(Chest. 2000;117:390S-397S.)
© 2000
American College of Chest Physicians
Exacerbations of COPD*
Environmental Mechanisms
William MacNee, MD and
Kenneth Donaldson, DSc
*
From the ELEGI Colt Research Laboratories (Professor MacNee), University of Edinburgh Medical School, Edinburgh, and the Department of Biological Sciences (Professor Donaldson), Napier University, Edinburgh, Scotland.
Correspondence to: Professor William MacNee, Respiratory Medicine, ELEGI, Colt Research Laboratories, Wilkie Building, Medical School, Teviot Place, Edinburgh EH8 9AG, Scotland; e-mail w.macnee@ed.ac.uk
 |
Abstract
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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 µm 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.
Key Words: air pollution • COPD • exacerbations • fine-particulate air pollution • mechanisms
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Evidence That Air Pollutants Cause Exacerbations of COPD
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The
adverse health effects of the visible air pollution of the 1940s and
1950s, which consisted of black smoke, acid aerosols, and sulfur
dioxide from the burning of fossil fuel from industrial and domestic
sources, are well known.1
2
Studies in the early 1950s
showed associations between the levels of these air pollutants and
mortality, as demonstrated most clearly by the sharp rise in black
smoke (1,600 µg/m3, four times the normal
value) and sulfur dioxide levels during the London smog of December
5–9, 1952, during which time there was an increase in the daily death
rate, resulting in around 4,000 extra deaths.1
2
Between
80 to 90% of the deaths during this episode were from
cardiorespiratory causes, and the greatest relative increase was deaths
from bronchitis, which rose ninefold. During the London smog of 1952,
hospital admissions rose by 50% and respiratory admissions by 160%.
Recognition of the adverse health effects of these very high
levels of air pollution led to worldwide legislation that dramatically
decreased emissions of air pollutants, particularly from industrial
sources.3
Until recently, this had resulted in a degree of
complacency that the problem of air pollution levels had been resolved.
However, alongside the decrease in the levels of these traditional air
pollutants, there has been a relative increase in motor vehicle
traffic. There is now overwhelming evidence showing associations
between adverse health effects and the levels of these
pollutants.4
These adverse effects are most strongly
associated with the levels of ozone,5
and with particulate
air pollution that has 50% of organic and inorganic particles with an
aerodynamic diameter of 
10 µm
(PM10).6
Numerous time-series
epidemiologic studies, which are reviewed elsewhere,6
have
shown significant associations with a increased ozone levels and a
range of adverse effects on the lungs, including decrements in lung
function, aggravation of preexisting respiratory disease, increases in
respiratory admissions, and premature respiratory deaths. Several
studies in Europe and the United States have shown increased relative
risk of hospital admission from exacerbations of COPD associated with
high levels of ozone,7
8
9
10
11
although not all studies have
supported this association (Fig 1
).12
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Figure 1. Reported relative risks (RR) for hospital
admissions for COPD associated with 100 parts-per-billion (ppb)
increase in daily 1 h maximum ozone (with 95% confidence
intervals) in three US cities and five European cities. Modified from
data by Thurston and Ito.5
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Epidemiologic evidence5
13
also indicates a clear
relationship between the levels of PM10 and
respiratory increased morbidity, including increased symptoms,
reductions in lung function,14
and hospital admissions in
patients with COPD.5
In addition, there is an association
between PM10 levels and deaths, not only from
respiratory causes, but also from vascular causes, such as myocardial
infarction and cerebrovascular accidents (Fig 2
).15
Furthermore, these associations have been shown in
diverse geographic locations, such as Utah, where the main source of
PM10 is from a steel mill, and Philadelphia,
where the major source is from motor vehicles. This suggests that a
common factor in the constituents of PM10 may
determine the mechanism of the harmful effects of particulate air
pollution. Recently, there has been much interest in the role of
reactive transition metals, such as iron and copper, as a factor
that accounts for the toxic effects of
PM10.16
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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
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One of the most compelling pieces of evidence for 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
µg/m3, the government’s own figures suggest
that around 8,000 deaths and around 10,000 excess hospital admissions
for exacerbations of airway disease occur as a result of increased
PM10 levels.18
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Mechanisms of the Harmful Effects of PM10 on the Lungs
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The ability of the lungs to protect themselves against inhaled
particles, and the susceptibility of individuals to the effects of
particles will also determine the outcome in terms of the adverse
effects of environmental particles. It is therefore important to ask
why PM10 is so toxic in such low concentrations.
The range of associations with mortality and morbidity described above
indicate that a wide variety of tissues are affected by
PM10.
Airways
An important defense mechanism against inhaled particles in the
airways is the mucociliary escalator. Mucus has a major role in
protecting the airways, particularly as it is a rich source
of antioxidants.19
In the large proximal airways, goblet
cells secrete mucus, which traps deposited particles and is then
propelled upwards by ciliated cells to be either expectorated or
swallowed. Mucus secretion is controlled by several
genes.20
Although mucus may in some circumstances have a
protective role, induction of increased mucus secretion by air
pollutants such as sulfur dioxide and possibly
PM1021
may contribute to the
development of exacerbations of COPD, by increasing airway resistance
and by the development of mucus plugging in the smaller peripheral
airways, a feature commonly present in patients dying of
COPD.22
In patients with COPD, and in cigarette smokers,
there is damage to the cilia, which, together with the
excess mucus produced, overwhelm the mucociliary escalator and will
reduce the ability of the lungs to deal adequately with inhaled
particles.
Airway epithelial cells also act as a barrier to inhaled pollutants,
and are an important target for the toxic and potentially inflammogenic
effects of particles. On exposure to particles and other forms of air
pollutants such as nitrogen dioxide,23
epithelial cells
can release inflammatory mediators such as interleukin (IL)-8, and the
chemokine RANTES (regulated upon activation, normal T-cell expressed
and secreted),24
which may lead to the influx of
inflammatory leukocytes.
Macrophages present in the airway walls and on the surfaces of the
airways can phagocytose particles, but may, as a result, release
inflammatory mediators such as IL-8 and tumor necrosis factor (TNF). In
COPD, numbers of macrophages are increased19
25
;
consequently, levels of inflammatory mediators are elevated in
sputum.26
The additional insult of an inhaled air
pollutant could clearly aggravate the background inflammation in COPD
leading to exacerbations.
Bronchoalveolar Region/Pulmonary Interstitium
Large numbers of inhaled particles deposit beyond the ciliated
airways in the terminal airways and proximal alveoli,27
where the net flow of air is zero and where, for very small particles,
deposition efficiency increases because of the
diffusion.28
Particles that then cross the airspace
epithelium and enter the lung interstitium are no longer cleared by the
normal processes, and will either remain in the subepithelial regions,
close to key responsive cell populations (such as interstitial
macrophages, fibroblasts, and endothelial cells), or drain to the lymph
nodes. Interstitial inflammation is likely to be potentially more
harmful than inflammation within the alveolar spaces.
Polymorphonuclear Neutrophils in the Pulmonary Microvasculature
Polymorphonuclear neutrophils (PMN) are thought to
play an important role in the pathogenesis of COPD, since they are
present in increased numbers in the airspaces and in the airway walls
of these patients. When activated, these cells release injurious
substances, such as proteases and reactive oxygen species. Neutrophils
are known to be held up (or sequestered) in the pulmonary
microcirculation under normal circumstances since, because of their
size, they have to deform to negotiate the smaller pulmonary capillary
segments.29
In addition to PMN-endothelial adhesion, PMN
deformability is a critical initiating factor in PMN
sequestration in the pulmonary microvasculature.30
Airway
inflammation, such as that in exacerbations of COPD, causes
decreased PMN deformability, and thus increased PMN
sequestration31
associated with evidence of systemic
oxidative stress.32
Oxidative stress also results from
acute smoking,32
which also causes decreased neutrophil
deformability33
and increased pulmonary sequestration of
PMN,34
and the subsequent migration of these cells
into the airspaces. Furthermore, carbon particles, which are an
important constituent of PM10, have been shown to
cause the release of immature neutrophils from the bone
marrow,35
and these cells are preferentially sequestered
in the pulmonary microcirculation. Thus, systemic effects of
PM10 on neutrophil rheology may be important as
an initiating event for the airspace inflammation induced by
PM10.36
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Toxicity of PM10
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In some studies, PM10 appears to have
adverse health effects without a dose threshold,13
suggesting that PM10 is a highly toxic material.
However, the individual components of PM10 are
not particularly toxic at the levels present in the air.
There is considerable evidence that PM10
contains an ultrafine component,37
defined as
particles < 100 nm in diameter, which may provide a
possible explanation for the toxicity of PM10.
One report has suggested that decrements in evening peak flow in a
group of asthmatics was best associated with the ultrafine component of
the airborne particles during pollution episodes.38
This
is despite the large number of particles in the ultrafine range
representing a relatively small fraction of the total
mass.36
Ultrafine particles are highly toxic to the lungs, 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 particles and
PM10 have been compared following
instillation in the same mass (125 µg) into rat lungs. Such
experiments have shown that ultrafine carbon particles and
PM10, and, to a much lesser extent, fine carbon
particles, produce the influx of inflammatory leukocytes into the
airspaces (Fig 3
).40
This suggests that ultrafine particles have toxicity
that results from their small size, rather than their chemical
composition.
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Figure 3. The number of neutrophils in BAL from rats 6
h after intratracheal instillation of PM10, fine (CB) and
ultrafine (ufCB) carbon black. The results in rats that had no
instillation (control) or instillation with phosphate-buffered saline
solution (PBS) are shown for comparison. Histograms and bars
represent the mean (SE) of three to six animals. From Li et
al.40
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The potential mechanisms that account for the toxicity of ultrafine
particles have been reviewed.41
The major
mechanisms are as follows: (1) particle number, (2) particle surface
area, (3) particle surface chemistry, (4) interstitialization of
particles, and (5) oxidative stress.
The deposition fraction in the lungs for ultrafine particles is high,
approaching 50% for particles 20 nm in size. Interestingly, the
deposition efficiency is greater in patients with COPD than in normal
subjects,28
probably because of their lower expiratory
flow. The resultant longer residence time for the particles in the
airspaces favors deposition that depends largely on brownian motion, as
is the case for these very small particles.28
In addition,
studies using radiolabeled particles indicate that particle deposition
is uneven in patients with airflow limitation, resulting in
accumulation of particles in certain areas in the
airways.42
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Particle Number/Surface Area
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Macrophages attempting to phagocytose a large number of ultrafine
particles may be stimulated to release inflammatory
mediators such as TNF. The inability of macrophages to phagocytose the
large numbers of ultrafine particles may also result in sustained
stimulation of epithelial cells, and increased production of
chemokines, such as IL-8/macrophage inflammatory
protein-1
,43
which would contribute to
inflammation.
In animal models, particularly in the rat, exposure to high
airborne concentrations of any particle, such that a high lung dose is
attained, will result in lung inflammation.44
This
phenomenon is termed overload and was thought to occur when
macrophages had phagocytosed a volume of particles equivalent to 60%
of their internal volume. At this point, macrophages began to show
impaired ability to move and carry their particle burden to 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
internal mass, of the particle. However, it is not immediately apparent
why nontoxic particles might mediate their effects via their surface.
Although 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 particle
inhalation47
suggest that overload is not the primary
factor that accounts for the lung inflammation. Furthermore, the
relevance of overload (which is a phenomenon relatively specific to the
rat) to humans remains to be determined.
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Particle Surface Chemistry
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The large surface area provided by ultrafine components 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 chemistry
to produce reactive oxygen species (see below).
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Transfer of Particles to the Lung Interstitium
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Interference with the normal process of phagocytosis and
macrophage migration to the mucociliary escalator can lead to particle
interstitialization.45
From the interstitium, particles
can chronically stimulate interstitial cells, or transfer to the lymph
nodes. Particle interstitialization, a prominent correlate of the onset
of inflammation for ultrafine TIO2 in the study
of Ferin and coworkers39
is likely to occur when there is
failed clearance resulting from either particle-mediated macrophage
toxicity, or impairment of macrophage motility or overload. Both of
these events would allow increased interaction between particles and
epithelium that would favor interstitialization. Additionally,
studies40
in rats have shown ultrafine particles and
PM10 to increase epithelial permeability (Fig 4
), thus enhancing interstitialization.
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Figure 4. Effect of intratracheal instillation of
PM10 CB and ufCB on epithelial permeability of rat lungs
in vivo, measured as total protein values in BAL fluid
6 h after instillation. The results in rats that had no
instillation (control) or instillation with PBS are shown for
comparison. Histograms and bars represent the mean (SE) of three to six
animals. From Li et al.40
See Figure 3
legend for
abbreviations.
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Transition Metals, Free Radicals, and Particle Toxicity
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The production of free radicals in the lungs is seen as a general
mechanism mediating the biological activity of a number of different
pathogenic particles.49
50
The oxidative stress is thought
to arise first from the particles themselves (through the localized
release of high concentrations of transition metals), and subsequently
by the release of reactive oxygen species from inflammatory leukocytes
that migrate into the airspaces as a result of the primary interaction
between lung cells and particles. Oxidative stress is a general
signaling mechanism within cells that stimulates the transcription of a
number of proinflammatory genes for cytokines, antioxidant enzymes,
receptors, and adhesion molecules.51
The ultrafine
component of PM10 with its large surface area
could generate free radicals that would be a substantial stimulus to
this transcription. Preliminary data also suggest that particulate
matter < 2.5 µm in diameter causes c-jun-dependent activator
protein-1 activation.52
The signal transduction
pathway for these events may be through oxidant-mediated activation of
Ras/mitogen-activated protein kinases.53
We have tested this free-radical hypothesis, and we found that
PM10 was able to generate free-radical activity,
as shown in a supercoiled plasmid DNA scission assay,49
and by the ability to form the hydroxylated derivative of salicylic
acid (2,3 dihydroxybenzoic acid).54
PM10 contains a large amount of iron and
generates the hydroxyl radical, an effect that was blocked by iron
chelators, confirming that Fenton chemistry is indeed the source of
hydroxyl radical.54
The majority of the available iron was
in the form of Fe3+, but the presence in the lung
of reductants such as superoxide anion and glutathione would be able to
initiate the reaction by reducing Fe3+ to
Fe2+.
As described above, the instillation of PM10 into
the lungs of rats produced neutrophil influx into the airspaces (Fig 3)
, and oxidative stress as shown by depletion of reduced
glutathione in lung lining fluid (Fig 5
).40
Importantly, PM10 caused
significantly more inflammation than a similar mass (125 µg) of
carbon black not in the ultrafine size range. Another toxic effect of
PM10 is to increase airspace epithelial
permeability (Fig 4) ,40
an effect that would enhance the
interstitialization of the particles and create interstitial
inflammation. Similar effects have been shown following inhalation of
ultrafine but not fine carbon black.55
These studies
support the concept that an ultrafine component of
PM10 is responsible for its toxic effects,
through an oxidant-mediated mechanism.
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Figure 5. Effect of intratracheal instillation of
PM10 and phosphate-buffered saline solution (PBS) on
reduced (GSH) and oxidized (GSSG) glutathione concentrations in BAL
fluid 6 h after instillation in rat lungs. Histograms and bars
represent the mean (SE) of three animals. From Li et al.40
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Residual oil fly ash (ROFA) has been used as a surrogate for
PM10, although in many respects it is very
different from PM10. ROFA causes pulmonary
inflammation after instillation, via a transition metal-mediated
mechanism.56
Furthermore, in rats instilled with ROFA,
intraperitoneal injection of the free-radical scavenger
dimethylthiourea decreased the influx of PMN into the
lungs.57
ROFA particles also caused increased
transcription of cytokine genes by human bronchial epithelial cells
in vitro via a transition metal-mediated
mechanism.58
Interestingly, the stimulation of cytokine
production could be mimicked by vanadium salts in solution, but not by
iron or nickel sulfate, suggesting a possible important role for
vanadium. Similarly, diesel oil particles have been shown in
preliminary studies to enhance the release of cytokines from primary
cultures of human bronchial epithelial cells.59
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Activation of Nuclear Factor- B in the Lungs by PM10
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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 and p50 proteins, is found in resting cells bound to its
inhibitor IB, which masks the nuclear translocation signal and so
prevents its translocation to the nucleus (Fig 6
). Under oxidative stress or a range of other stimuli such as TNF, the
IB is phosphorylated and then degraded via the ubiquitin proteosome
system, allowing the NF-B to relocate to the nucleus. Genes that
have a B binding site in their promoter include cytokines, growth
factors, chemokines, 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 transcription factors, that initiate a cascade of
gene expression, leading to airway inflammation.
|
Implications of an Oxidative Stress-Mediated Mechanism
|
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Since particles deposit on the epithelium, prior to phagocytosis,
it seems likely that the epithelium is a target for the
PM10, which may have a role in the observed
increase in COPD exacerbations in response to
PM10. There is evidence that environmental
particles such as ROFA57
and
PM1040
can compromise the epithelium
by causing injury or oxidative stress. In addition, the underlying
inflammation in the airways of patients with COPD means that they are
in a "primed" state for the further oxidative stress caused by
depositing PM10.
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Conclusion
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The principal pulmonary effects of PM10 are
seen in susceptible populations, including those with airways disease
such as COPD. If, as hypothesized here, the PM10
has its effect mainly by a mechanism that involves oxidative stress,
then these susceptible populations might be susceptible because of
preexisting oxidative stress, which has been demonstrated in patients
with airways disease.32
Furthermore, only 15% of smokers
develop COPD, and at least part of this susceptibility to the effects
of COPD may be genetic, relating to the ability of the subject to
detoxify injurious components of cigarette smoke, including oxidants.
Such genetic polymorphisms may also be associated with susceptibility
to the effects of air pollutants.
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Footnotes
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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 µm; PMN = polymorphonuclear
neutrophils; ROFA = residual oil fly ash; TNF = tumor necrosis
factor
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Abstract
Evidence That Air Pollutants...
