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

Exacerbations of COPD* : Environmental
Mechanisms
William MacNee and Kenneth Donaldson

Chest 2000;117;390S-397S
DOI 10.1378/chest.117.5_suppl_2.390S
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Exacerbations of COPD*
Environmental Mechanisms
William 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 Until

T 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 been
black smoke, acid aerosols, and sulfur dioxide from resolved. However, alongside the decrease in the levels
the burning of fossil fuel from industrial and domes- of these traditional air pollutants, there has been a
tic sources, are well known.1,2 Studies in the early relative increase in motor vehicle traffic. There is now
1950s showed associations between the levels of overwhelming evidence showing associations between
these 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 air
dioxide 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 m
in 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 significant
during this episode were from cardiorespiratory associations with a increased ozone levels and a range
causes, and the greatest relative increase was deaths of adverse effects on the lungs, including decrements in
from bronchitis, which rose ninefold. During the lung function, aggravation of preexisting respiratory
London 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 all
Nee), University of Edinburgh Medical School, Edinburgh, and
the Department of Biological Sciences (Professor Donaldson), studies have supported this association (Fig 1).12
Napier University, Edinburgh, Scotland. Epidemiologic evidence5,13 also indicates a clear
Correspondence 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 increased
e-mail w.macnee@ed.ac.uk symptoms, reductions in lung function,14 and hospi-

390S COPD: Working Towards a Greater Understanding


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 around
Figure 1. Reported relative risks (RR) for hospital admissions 8,000 deaths and around 10,000 excess hospital
for COPD associated with 100 parts-per-billion (ppb) increase in admissions for exacerbations of airway disease occur
daily 1 h maximum ozone (with 95% confidence intervals) in as a result of increased PM10 levels.18
three US cities and five European cities. Modified from data by
Thurston and Ito.5

Mechanisms of the Harmful Effects of
tal admissions in patients with COPD. In addition,
5 PM10 on the Lungs
there is an association between PM10 levels and The ability of the lungs to protect themselves
deaths, not only from respiratory causes, but also against inhaled particles, and the susceptibility of
from 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 of
more, these associations have been shown in diverse environmental particles. It is therefore important to
geographic 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 of
suggests that a common factor in the constituents of tissues are affected by PM10.
PM10 may determine the mechanism of the harmful
effects of particulate air pollution. Recently, there
Airways
has been much interest in the role of reactive
transition metals, such as iron and copper, as a factor An important defense mechanism against inhaled
that 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

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 normal
Particulate 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, and
Hospital 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 Pulmonary
particularly as it is a rich source of antioxidants.19 In
Microvasculature
the large proximal airways, goblet cells secrete mucus,
which traps deposited particles and is then propelled Polymorphonuclear neutrophils (PMN) are thought
upwards 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 the
genes.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 to
smaller peripheral airways, a feature commonly present deform to negotiate the smaller pulmonary capillary
in 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 in
which, 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 Oxidative
inhaled pollutants, and are an important target for stress also results from acute smoking,32 which also
the 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 the
air 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 an
interleukin (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 the
and secreted),24 which may lead to the influx of bone marrow,35 and these cells are preferentially
inflammatory 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 the
but may, as a result, release inflammatory mediators airspace inflammation induced by PM10.36
such as IL-8 and tumor necrosis factor (TNF). In
COPD, numbers of macrophages are increased19,25;
consequently, levels of inflammatory mediators are Toxicity of PM10
elevated in sputum.26 The additional insult of an
inhaled air pollutant could clearly aggravate the In some studies, PM10 appears to have adverse
background inflammation in COPD leading to exac- health effects without a dose threshold,13 suggesting
erbations. 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 particles
yond the ciliated airways in the terminal airways and 100 nm in diameter, which may provide a possible



explanation for the toxicity of PM10. One report has flow. The resultant longer residence time for the
suggested 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 for
ultrafine component of the airborne particles during these very small particles.28 In addition, studies using
pollution 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.42
even when they are formed from materials that are
nontoxic, and when they are components of larger,
respirable particles.39 The effects of fine (260 nm
diameter) and ultrafine (14 nm diameter) carbon Particle Number/Surface Area
particles and PM10 have been compared following Macrophages attempting to phagocytose a large
instillation in the same mass (125 g) into rat lungs. number of ultrafine particles may be stimulated to
Such experiments have shown that ultrafine carbon
release inflammatory mediators such as TNF. The
particles 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 sustained
leukocytes into the airspaces (Fig 3).40 This suggests
that ultrafine particles have toxicity that results from stimulation of epithelial cells, and increased production
their 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, will
chemistry, (4) interstitialization of particles, and (5) result in lung inflammation.44 This phenomenon is
oxidative 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. At
nm in size. Interestingly, the deposition efficiency is this point, macrophages began to show impaired
greater in patients with COPD than in normal ability to move and carry their particle burden to
subjects,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 the
intratracheal 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 overload
or instillation with phosphate-buffered saline solution (PBS) are
shown 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.


Particle Surface Chemistry
The large surface area provided by ultrafine com-
ponents of PM10 may allow absorption of substances
from the environment, or from the lung epithelial
lining fluid onto the particle surface, which may
increase the reactivity of the particles.48 One such
substance 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 mucociliary
escalator can lead to particle interstitialization.45
From 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 as
Particle interstitialization, a prominent correlate of total protein values in BAL fluid 6 h after instillation. The results
the onset of inflammation for ultrafine Tio2 in the in rats that had no instillation (control) or instillation with PBS
study 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 3
when there is failed clearance resulting from either legend for abbreviations.
particle-mediated macrophage toxicity, or impair-
ment of macrophage motility or overload. Both of
these 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.53
shown ultrafine particles and PM10 to increase epi-
We have tested this free-radical hypothesis, and
thelial permeability (Fig 4), thus enhancing intersti-
we found that PM10 was able to generate free-radical
tialization.
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 that
as a general mechanism mediating the biological Fenton chemistry is indeed the source of hydroxyl
activity of a number of different pathogenic parti- radical.54 The majority of the available iron was in
cles.49,50 The oxidative stress is thought to arise first the form of Fe3 , but the presence in the lung of
from the particles themselves (through the localized reductants such as superoxide anion and glutathione
release of high concentrations of transition metals), would be able to initiate the reaction by reducing
and subsequently by the release of reactive oxygen Fe3 to Fe2 .
species from inflammatory leukocytes that migrate As described above, the instillation of PM10 into
into the airspaces as a result of the primary interac- the lungs of rats produced neutrophil influx into the
tion between lung cells and particles. Oxidative airspaces (Fig 3), and oxidative stress as shown by
stress is a general signaling mechanism within cells depletion of reduced glutathione in lung lining fluid
that stimulates the transcription of a number of (Fig 5).40 Importantly, PM10 caused significantly
proinflammatory genes for cytokines, antioxidant more inflammation than a similar mass (125 g) of
enzymes, receptors, and adhesion molecules.51 The carbon black not in the ultrafine size range. Another
ultrafine component of PM10 with its large surface toxic effect of PM10 is to increase airspace epithelial
area could generate free radicals that would be a permeability (Fig 4),40 an effect that would enhance
substantial stimulus to this transcription. Preliminary the interstitialization of the particles and create
data also suggest that particulate matter 2.5 m in interstitial inflammation. Similar effects have been
diameter causes c-jun-dependent activator protein-1 shown following inhalation of ultrafine but not fine
activation.52 The signal transduction pathway for carbon black.55 These studies support the concept



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 gene
phate-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 Mechanism
that an ultrafine component of PM10 is responsible Since particles deposit on the epithelium, prior to
for its toxic effects, through an oxidant-mediated phagocytosis, it seems likely that the epithelium is a
mechanism. 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 oxidative
mediated mechanism.56 Furthermore, in rats in- stress. In addition, the underlying inflammation in
stilled with ROFA, intraperitoneal injection of the the airways of patients with COPD means that they
free-radical scavenger dimethylthiourea decreased are in a “primed” state for the further oxidative stress
the influx of PMN into the lungs.57 ROFA particles caused by depositing PM10.
also caused increased transcription of cytokine genes
by human bronchial epithelial cells in vitro via a
transition metal-mediated mechanism.58 Interest-
ingly, the stimulation of cytokine production could
be mimicked by vanadium salts in solution, but not
by iron or nickel sulfate, suggesting a possible im-
portant role for vanadium. Similarly, diesel oil parti-
cles have been shown in preliminary studies to
enhance 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 rel
family that is translocated to the nucleus to permit
expression of a wide range of proinflammatory
genes.51 The NF- B heterodimer, comprising p65 Figure 6. The effect of particle-induced oxidative stress on gene
and p50 proteins, is found in resting cells bound to transcription through activation of the transcription factor NF- B.


Conclusion pulmonary function of smokers with mild to moderate
chronic obstructive pulmonary disease. Am Rev Respir Dis
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Exacerbations of COPD* : Environmental Mechanisms
William MacNee and Kenneth Donaldson
Chest 2000;117; 390S-397S
DOI 10.1378/chest.117.5_suppl_2.390S
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