increased circulating markers of inflammation and thrombosis. The causal components driving the PM associations remain to be identified. Epidemiologic data using pollutant gases and particle characteristics such as particle number concentration and elemental carbon have provided indirect evidence that products of fossil fuel combustion are important. Ultrafine particles < 0.1 μm (UFPs) dominate particle number concentrations and surface area and are therefore capable of carrying large concentrations of adsorbed or condensed toxic air pollutants. It is likely that redox-active components in UFPs from fossil fuel combustion reach cardiovascular target sites. High UFP exposures may lead to systemic inflammation through oxidative stress responses to reactive oxygen species and thereby promote the progression of atherosclerosis and precipitate acute cardiovascular responses ranging from increased blood pressure to myocardial infarction. The next steps in epidemiologic research are to identify more clearly the putative PM casual components and size fractions linked to their sources. To advance this, we discuss in a companion article (Sioutas C, Delfino RJ, Singh M. 2005. Environ Health Perspect 113:947–955) the need for and methods of UFP exposure assessment

The effect of lipocortin 1 on neutrophil deformability

Lipocortn 1 (Lc1) is an anti-inflammatory protein, which, given systemically, inhibits polymorphonuclear neutrophil (PMN) emigration from the circulation to sites of inflammation; delivery of Lc1 to the inflamed site is ineffective. We have examined the effect of Lc1 on changes in PMN deformability, and observed a consistent improvement in the deformability of unstimulated PMN; N-formyl-methionyl-leucyl-phenylalanine (fMLP)-activated cell deformability was unaltered. A Lc1-induced increase in cell deformability may reduce PMN sequestration so contributing to the anti-migratory effects of systemic Lc1 previously demonstrated in vivo

Free radical activity of industrial fibers: role of iron in oxidative stress and activation of transcription factors.

We studied asbestos, vitreous fiber (MMVF10), and refractory ceramic fiber (RCF1) from the Thermal Insulation Manufacturers' Association fiber repository regarding the following: free radical damage to plasmid DNA, iron release, ability to deplete glutathione (GSH), and activate redox-sensitive transcription factors in macrophages. Asbestos had much more free radical activity than any of the man-made vitreous fibers. More Fe3+ was released than Fe2+ and more of both was released at pH 4.5 than at pH 7.2. Release of iron from the different fibers was generally not a good correlate of ability to cause free radical injury to the plasmid DNA. All fiber types caused some degree of oxidative stress, as revealed by depletion of intracellular GSH. Amosite asbestos upregulated nuclear binding of activator protein 1 transcription factor to a greater level than MMVF10 and RCF1; long-fiber amosite was the only fiber to enhance activation of the transcription factor nuclear factor kappa B (NF kappa B). The use of cysteine methyl ester and buthionine sulfoximine to modulate GSH suggested that GSH homeostasis was important in leading to activation of transcription factors. We conclude that the intrinsic free radical activity is the major determinant of transcription factor activation and therefore gene expression in alveolar macrophages. Although this was not related to iron release or ability to deplete macrophage GSH at 4 hr, GSH does play a role in activation of NF kappa B

Miscellaneous Problems

Contains reports on four research projects

Pulmonary function is associated with distal aortic calcium, not proximal aortic distensibility. MESA lung study

Forced expiratory volume in one second strongly predicts mortality from cardiovascular disease. FEV1 has been associated with aortic stiffness a strong independent predictor of cardiovascular mortality. However, the anatomical site and possible mechanisms linking aortic stiffness and lung function are unknown. We therefore examined if FEV1 and CT percent emphysema were associated with calcification of the abdominal aorta or reduced distensibility of the proximal thoracic aorta.The Multi-Ethnic Study of Atherosclerosis (MESA) measured aortic calcification on cardiac and abdominal CT scans and proximal aortic distensibility using magnetic resonance among participants aged 45–84 years without clinical cardiovascular disease. Spirometry was measured following ATS/ERS guidelines and percent emphysema was measured in the lung fields of cardiac CT scans. Multivariate analyses adjusted for age, sex, race/ethnicity and cardiovascular risk factors. Of 1,917 participants with aortic distensibility measures, 13% were current and 38% were former smokers. Eighteen percent had airflow limitation without asthma. FEV1 was associated with the extent of distal aortic calcification (0.76; 95%CI 0.60–0.97, p = 0.02) but not proximal aortic calcification or proximal aortic distensibility (−0.04 mmHg−1; 95%CI −0.16–0.09 mmHg−1, p = 0.60). Percent emphysema was associated with neither measure. FEV1 was associated with severity of distal aortic calcification where it was present independently of smoking and other cardiovascular risk factors but not with distensibility or calcification of the proximal aorta

Diagnosis, assessment, and phenotyping of COPD: beyond FEV1

COPD is now widely recognized as a complex heterogeneous syndrome, having both pulmonary and extrapulmonary features. In clinical practice, the diagnosis of COPD is based on the presence of chronic airflow limitation, as assessed by post-bronchodilator spirometry. The severity of the airflow limitation, as measured by percent predicted FEV1, provides important information to the physician to enable optimization of management. However, in order to accurately assess the complexity of COPD, there need to be other measures made beyond FEV1. At present, there is a lack of reliable and simple blood biomarkers to confirm and further assess the diagnosis of COPD. However, it is possible to identify patients who display different phenotypic characteristics of COPD that relate to clinically relevant outcomes. Currently, validated phenotypes of COPD include alpha-1 antitrypsin deficiency, and “frequent exacerbators”. Recently, a definition and assessment of a new phenotype comprising patients with overlapping features of asthma and COPD has been suggested and is known as “asthma COPD overlap syndrome”. Several other phenotypes have been proposed, but require validation against clinical outcomes. Defining phenotypes requires the assessment of multiple factors indicating disease severity, its impact, and its activity. Recognition and validation of COPD phenotypes has an important role to play in the selection of evidence-based targeted therapy in the future management of COPD, but regardless of the diagnostic terms, patients with COPD should be assessed and treated according to their individual treatable characteristics.The article is freely available via Open Access. Click on the 'Additional Link' above to access the full-text from the publisher's site.Published, with link to publisher's site

Free radical activity of PM10: iron-mediated generation of hydroxyl radicals.

The purpose of this study was to test the hypothesis that particulate matter < or = 10 microns in aerodynamic diameter (PM10) particles have the ability to generate free radical activity at their surface. We collected PM10 filters from the Edinburgh, United Kingdom, Enhanced Urban Network sampling site, removed particles from the filter, and tested their ability to cause free radical damage to supercoiled plasmid DNA. We found that the PM10 particles did cause damage to the DNA that was mediated by hydroxyl radicals, as shown by inhibition of the injury with mannitol. The PM10-associated hydroxyl radical activity was confirmed using a high-performance liquid chromatography-based assay to measure the hydroxyl radical adduct of salicylic acid. Desferrioxamine abolished the hydroxyl radical-mediated injury, which suggests that iron was involved. Analysis of PM10 filters confirmed the presence of large amounts of iron and leaching studies confirmed that the PM10 samples could release substantial amounts of Fe(III) and lesser amounts of Fe(II). To investigate the size of the particles involved in the hydroxyl radical injury, we centrifuged the suspension of PM10 to clarity, tested the clear supernatant, and found that it had all of the suspension activity. We conclude, therefore, that the free radical activity is derived either from a fraction that is not centrifugeable on a bench centrifuge, or that the radical generating system is released into solution

Validity of physical activity monitors during daily life in patients with COPD.

Symptoms during physical activity (PA) and physical inactivity are COPD. Our aim was to evaluate the validity and usability of six activity in patients with COPD against the doubly labelled water (DLW) indirect calorimetry method.Eighty COPD patients (age 68+/-6 years, FEV1 57+/-19% predicted) recruited in four centres each wore simultaneously three or six commercially available monitors validated in chronic conditions for consecutive days. A priori validity criteria were defined. These ability to explain total energy expenditure (TEE) variance through regression analysis, using TEE as the dependent variable with total body (TBW) plus several PA monitors outputs as independent variables; and with DLW measured activity energy expenditure (AEE).The Actigraph GT3X DynaPort MoveMonitor best explained the majority of the TEE variance not explained by TBW (53% and 70% respectively) and showed the most correlations with AEE (r=0.71 p<0.001, r=0.70 p<0.0001, of this study should guide users in choosing valid activity monitors for or for clinical use in patients with chronic diseases such as COPD