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Abstract | Asthma and chronic obstructive pulmonary disease (COPD) are both obstructive
airway diseases that involve chronic inflammation of the respiratory tract, but the type of
inflammation is markedly different between these diseases, with different patterns
of inflammatory cells and mediators being involved. As described in this Review, these
inflammatory profiles are largely determined by the involvement of different immune cells,
which orchestrate the recruitment and activation of inflammatory cells that drive the
distinct patterns of structural changes in these diseases. However, it is now becoming clear
that the distinction between these diseases becomes blurred in patients with severe
asthma, in asthmatic subjects who smoke and during acute exacerbations. This has
important implications for the development of new therapies.
Chronic obstructive
pulmonary disease
(COPD). A group of diseases
characterized by the
pathological limitation of
airflow in the airway, including
chronic obstructive bronchitis
and emphysema. It is most
often caused by tobacco
smoking, but can also be
caused by other airborne
irritants, such as coal dust, and
occasionally by genetic
abnormalities, such as
1-antitrypsin deficiency.
REVIEWS
Inhaled allergens
Epithelial cells
CCL11
SCF
Mast cell
TSLP
Histamine, cysteinyl
leukotrienes and
prostaglandin D2
IL-9
CCR4
Smooth-muscle
cell
Bronchoconstriction
Dendritic
cell
CCL17 and
CCL22
IgE
TH2 cell
Antibody
production
IL-13
IL-4
TReg
cells?
IL-5
CCR3
Eosinophil
B cell
Eosinophilic inflammation
Emphysema
Destruction of the alveolar
walls, resulting in decreased
gas exchange and contributing
to airflow limitation by loss of
alveolar attachments to the
small airways that serve to
keep the airways open during
expiration.
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Pseudostratification
Increased proliferation of
airway epithelial cells in chronic
obstructive pulmonary disease,
as a result of the release of
epithelial-cell growth factors,
which lead to increased
thickness of the epithelial-cell
layer.
TypeI pneumocytes
Flat alveolar cells that make up
most of the epithelial-cell layer
of the alveolar wall and that are
responsible for gas exchange in
the alveoli.
Bronchoconstrictor
An agent that induces
contraction of airway smooth
muscle and thereby narrows
the airways, thus reducing the
flow of air.
Epithelial cells
Macrophage
CXCL9, CXCL10
and CXCL11
CCL2
CXCL1
and CXCL8
TGF
CXCR2
CXCR3
Fibroblast
TH1 cell
TC1 cell
Neutrophil
CCR2
Monocyte
Airway
epithelial
cell
Mucus
Smoothmuscle
cell
Fibrosis
(small airways)
Alveoli
Goblet
cell
Mucus gland
Mucus
hypersecretion
Immune responses
The immune mechanisms that drive the different inflammatory processes of asthma and COPD are mediated by
different types of immune cell, in particular by different
Tcell subsets. An understanding of which immune cells
are involved is now emerging and may lead to the development of new and more-specific therapies for airway
diseases in the future (FIGS1,2).
Tcells. In asthmatic patients, there is an increase in the
number of CD4+ Tcells in the airways and these are predominantly T helper 2 (TH2) cells, whereas in normal airways TH1 cells predominate33. By secreting the cytokines
IL4 and IL13, which drive IgE production by Bcells,
IL5, which is solely responsible for eosinophil differentiation in the bone marrow, and IL9, which attracts and
drives the differentiation of mast cells34, TH2 cells have a
central role in allergic inflammation and therefore their
regulation is an area of intense research.
The transcription factor GATA3 (GATA-binding protein 3) is crucial for the differentiation of uncommitted
naive Tcells into TH2 cells and it also regulates the secretion of TH2-type cytokines35,36. Accordingly, there is an
increase in the number of GATA3+ Tcells in the airways
volume 8 | march 2008 | 185
REVIEWS
Asthma
COPD
Inflammation
Airway smooth muscle
Basement membrane
Fibrosis
Alveolar disruption
Airway hyperresponsiveness
Increased narrowing of the
airways, initiated by exposure
to a defined stimulus that
usually has little or no effect
on airway function in normal
individuals. This is a defining
physiological characteristic of
asthma.
TH2 cells
TH1 cells
Inflammation
+++
+++
+++
Basement membrane
++
Fibrosis
+ (subepithelial)
+++ (peribronchiolar)
Alveolar disruption
+++
Airway vessels
++
No change
Mast cells
++ (and activated)
Normal
Dendritic cells
++
ND
Eosinophils
++
Normal
Neutrophils
Normal
++
Lymphocytes
TH2 type
Epithelium
Often shed
Pseudostratified
Goblet cells
++
++
Figure 3 | Contrasting histopathology of asthma and chronic obstructive pulmonary disease (COPD). A small airway
from a patient who died from asthma and a similar sized airway from a patient with severe COPD are shown. There is an
Nature Reviews | Immunology
infiltration of inflammatory cells in both diseases. The airway smooth-muscle cell layer is thickened in asthma but only to
a minimal degree in COPD. The basement membrane is thickened in asthma due to collagen deposition (subepithelial
fibrosis) but not in COPD, whereas in COPD collagen is deposited mainly around the airway (peribronchiolar fibrosis). The
alveolar attachments are intact in asthma, but disrupted in COPD as a result of emphysema. Images courtesy of Dr J. Hogg
(Vancouver, Canada). Other differences in the cellular infiltrate in the two diseases are also shown. ND, not determined;
TC1, type 1 cytotoxic T; TH1, T helper 1.
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Regulatory Tcells
A specialized type of CD4+
Tcells that can suppress the
responses of other Tcells.
These cells provide a crucial
mechanism for the
maintenance of peripheral selftolerance and a subset of these
cells is characterized by
expression of CD25 and the
transcription factor forkhead
box P3 (FOXP3).
Allergic rhinitis
Allergic inflammation that is
caused by the pollen of specific
seasonal plants, such as
grasses (causing hay fever), and
house dust (causing perennial
rhinitis) in people who are
allergic to these substances. It
is characterized by sneezing,
and a runny and blocked nose.
TH17 cells
IL-12
IL-4
STAT1
STAT4
STAT6
TH1 cells
T-bet
TH1-type cytokines
(IL-2 and IFN)
IL-33
REVIEWS
IL-6
IL-23
TGF
?
TH17 cell
ROR t
STAT3
IL-21
TNF
IL-6
IL-22
IL-17 and
IL-17F
CD8+ T cell
CXCL1 and
CXCL8
Neutrophils
Epithelial cells
IL-10
Acute-phase
proteins
Immunoglobulin class
switching
The somatic-recombination
process by which the class of
immunoglobulin expressed by
activated Bcells is switched
from IgM to IgG, IgA or IgE.
Corticosteroids
Anti-inflammatory drugs that
are derived from cortisol
secreted by the adrenal cortex
and that are effective in
suppressing inflammation
in asthma but not in chronic
obstructive pulmonary disease.
FEV1
Dendritic cells. Dendritic cells (DCs) have an important role in asthma as regulators of T H2 cells and in
the presentation of processed peptides from inhaled
allergens to TH2 cells77. They are not only involved in
the initial sensitization to allergens, but also in driving
the chronic inflammatory response in the lungs, and
therefore provide a link between allergen exposure and
allergic inflammation in asthma. The cytokine thymic
stromal lymphopoietin (TSLP), which is secreted in large
amounts by epithelial cells and mast cells of asthmatic
patients78,79, might have a critical role in the maturation
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Acute exacerbations. Acute exacerbations (worsening of
symptoms) occur in patients with asthma and COPD,
and are a major cause of patient suffering and medical
expenditure89,90. Exacerbations in asthmatic individuals
are usually triggered by upper respiratory tract infections,
such as with rhinoviruses, and less commonly by inhaled
allergens and air pollutants, whereas exacerbations in
patients with COPD are usually triggered by either bacterial or viral infections. In both diseases, exacerbations are
associated with a further increase in airway inflammation, increased numbers of cells infiltrating the lungs and
higher concentrations of inflammatory mediators than are
present in the steady state. However, there may also be
changes in the pattern of inflammation. In exacerbations
of asthma triggered by viruses, there can be increases in
the numbers of neutrophils, as well as of eosinophils89,
whereas in COPD exacerbations, particularly those due to
viruses, there may be an increase in eosinophil numbers91.
So, during episodes of disease exacerbation, the pattern of
inflammation becomes similar in COPD and asthma.
Theophylline
A drug that is used at high
doses as a bronchodilator in
the treatment of asthma and
chronic obstructive pulmonary
disease. However, it is now less
widely used as the high doses
can have side effects, including
nausea, headaches, cardiac
arrhythmias and seizures.
More recently, it has been
shown to have antiinflammatory effects at lower
doses and may reverse
corticosteroid resistance by
increasing the activity of
histone deacetylase.
Cyclosporin A and
tacrolimus
Calcineurin inhibitors that are
used to prevent transplant
rejection and that function by
inhibiting nuclear factor of
activated Tcells (NFAT).
Rapamycin
An immunosuppressive drug
that, in contrast to calcineurin
inhibitors, does not prevent
Tcell activation but blocks
interleukin2-mediated clonal
expansion by blocking mTOR
(mammalian target of
rapamycin).
Mycophenolate mofetil
An immunosuppressant that
inhibits purine synthesis and
has an inhibitory effect on
Tcells and Bcells. It is
currently used to treat
transplant rejection and
rheumatoid arthritis.
Epithelial cells
Macrophage
CXCR3
TH1 cell
TC1 cell
Perforin and
granzyme B
Emphysema
(apoptosis of type I
pneumocytes)
REVIEWS
Table 1 | Comparison between patterns of inflammation in asthma and COPD
Asthma
COPD
Refs
Mild
Severe
Exacerbation
Mild
Severe
Exacerbation
Neutrophils
++
++++
++
+++
++++
Eosinophils
++
+++
110,111
Mast cells
++
+++
+++?
7,26,112
Macrophages
+++
++++
++++
T cells
TH2 cells: ++
iNKT cells: ?
TH1 cells: +
TH2 cells: +
TC1 cells: +
TC2 cells: +?
TH17 cells: ?
TC1 cells: +
18,66,114
B cells
IgE producing
IgE producing
+++
18,73
Dendritic cells
+?
+?
115
Chemokines
CCL11: +
CXCL8: +
CXCL8: ++
CXCL8: +
CXCL1: +
CCL2: +
CXCL8: ++
CXCL8: +++
116
Cytokines
IL-4: ++
IL-5: ++
IL-13: ++
TNF: ++
TNF: +
TNF: ++
TNF: +++
117,118
Lipid mediators
LTD4: ++
PGD2: +
LTB4: ++
PGD2: +
LTB4: +
LTB4: ++
LTB4: +++
10,11
Oxidative stress
++
+++
++
+++
++++
Steroid response
++++
++
113
119122
92
0, no response; + to ++++, magnitude scale; ?, uncertain. CCL, CC-chemokine ligand; COPD, chronic obstructive pulmonary disease; CXCL, CXC-chemokine ligand;
iNKT, invariant natural killer T; LTB4, leukotriene B4; LTD4, leukotriene D4; PGD2, prostaglandin D2; TC1, type 1 cytotoxic T; TH, T helper; TNF, tumour-necrosis factor.
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involvement in COPD. However, these distinctions
between asthma and COPD may not be as clear as
previously believed, as in patients with severe asthma
and in asthmatic individuals who smoke there is a
neutrophilic pattern of inflammation, and acute exacerbations of asthma and of COPD have similar inflammatory features. The role of TH17 cells in severe asthma
and COPD as a driving mechanism of neutrophilic
inflammation is not yet fully understood and deserves
more research; understanding these mechanisms may
lead to new therapeutic approaches.
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DATABASES
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=gene
CCR2 | CCR3 | CCR4 | CXCR2 | CXCR3 | CXCR4 | GATA3 |
IFN| IL4 | IL5 | IL-6 | IL-9 | IL13 | IL17 | IL33 | p38 | TSLP
FURTHER INFORMATION
Peter Barness homepage: http://www1.imperial.ac.uk/
medicine/people/p.j.barnes.html
All links are active in the online pdf
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