Increase in hospital admissions due to copd exacerbations associated to ultrafine particles


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    L’aria è elemento essenziale per la vita dell’uomo.La “mission” di questo blog è quello di soddisfare le esigenze di ricerca e di conoscenza delle tecnologie che possono permettere alle persone di respirare ogni giorno un’aria più pulita e sana, migliorando la qualità e la durata della loro vita.
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Increase in hospital admissions due to copd exacerbations associated to ultrafine particles

  1. 1. Exacerbations of COPD* : Environmental Mechanisms William MacNee and Kenneth Donaldson Chest 2000;117;390S-397S DOI 10.1378/chest.117.5_suppl_2.390S The online version of this article, along with updated information and services can be found online on the World Wide Web at: Chest is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright2000by the American College of Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. ( ISSN:0012-3692Downloaded from by guest on October 15, 2011 © 2000 American College of Chest Physicians
  2. 2. Exacerbations of COPD*Environmental MechanismsWilliam MacNee, MD; and Kenneth Donaldson, DSc Air pollution as a trigger for exacerbations of COPD has been recognized for > 50 years, and has led to the development of air quality standards in many countries that substantially decreased the levels of air pollutants derived from the burning of fossil fuels, such as black smoke and sulfur dioxide. However, the recent dramatic increase in motor vehicle traffic has produced a relative increase in the levels of newer pollutants, such as ozone and fine-particulate air pollution < 10 m in diameter. Numerous epidemiologic studies have shown associations between the levels of these air pollutants and adverse health effects, such as exacerbations of airways diseases and even deaths from respiratory and cardiovascular causes. Elucidation of the mechanism of the harmful effects of these pollutants should allow improved risk assessment for patients with airways diseases who are be susceptible to the effects of these air pollutants. (CHEST 2000; 117:390S–397S) Key words: air pollution; COPD; exacerbations; fine-particulate air pollution; mechanisms Abbreviations: IL interleukin; NF- B nuclear factor- B; PM10 particulate air pollution that has 50% of organic and inorganic particles with an aerodynamic diameter 10 m; PMN polymorphonuclear neutrophils; ROFA residual oil fly ash; TNF tumor necrosis factor Evidence That Air Pollutants Cause very high levels of air pollution led to worldwide Exacerbations of COPD legislation that dramatically decreased emissions of air pollutants, particularly from industrial sources.3 UntilT he adverse health and 1950s,the visible air pollu- tion of the 1940s effects of which consisted of recently, this had resulted in a degree of complacency that the problem of air pollution levels had beenblack smoke, acid aerosols, and sulfur dioxide from resolved. However, alongside the decrease in the levelsthe burning of fossil fuel from industrial and domes- of these traditional air pollutants, there has been atic sources, are well known.1,2 Studies in the early relative increase in motor vehicle traffic. There is now1950s showed associations between the levels of overwhelming evidence showing associations betweenthese air pollutants and mortality, as demonstrated adverse health effects and the levels of these pollut-most clearly by the sharp rise in black smoke (1,600 ants.4 These adverse effects are most strongly associ- g/m3, four times the normal value) and sulfur ated with the levels of ozone,5 and with particulate airdioxide levels during the London smog of December pollution that has 50% of organic and inorganic parti-5–9, 1952, during which time there was an increase cles with an aerodynamic diameter of 10 min the daily death rate, resulting in around 4,000 (PM10).6 Numerous time-series epidemiologic studies,extra deaths.1,2 Between 80 to 90% of the deaths which are reviewed elsewhere,6 have shown significantduring this episode were from cardiorespiratory associations with a increased ozone levels and a rangecauses, and the greatest relative increase was deaths of adverse effects on the lungs, including decrements infrom bronchitis, which rose ninefold. During the lung function, aggravation of preexisting respiratoryLondon smog of 1952, hospital admissions rose by disease, increases in respiratory admissions, and pre-50% and respiratory admissions by 160%. mature respiratory deaths. Several studies in Europe Recognition of the adverse health effects of these and the United States have shown increased relative risk of hospital admission from exacerbations of COPD*From the ELEGI Colt Research Laboratories (Professor Mac- associated with high levels of ozone,7–11 although not allNee), University of Edinburgh Medical School, Edinburgh, andthe Department of Biological Sciences (Professor Donaldson), studies have supported this association (Fig 1).12Napier University, Edinburgh, Scotland. Epidemiologic evidence5,13 also indicates a clearCorrespondence to: Professor William MacNee, Respiratory Med- relationship between the levels of PM10 and respi-icine, ELEGI, Colt Research Laboratories, Wilkie Building,Medical School, Teviot Place, Edinburgh EH8 9AG, Scotland; ratory increased morbidity, including increasede-mail symptoms, reductions in lung function,14 and hospi-390S COPD: Working Towards a Greater Understanding Downloaded from by guest on October 15, 2011 © 2000 American College of Chest Physicians
  3. 3. the adverse effects of PM10 comes from the Utah valley in the United States, near the town of Linden. During closure of the steel mill, levels of PM10 fell substantially (Table 1).17 This was associated with a reduction in the number of hospital admissions for exacerbations of airways diseases in the region, which rose again when the mill reopened.9,17 The levels of particulate air pollution in the United States and Europe are on an order of magnitude lower than those in the 1950s and those experienced in “dusty” trades. However, although the levels of PM10 in the United Kingdom infrequently exceed the government’s air quality standard of 50 g/m3, the government’s own figures suggest that aroundFigure 1. Reported relative risks (RR) for hospital admissions 8,000 deaths and around 10,000 excess hospitalfor COPD associated with 100 parts-per-billion (ppb) increase in admissions for exacerbations of airway disease occurdaily 1 h maximum ozone (with 95% confidence intervals) in as a result of increased PM10 levels.18three US cities and five European cities. Modified from data byThurston and Ito.5 Mechanisms of the Harmful Effects oftal admissions in patients with COPD. In addition, 5 PM10 on the Lungsthere is an association between PM10 levels and The ability of the lungs to protect themselvesdeaths, not only from respiratory causes, but also against inhaled particles, and the susceptibility offrom vascular causes, such as myocardial infarction individuals to the effects of particles will also deter-and cerebrovascular accidents (Fig 2).15 Further- mine the outcome in terms of the adverse effects ofmore, these associations have been shown in diverse environmental particles. It is therefore important togeographic locations, such as Utah, where the main ask why PM10 is so toxic in such low concentrations.source of PM10 is from a steel mill, and Philadelphia, The range of associations with mortality and morbid-where the major source is from motor vehicles. This ity described above indicate that a wide variety ofsuggests that a common factor in the constituents of tissues are affected by PM10.PM10 may determine the mechanism of the harmfuleffects of particulate air pollution. Recently, there Airwayshas been much interest in the role of reactivetransition metals, such as iron and copper, as a factor An important defense mechanism against inhaledthat accounts for the toxic effects of PM10.16 particles in the airways is the mucociliary escalator. One of the most compelling pieces of evidence for Mucus has a major role in protecting the airways, Figure 2. Summary of the percent change in adverse health effects per 10 mg/L3 change in PM10 for acute exposure studies in patients with respiratory (Resp) and cardiovascular (Cardio) conditions. PEF peak expiratory flow. Modified from data by Pope and Dockery.6 CHEST / 117 / 5 / MAY, 2000 SUPPLEMENT 391S Downloaded from by guest on October 15, 2011 © 2000 American College of Chest Physicians
  4. 4. Table 1—Particulate Air Pollution Levels and Hospital proximal alveoli,27 where the net flow of air is zero Admissions* and where, for very small particles, deposition effi- Mill Status ciency increases because of the diffusion.28 Particles that then cross the airspace epithelium and enter the Variables Open Closed Open lung interstitium are no longer cleared by the normalParticulate levels, g/m3 processes, and will either remain in the subepithelial TSP 34 64 95 regions, close to key responsive cell populations PM10 74 35 52 (such as interstitial macrophages, fibroblasts, andHospital admissions, no. All 302 205 340 endothelial cells), or drain to the lymph nodes. Bronchitis and asthma 78 23 78 Interstitial inflammation is likely to be potentially*In Lindon, UT, over the period of closure of a steel mill; TSP total more harmful than inflammation within the alveolar suspended particles. Modified from Pope.17 spaces. Polymorphonuclear Neutrophils in the Pulmonaryparticularly as it is a rich source of antioxidants.19 In Microvasculaturethe large proximal airways, goblet cells secrete mucus,which traps deposited particles and is then propelled Polymorphonuclear neutrophils (PMN) are thoughtupwards by ciliated cells to be either expectorated or to play an important role in the pathogenesis of COPD,swallowed. Mucus secretion is controlled by several since they are present in increased numbers in thegenes.20 Although mucus may in some circumstances airspaces and in the airway walls of these patients.have a protective role, induction of increased mucus When activated, these cells release injurious sub-secretion by air pollutants such as sulfur dioxide and stances, such as proteases and reactive oxygen species.possibly PM1021 may contribute to the development of Neutrophils are known to be held up (or sequestered)exacerbations of COPD, by increasing airway resistance in the pulmonary microcirculation under normal cir-and by the development of mucus plugging in the cumstances since, because of their size, they have tosmaller peripheral airways, a feature commonly present deform to negotiate the smaller pulmonary capillaryin patients dying of COPD.22 In patients with COPD, segments.29 In addition to PMN-endothelial adhesion,and in cigarette smokers, there is damage to the cilia, PMN deformability is a critical initiating factor inwhich, together with the excess mucus produced, PMN sequestration in the pulmonary microvascula-overwhelm the mucociliary escalator and will reduce ture.30 Airway inflammation, such as that in exacer-the ability of the lungs to deal adequately with bations of COPD, causes decreased PMN deformabil-inhaled particles. ity, and thus increased PMN sequestration31 associated Airway epithelial cells also act as a barrier to with evidence of systemic oxidative stress.32 Oxidativeinhaled pollutants, and are an important target for stress also results from acute smoking,32 which alsothe toxic and potentially inflammogenic effects of causes decreased neutrophil deformability33 and in-particles. On exposure to particles and other forms of creased pulmonary sequestration of PMN,34 and theair pollutants such as nitrogen dioxide,23 epithelial subsequent migration of these cells into the air-cells can release inflammatory mediators such as spaces. Furthermore, carbon particles, which are aninterleukin (IL)-8, and the chemokine RANTES important constituent of PM10, have been shown to(regulated upon activation, normal T-cell expressed cause the release of immature neutrophils from theand secreted),24 which may lead to the influx of bone marrow,35 and these cells are preferentiallyinflammatory leukocytes. sequestered in the pulmonary microcirculation. Macrophages present in the airway walls and on Thus, systemic effects of PM10 on neutrophil rheol-the surfaces of the airways can phagocytose particles, ogy may be important as an initiating event for thebut may, as a result, release inflammatory mediators airspace inflammation induced by PM10.36such as IL-8 and tumor necrosis factor (TNF). InCOPD, numbers of macrophages are increased19,25;consequently, levels of inflammatory mediators are Toxicity of PM10elevated in sputum.26 The additional insult of aninhaled air pollutant could clearly aggravate the In some studies, PM10 appears to have adversebackground inflammation in COPD leading to exac- health effects without a dose threshold,13 suggestingerbations. that PM10 is a highly toxic material. However, the individual components of PM10 are not particularly toxic at the levels present in the air.Bronchoalveolar Region/Pulmonary Interstitium There is considerable evidence that PM10 con- Large numbers of inhaled particles deposit be- tains an ultrafine component,37 defined as particlesyond the ciliated airways in the terminal airways and 100 nm in diameter, which may provide a possible392S COPD: Working Towards a Greater Understanding Downloaded from by guest on October 15, 2011 © 2000 American College of Chest Physicians
  5. 5. explanation for the toxicity of PM10. One report has flow. The resultant longer residence time for thesuggested that decrements in evening peak flow in a particles in the airspaces favors deposition that de-group of asthmatics was best associated with the pends largely on brownian motion, as is the case forultrafine component of the airborne particles during these very small particles.28 In addition, studies usingpollution episodes.38 This is despite the large num- radiolabeled particles indicate that particle deposi-ber of particles in the ultrafine range representing a tion is uneven in patients with airflow limitation,relatively small fraction of the total mass.36 resulting in accumulation of particles in certain areas Ultrafine particles are highly toxic to the lungs, in the airways.42even when they are formed from materials that arenontoxic, and when they are components of larger,respirable particles.39 The effects of fine (260 nmdiameter) and ultrafine (14 nm diameter) carbon Particle Number/Surface Areaparticles and PM10 have been compared following Macrophages attempting to phagocytose a largeinstillation in the same mass (125 g) into rat lungs. number of ultrafine particles may be stimulated toSuch experiments have shown that ultrafine carbon release inflammatory mediators such as TNF. Theparticles and PM10, and, to a much lesser extent, fine inability of macrophages to phagocytose the large num-carbon particles, produce the influx of inflammatory bers of ultrafine particles may also result in sustainedleukocytes into the airspaces (Fig 3).40 This suggeststhat ultrafine particles have toxicity that results from stimulation of epithelial cells, and increased productiontheir small size, rather than their chemical composition. of chemokines, such as IL-8/macrophage inflammatory The potential mechanisms that account for the protein-1 ,43 which would contribute to inflammation.toxicity of ultrafine particles have been reviewed.41 In animal models, particularly in the rat, expo-The major mechanisms are as follows: (1) particle sure to high airborne concentrations of any parti-number, (2) particle surface area, (3) particle surface cle, such that a high lung dose is attained, willchemistry, (4) interstitialization of particles, and (5) result in lung inflammation.44 This phenomenon isoxidative stress. termed overload and was thought to occur when The deposition fraction in the lungs for ultrafine macrophages had phagocytosed a volume of parti-particles is high, approaching 50% for particles 20 cles equivalent to 60% of their internal volume. Atnm in size. Interestingly, the deposition efficiency is this point, macrophages began to show impairedgreater in patients with COPD than in normal ability to move and carry their particle burden tosubjects,28 probably because of their lower expiratory the start of the mucociliary escalator for removal from the lungs. Morrow45 also calculated that by the time the average volume of particles inside macrophages reaches 60% of the total macrophage volume, their ability to move, and hence clearance, is completely inhibited. However, data from the rat have suggested that overload is best correlated to the surface area and not mass, volume, or number of particles.46 A role for surface area appears intuitively likely for toxic particles, since the interaction between particles and biological systems will occur with the surface, not the inter- nal mass, of the particle. However, it is not immediately apparent why nontoxic particles might mediate their effects via their surface. Al- though overload may account for part of the mechanism of lung inflammation in response to instillation of ultrafine particles in some animal models,47 calculations of the potential surface area in models of PM10 instillation40 or ultrafine parti-Figure 3. The number of neutrophils in BAL from rats 6 h after cle inhalation47 suggest that overload is not theintratracheal instillation of PM10, fine (CB) and ultrafine (ufCB) primary factor that accounts for the lung inflam-carbon black. The results in rats that had no instillation (control) mation. Furthermore, the relevance of overloador instillation with phosphate-buffered saline solution (PBS) areshown for comparison. Histograms and bars represent the mean (which is a phenomenon relatively specific to the(SE) of three to six animals. From Li et al.40 rat) to humans remains to be determined. CHEST / 117 / 5 / MAY, 2000 SUPPLEMENT 393S Downloaded from by guest on October 15, 2011 © 2000 American College of Chest Physicians
  6. 6. Particle Surface Chemistry The large surface area provided by ultrafine com-ponents of PM10 may allow absorption of substancesfrom the environment, or from the lung epitheliallining fluid onto the particle surface, which mayincrease the reactivity of the particles.48 One suchsubstance for which this may be relevant is iron,which can subsequently take part in Fenton chem-istry to produce reactive oxygen species (see below). Transfer of Particles to the Lung Interstitium Interference with the normal process of phagocy-tosis and macrophage migration to the mucociliaryescalator can lead to particle interstitialization.45From the interstitium, particles can chronically stim-ulate interstitial cells, or transfer to the lymph nodes. Figure 4. Effect of intratracheal instillation of PM10 CB and ufCB on epithelial permeability of rat lungs in vivo, measured asParticle interstitialization, a prominent correlate of total protein values in BAL fluid 6 h after instillation. The resultsthe onset of inflammation for ultrafine Tio2 in the in rats that had no instillation (control) or instillation with PBSstudy of Ferin and coworkers39 is likely to occur are shown for comparison. Histograms and bars represent the mean (SE) of three to six animals. From Li et al.40 See Figure 3when there is failed clearance resulting from either legend for abbreviations.particle-mediated macrophage toxicity, or impair-ment of macrophage motility or overload. Both ofthese events would allow increased interaction be-tween particles and epithelium that would favor these events may be through oxidant-mediated acti-interstitialization. Additionally, studies40 in rats have vation of Ras/mitogen-activated protein kinases.53shown ultrafine particles and PM10 to increase epi- We have tested this free-radical hypothesis, andthelial permeability (Fig 4), thus enhancing intersti- we found that PM10 was able to generate free-radicaltialization. activity, as shown in a supercoiled plasmid DNA scission assay,49 and by the ability to form the Transition Metals, Free Radicals, and hydroxylated derivative of salicylic acid (2,3 dihy- Particle Toxicity droxybenzoic acid).54 PM10 contains a large amount of iron and generates the hydroxyl radical, an effect The production of free radicals in the lungs is seen that was blocked by iron chelators, confirming thatas a general mechanism mediating the biological Fenton chemistry is indeed the source of hydroxylactivity of a number of different pathogenic parti- radical.54 The majority of the available iron was incles.49,50 The oxidative stress is thought to arise first the form of Fe3 , but the presence in the lung offrom the particles themselves (through the localized reductants such as superoxide anion and glutathionerelease of high concentrations of transition metals), would be able to initiate the reaction by reducingand subsequently by the release of reactive oxygen Fe3 to Fe2 .species from inflammatory leukocytes that migrate As described above, the instillation of PM10 intointo the airspaces as a result of the primary interac- the lungs of rats produced neutrophil influx into thetion between lung cells and particles. Oxidative airspaces (Fig 3), and oxidative stress as shown bystress is a general signaling mechanism within cells depletion of reduced glutathione in lung lining fluidthat stimulates the transcription of a number of (Fig 5).40 Importantly, PM10 caused significantlyproinflammatory genes for cytokines, antioxidant more inflammation than a similar mass (125 g) ofenzymes, receptors, and adhesion molecules.51 The carbon black not in the ultrafine size range. Anotherultrafine component of PM10 with its large surface toxic effect of PM10 is to increase airspace epithelialarea could generate free radicals that would be a permeability (Fig 4),40 an effect that would enhancesubstantial stimulus to this transcription. Preliminary the interstitialization of the particles and createdata also suggest that particulate matter 2.5 m in interstitial inflammation. Similar effects have beendiameter causes c-jun-dependent activator protein-1 shown following inhalation of ultrafine but not fineactivation.52 The signal transduction pathway for carbon black.55 These studies support the concept394S COPD: Working Towards a Greater Understanding Downloaded from by guest on October 15, 2011 © 2000 American College of Chest Physicians
  7. 7. its inhibitor I B, which masks the nuclear transloca- tion signal and so prevents its translocation to the nucleus (Fig 6). Under oxidative stress or a range of other stimuli such as TNF, the I B is phosphory- lated and then degraded via the ubiquitin proteo- some system, allowing the NF- B to relocate to the nucleus. Genes that have a B binding site in their promoter include cytokines, growth factors, chemo- kines, and adhesion molecules and receptors.51 We have demonstrated translocation of NF- B from the cytoplasm to the nucleus by PM10 in lung epithelial cells.60 Preliminary data also suggest that increased intracellular calcium may be involved in the signaling pathways in response to PM10 and ultrafine particles in lung cells.61 The deposition of particles that deliver oxidative stress to the lungs may cause activation of NF- B, and possibly other oxidative stress-responsive tran-Figure 5. Effect of intratracheal instillation of PM10 and phos- scription factors, that initiate a cascade of genephate-buffered saline solution (PBS) on reduced (GSH) and oxi-dized (GSSG) glutathione concentrations in BAL fluid 6 h after expression, leading to airway inflammation.instillation in rat lungs. Histograms and bars represent the mean(SE) of three animals. From Li et al.40 Implications of an Oxidative Stress-Mediated Mechanismthat an ultrafine component of PM10 is responsible Since particles deposit on the epithelium, prior tofor its toxic effects, through an oxidant-mediated phagocytosis, it seems likely that the epithelium is amechanism. target for the PM10, which may have a role in the Residual oil fly ash (ROFA) has been used as a observed increase in COPD exacerbations in re-surrogate for PM10, although in many respects it is sponse to PM10. There is evidence that environmen-very different from PM10. ROFA causes pulmonary tal particles such as ROFA57 and PM1040 can com-inflammation after instillation, via a transition metal- promise the epithelium by causing injury or oxidativemediated mechanism.56 Furthermore, in rats in- stress. In addition, the underlying inflammation instilled with ROFA, intraperitoneal injection of the the airways of patients with COPD means that theyfree-radical scavenger dimethylthiourea decreased are in a “primed” state for the further oxidative stressthe influx of PMN into the lungs.57 ROFA particles caused by depositing PM10.also caused increased transcription of cytokine genesby human bronchial epithelial cells in vitro via atransition metal-mediated mechanism.58 Interest-ingly, the stimulation of cytokine production couldbe mimicked by vanadium salts in solution, but notby iron or nickel sulfate, suggesting a possible im-portant role for vanadium. Similarly, diesel oil parti-cles have been shown in preliminary studies toenhance the release of cytokines from primary cul-tures of human bronchial epithelial cells.59 Activation of Nuclear Factor- B in the Lungs by PM10 The transcriptional activator nuclear factor- B(NF- B) is a cytosolic transcription factor of the relfamily that is translocated to the nucleus to permitexpression of a wide range of proinflammatorygenes.51 The NF- B heterodimer, comprising p65 Figure 6. The effect of particle-induced oxidative stress on geneand p50 proteins, is found in resting cells bound to transcription through activation of the transcription factor NF- B. CHEST / 117 / 5 / MAY, 2000 SUPPLEMENT 395S Downloaded from by guest on October 15, 2011 © 2000 American College of Chest Physicians
  8. 8. Conclusion pulmonary function of smokers with mild to moderate chronic obstructive pulmonary disease. Am Rev Respir Dis The principal pulmonary effects of PM10 are seen 1993; 147:1336 –1340in susceptible populations, including those with air- 15 Dochery DW, Pope CA III. Epidemiology of acute healthways disease such as COPD. If, as hypothesized effects: summary of time series studies. In: Wilson R, Span- gler J, eds. Particles in our air. Cambridge, MA: Harvardhere, the PM10 has its effect mainly by a mechanism University Press, 1996; 123–132that involves oxidative stress, then these susceptible 16 Ghio AJ, Samet JM. Metals and air pollution particles. In:populations might be susceptible because of preex- Holgate ST, Samet JM, Koren HS, et al, eds. Air pollutionisting oxidative stress, which has been demonstrated and health. London, UK: Academic Press, 1999; 635– 651in patients with airways disease.32 Furthermore, only 17 Pope CA III. 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  10. 10. Exacerbations of COPD* : Environmental Mechanisms William MacNee and Kenneth Donaldson Chest 2000;117; 390S-397S DOI 10.1378/chest.117.5_suppl_2.390S This information is current as of October 15, 2011Updated Information & ServicesUpdated Information and services can be found at: article cites 42 articles, 11 of which can be accessed free at: BysThis article has been cited by 1 HighWire-hosted articles: & LicensingInformation about reproducing this article in parts (figures, tables) or in its entirety can befound online at: about ordering reprints can be found online: AlertsReceive free e-mail alerts when new articles cite this article. To sign up, select the"Services" link to the right of the online article.Images in PowerPoint formatFigures that appear in CHEST articles can be downloaded for teaching purposes inPowerPoint slide format. See any online figure for directions. Downloaded from by guest on October 15, 2011 © 2000 American College of Chest Physicians