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Chronic Obstructive Pulmonary Disease 1


New insights into the immunology of chronic obstructive
pulmonary disease
Guy G Brusselle, Guy F Joos, Ken R Bracke

Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome associated with abnormal inflammatory Lancet 2011; 378: 1015–26
immune responses of the lung to noxious particles and gases. Cigarette smoke activates innate immune cells such as This is the first in a Series of
epithelial cells and macrophages by triggering pattern recognition receptors, either directly or indirectly via the release three papers about chronic
obstructive pulmonary disease
of damage-associated molecular patterns from stressed or dying cells. Activated dendritic cells induce adaptive
Laboratory for Translational
immune responses encompassing T helper (Th1 and Th17) CD4+ T cells, CD8+ cytotoxicity, and B-cell responses,
Research of Obstructive
which lead to the development of lymphoid follicles on chronic inflammation. Viral and bacterial infections not only Pulmonary Disease,
cause acute exacerbations of COPD, but also amplify and perpetuate chronic inflammation in stable COPD via Department of Respiratory
pathogen-associated molecular patterns. We discuss the role of autoimmunity (autoantibodies), remodelling, Medicine, Ghent University
Hospital and Ghent University,
extracellular matrix-derived fragments, impaired innate lung defences, oxidative stress, hypoxia, and dysregulation of
Ghent, Belgium
microRNAs in the persistence of the pulmonary inflammation despite smoking cessation. (Prof G G Brusselle MD,
Prof G F Joos MD,
Introduction endothelial cells).9 Disruption of the balance between cell K R Bracke PhD)

Chronic obstructive pulmonary disease (COPD) affects death and replenishment of structural cells in the lung Correspondence to:
Guy G Brusselle, Department
more than 200 million people worldwide and is the contribute to the destruction of alveolar septa, leading to
of Respiratory Medicine 7K12,
fourth leading cause of death.1 Although the major emphysema. Additionally, age-related changes and cellular Ghent University Hospital,
environmental risk factor for COPD is tobacco smoking, senescence further impair tissue repair in response to Ghent B-9000, Belgium
only 20% of smokers develop COPD.2 Indoor air pollution repetitive cigarette smoke-induced injury of the lungs.10 guy.brusselle@ugent.be
from burning biomass fuels is associated with an Autoimmunity has been proposed as a late pathogenic
increased risk of COPD in developing countries.3 event in the progressive course of the disease.11 The diverse
Immune dysregulation arises in the peripheral blood of mechanisms do not operate separately in the pathogenesis
patients with COPD, and might contribute to the of COPD, but are strongly interrelated. Oxidative stress,
pathogenesis of the extrapulmonary effects of the disorder.4,5 for example, contributes to the imbalance between
Although overspill of inflammation in the lung into the proteinase and antiproteinase by inactivating anti-
circulation is suggested to cause systemic inflammation in proteinases, whereas an excess of apoptotic cells leads to
a subset of patients with COPD,4 other pathogenic secondary necrosis and can exaggerate continuing
mechanisms such as smoking, ageing, abdominal obesity, pulmonary inflammation.12,13
and physical inactivity are probably involved.6 We focus on
the role of local immune responses in the airways and Innate immune responses in COPD
lungs in the pathogenesis and progression of COPD due To prevent invasion of pathogenic microbes into the
to cigarette smoking (figure 1). Table 1 shows characteristics lower respiratory tract, the airways and lungs have innate
of the innate and adaptive immune system. defence mechanisms encompassing the epithelial barrier,
Several mechanistic concepts have been implicated in mucociliary clearance, humoral factors (eg, antimicrobial
the pathogenesis of COPD. First, the hallmark of COPD is peptides, complement proteins, and surfactant proteins)
development of exaggerated chronic inflammation in the and cells that participate in innate immunity: macro-
lung in response to inhalation of cigarette smoke phages, dendritic cells, monocytes, neutrophils, natural
compared with smokers without lung disease.7 Host killer cells, and mast cells. See Online for webappendix
factors including genetic susceptibility, epigenetic
changes, and oxidative stress (webappendix p 2) contribute
by amplifying inflammation induced by cigarette smoke. Search strategy and selection criteria
Second, patients with deficiency of α1-antitrypsin, the We searched Medline for the past 10 years with the search terms “COPD” or “emphysema”
main inhibitor of neutrophil elastase, develop emphysema in combination with one of the following terms: “immunity”, “macrophages”,
early in life,8 due to an imbalance between proteinases and “neutrophils”, “mast cells”, “natural killer cells”, “T-cells (Th1, Th2, Th17, or Treg)”, “B-cells”
antiproteinases leading to a net increase in proteolytic or “(auto)antibodies”. We largely selected publications in the past 5 years, but did not
activity. Third, an imbalance between oxidants and exclude commonly referenced and highly regarded older publications. The date of the last
antioxidants in the lungs of patients with COPD, resulting search was April 26, 2011. We also searched the reference lists of articles identified by this
in excessive oxidative stress, not only amplifies airway search strategy and selected those we judged relevant. Review articles are cited to provide
inflammation in smokers, but also induces cell death of readers with more details and more references than this Review has room for.
structural cells in the lung (mainly alveolar epithelial and

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Macrophage

Neutrophil
Lumen
Goblet cell

Epithelium
Lymphoid follicle
Mucosa

Dendritic cell
Natural killer cell

B cell

Mast cell
CD4+ T cell

CD8+ T cell
Innate immune cells Adaptive immune cells

Smooth muscle cells

Blood circulation Lymph node

Figure 1: Innate and adaptive immune cells in the pathogenesis and course of chronic obstructive pulmonary disease
Cigarette smoke activates epithelial cells and innate immune cells such as macrophages, neutrophils, and natural killer cells. Activated dendritic cells orchestrate adaptive immune responses including
cytotoxic CD8+ T cells, T helper CD4+T cells, and B-cell responses, leading to the development of lymphoid follicles on chronic inflammation. CD=cluster of differentiation.

The first step towards the induction of innate immune lead to the release of DAMPs by injured airways after
responses is recognition of different microbes by cigarette smoke exposure. Concentrations of high-mobility
identification of molecules that are exclusive to microbes— group box 1 (HMGB1),15 uric acid, and extracellular ATP16
pathogen-associated molecular patterns (PAMPs). This are increased in bronchoalveolar lavage fluid of patients
recognition is achieved by several families of pattern with COPD compared with smokers without COPD.
recognition receptors (PRRs) expressed in alveolar Moreover, expression of receptor for advanced glycation
macrophages, dendritic cells, and epithelial cells, which end products (RAGE), which binds HMGB1, is raised in
first contact microbial pathogens (webappendix p 2). The airway epithelium of patients with COPD.15 Activation of
PRRs include transmembrane Toll-like receptors (TLRs), PRRs such as TLRs and RAGE leads to increased
cytosolic NOD-like receptors (NLRs), and RIG-I-like expression of pro-interleukin 1β, which is subsequently
receptors (RLRs).14 In addition to PAMPs, PRRs are cleaved into mature interleukin 1β by NLR family, pyrin
activated by specific endogenous molecules, which are domain-containing (NLRP) inflammasomes (figure 2).
normally intracellular, but are released after cell damage. IL-1R knock-out mice showed attenuated pulmonary
After release from injured or dying cells, these endogenous inflammation after acute exposure to cigarette smoke and
molecules are called damage-associated molecular patterns were significantly protected against emphysema after
(DAMPs). The recognition of PAMPs and DAMPs by chronic exposure to cigarette smoke.17 Moreover, inhibition
PRRs is crucial in mediation of inflammatory responses to of P2 purinergic receptors—which bind extracellullar
infection and sterile tissue damage, respectively (figure 2). ATP—prevented the development of smoke-induced lung
Acute exposure to cigarette smoke leads to activation of injury and emphysema in a COPD model.18
several PRRs, either directly by individual components of In lung cells, another general inducible response to
cigarette smoke, or indirectly by causing injury to injury resulting from exposure to cigarette smoke and
For more on the global initiative
epithelial cells, which release DAMPs (table 2). Several oxidative stress is autophagy (webappendix p 3). In lung
of obstructive lung disease see mechanisms, including inhalation of toxic agents and tissue from patients with COPD, as early as stage 0 on the
http://www.goldcopd.org irritants, oxidative stress, infections, and tissue hypoxia, global initiative of obstructive lung disease scale, autophagy

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is increased as indicated by increased autophagic vacuoles


Innate immunity Adaptive immunity
(autophagosomes and autolysosomes) on electronic
microscopic analysis and by increased activation of Recognition

autophagic proteins such as Atg4B, Atg5-Atg12, and Atg7.19 Receptors Pattern recognition receptors T-cell and B-cell receptors
In human pulmonary epithelial cells, exposure to cigarette Molecules Pathogen-associated molecular Processed antigens; antigen-antibody
patterns; damage-associated complexes
smoke extract in vitro rapidly induces autophagy. The molecular patterns
autophagic protein microtubule-associated protein 1 light Response
chain 3B (LC3B) has a pivotal role not only in autophagy, Onset Immediate Delayed (4–5 days)
but also in apoptosis since it associates with the extrinsic Specificity Fixed repertoire Specific
apoptotic factor Fas; LC3B knock-out mice have significantly
Immunological memory No Yes
decreased rates of apoptosis in the lungs after exposure to
Ontology Ancient Recent
cigarette smoke and display resistance to cigarette-smoke-
Cellular component
induced emphysema in vivo.20 The transcription factor
Haematopoietic Neutrophils, macrophages, T lymphocytes, B lymphocytes
early growth response-1 (Egr-1) is believed to regulate LC3B dendritic cells, eosinophils,
and promote autophagy and apoptosis in response to natural killer cells
cigarette smoke, because activation of autophagic proteins Structural Epithelial cells Follicular dendritic cells
and apoptotic factors is attenuated in Egr-1 knock-out mice Effector molecules Acute phase proteins, B cells: immunoglobulins (antibodies)
that are exposed to cigarette smoke.19 complement, cytokines, CD4+ T cells: Th1,Th2, Th17, Treg cytokines
chemokines, growth factors, CD8+ T cells: perforins, granzymes
In the effector phase of innate immune responses, antimicrobial peptides (cytotoxicity)
cigarette-smoke-induced release of proinflammatory
cytokines and chemokines—such as tumour necrosis CD=cluster of differentiation. Th=T helper. Treg=regulatory T cell.
factor α (TNFα) and chemokine (c-x-c motif) ligand Table 1: Characteristics of innate and adaptive immune systems
(CXCL)8—by airway epithelial cells and alveolar
macrophages elicits the expression of adhesion molecules
on endothelial cells and the recruitment of neutrophils Although mast cells have been traditionally associated
and inflammatory monocytes to the lungs. Numbers of with the pathophysiological mechanisms of allergic
neutrophils and macrophages are increased in the lungs asthma, evidence suggests that mast cells could be
of smokers and patients with COPD. At sites of sterile implicated in the pathogenesis of COPD. Histological
inflammation neutrophils contribute to wound healing, studies of human lungs have shown that as COPD pro-
but can cause tissue damage. Activated neutrophils and gresses to its severe stages mast cell populations undergo
macrophages cause lung destruction through the release changes in density, morphology, and distribution, including
of oxygen radicals and proteolytic enzymes such as an increase in the number of luminal mast cells.30 Although
neutrophil elastase and matrix metalloproteinases natural killer cells are classified as lymphocytes on the
(MMPs), including MMP-8, MMP-9, and MMP-12 basis of their morphology, the expression of lymphoid
(formerly called macrophage elastase).21,22 CD8+ T cells markers, and their origin from a common lymphoid
and natural killer cells contribute to cytotoxicity of lung progenitor cell, they are deemed components of innate
tissue cells through the release of the proteolytic enzymes immune defence because they lack antigen-specific cell
perforin and granzyme B.23,24 In addition to its ability to surface receptors.31 Natural killer cells act as cytolytic
breakdown extracellular matrix, neutrophil elastase is a effector lymphocytes, which can directly induce the death
potent stimulator of mucin production and secretion. not only of virus-infected cells and tumour cells, but also of
Neutrophil elastase-induced production of mucin occurs structural cells in the lungs, which die by apoptosis or
via proteolytic cleavage of transforming growth factor α necrosis from damage caused by perforin and
(TGFα), a ligand of epidermal growth factor receptor. granzyme B.11,24 Increased proportions of natural killer cells
Excessive mucus production and impaired mucociliary that are CD3– and CD56+ and increased cytotoxic activity
clearance contribute to airway obstruction in patients of natural killer cells expressing both perforin and
with COPD.25 granzyme B, have been shown in induced sputum of
In models of COPD, chronic exposure of mice to cigarette patients with COPD compared with healthy smokers.24
smoke for 6 months induces several pathological hallmarks Additionally, natural killer cells cross-talk with dendritic
of the disorder, including pulmonary inflammation, airway cells, promoting the maturation of dendritic cells by
remodelling and airspace enlargement due to destruction producing interferon γ and TNFα.32
of alveolar walls (ie, emphysema).26 In much the same way
as differences in genetic susceptibility in human smokers Dendritic cells and innate and adaptive immunity
affect development of COPD, the induction of emphysema Dendritic cells are specialised antigen-presenting cells
in mice is strain dependent.27 Importantly, in immuno- that link innate and adaptive immune responses (figure 1
deficient mice lacking B cells and T cells, the innate and webappendix p 3).33 By the integration of many
immune system suffices to develop cigarette smoke- signals of the microenvironment dendritic cells promote
induced inflammation28,29 and emphysema.28 CD4+ T helper (Th) cell differentiation and CD8+

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Sensing cigarette smoke and danger signals

Bacteria Viruses Autophagy

ROS

Cell death
(autophagic,
apoptotic,
necrotic)
RAGE PAMPs DAMPs

,...

Interle
B1 , HA

LPS,...
MG

P
,H

AT
HSP

ukin 1α
cid
Uric a
P2X7
P2Y2 TLRs
TLRs Interleukin 1R

P2X7
NF-κB
NLRPs

Pro
caspase-1

Inflammasome

caspase-1

TNFα Pro
CXCL8 interleukin 1β
Effector phase Mature
interleukin 1β

Pro-inflammatory ROS Proteolytic enzymes


cytokines and chemokines (NE, MMP-9, MMP-12,...)
(TNFα, interleukin 1β, CXCL8,...)
Interleukin 1β secretion

Figure 2: Afferent and efferent part of innate immune responses in chronic obstructive pulmonary disease
Cigarette smoke activates epithelial cells, macrophages, and neutrophils via oxidative stress and by triggering pattern recognition receptors (PRR) such as
Toll-like receptors (TLRs) and purinergic receptors (eg, P2X7 and P2Y2), either directly by cigarette components or indirectly via the release of damage-associated
molecular patterns (DAMPs) by dying—autophagic death, apoptotic or necrotic—cells. Viral and bacterial respiratory tract infections amplify the chronic
inflammation in COPD by triggering PRRs via pathogen-associated molecular patterns (PAMPs). On activation, the innate immune cells release
pro-inflammatory cytokines and chemokines, reactive oxygen species (ROS) and proteolytic enzymes (neutrophil elastase [NE] and matrix metalloproteinases
[MMPs]). More research is needed to show the importance of NOD-like receptor family, pyrin domain containing (NLRP) inflammasomes in chronic obstructive
pulmonary disease. HSP=heat shock protein. HMGB1=high-mobility group box 1. HA=hyaluronic acid. NF-κB=nuclear factor κB. CXCL=chemokine (c-x-c motif)
ligand. RAGE=Receptor for Advanced Glycation End products.

cytotoxicity (figure 3). Smoking of cigarettes has been increased expression of chemokine (c-c motif) ligand
associated with an expansion in the population of (CCL) 2036 (figure 4). The Langerin+ subset of myeloid
Langerhans-like dendritic cells in the epithelial surface dendritic cells is mainly present in the airway epithelium
of the lower respiratory tract. After acute smoke exposure, and is segregated from the interstitial myeloid dendritic
myeloid dendritic cells are immediately and selectively cell subset that is positive for dendritic cell-specific
recruited into the bronchoalveolar lavage fluid of intracellular adhesion molecule 3–grabbing non-integrin,
smokers.34 Moreover, expression of Langerin and CD1a which is located in the lamina propria and adventitia and
(markers of Langerhans-like dentritic cells) is increased, does not increase in patients with COPD (figure 4).
as is that of costimulatory markers CD80 and CD86 on Langerin+ dendritic cells have been linked to the induction
myeloid dendritic cells from the bronchoalveolar lavage of CD8+ T-cell responses by cross-presentation.37
fluid of smokers compared with never-smokers.
In COPD, several dendritic cell subsets in the Adaptive immune responses in COPD
lung parenchyma showed significant increases in In both the airway and alveolar compartment, the CD8+
costimulatory molecule expression, which correlated with cytotoxic T cell is the predominant T cell in patients
COPD severity.35 By immunohistochemistry we showed with COPD.11,23 The number of pulmonary CD8+ T cells
selective accumulation of Langerin+ myeloid dendritic in COPD increases substantially with higher stages of
cells in the small airways of patients with COPD, which airflow limitation and emphysema.23 The expression of
increased with disease severity and was associated with the chemokine receptor CXCR3, preferentially

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expressed on type 1 T lymphocytes, and its ligand


Receptor (cellular [soluble])
interferon-induced protein 10 (also known as CXCL10)
(table 3) is increased in peripheral airways of smokers Cigarette smoke components

with COPD, suggesting that the axis between CXCL10 Endotoxin (lipopolysaccharide) TLR4 and CD14, [lipopolysaccharide-binding protein]
and chemokine (c-x-c motif ) receptor (CXCR) 3 might Nicotine nAChR, TRPA1
be implicated in CD8+ T-cell recruitment in COPD.38 Reactive oxygen species, free radicals NLRP3
On activation, CD8+ T cells release proteolytic enzymes Acrolein TRPA1
such as perforin and granzymes, which cause cell death Polycyclic aromatic hydrocarbon AhR
of structural cells by apoptosis or necrosis11,24 (figure 5). DAMP released from stressed, apoptotic, and necrotic cells
Numbers of CD4+ T cells are raised in the airways and ATP P2XR, P2YR
lungs of smokers with COPD. At least two different types Uric acid NLRP3
of effector CD4+ Th cells accumulate in the lungs of High-mobility group box 1 TLR2, TLR4, TLR9, RAGE, CD24
patients with stable COPD: Th1 cells and Th17 cells.39,40 Th1 S100 molecules TLR9, RAGE
cells expressing chemokine receptors CCR5 and CXCR3 Heat shock proteins TLR2, TLR4, CD91, CD24, CD14, CD40
produce interferon γ and promote accumulation of β defensins TLR4, CCR6
inflammatory cells to the lungs. Lung lymphocytes in Interleukin 1α Interleukin 1R
patients with COPD and emphysema have higher DNA (mitochondrial) TLR9
percentages of CD4+ Th1 cells and secrete more interferon Formyl peptides (mitochondrial) FPR1
γ than in control smokers.39 Interleukin 18, which promotes DAMP released from breakdown of ECM
Th1 cell development, is strongly expressed in alveolar Hyaluronic acid TLR2 , TLR4, CD44
macrophages, CD8+ T cells, and both bronchiolar and Fibronectin TLR4, α5β1 integrin, αVβ3 integrin
alveolar epithelia in lungs of patients with severe COPD.41 Heparan sulphate TLR4
Th17 cells are a distinct lineage of activated CD4+ Versican TLR2
T cells, regulating tissue inflammation by producing Biglycan TLR2, TLR4, P2XR
interleukin 17A and interleukin 17F.42 They mediate N-acetyl-proline-glycine-proline CXCR1, CXCR2
immunity against extracellular pathogens, but have also
been implicated in autoimmunity.42 Th17 cytokines TLR=Toll-like receptor. CD=cluster of differentiation. nAChR=nicotinic acetylcholine receptor. TRPA1=transient
receptor potential A1. AhR=aryl hydrocarbon receptor. P2XR=purinergic receptor P2XR. P2YR=purinergic receptor
induce epithelial cells to produce antimicrobial peptides P2YR. NLRP3=NOD-like receptor family, pyrin domain containing 3. RAGE=receptor for advanced glycation end
(such as β defensins), chemokines, and the granulocyte products; FPR1=formyl peptide receptor 1. ECM=extracellular matrix. CXCR=chemokine (c-x-c motif) receptor.
growth factors G-CSF and GM-CSF to promote neutrophil
Table 2: Sensing of cigarette smoke components and Damage Associated Molecular patterns (DAMP) by
accumulation at the site of tissue injury. Patients with Pattern Recognition Receptors (PRR) and other receptors of the innate immune system
COPD have increased numbers of interleukin 23+
immunoreactive cells in the bronchial epithelium and
interleukin 17A+ cells in the bronchial submucosa.40 smokers with normal lung function compared with people
However, because interleukin 17A production is linked to who had never smoked and patients with moderate COPD
structural cells such as endothelial cells, sources other in one study,45 whereas bronchoalveolar lavage CD4+
than T cells might be important.40 CD25-bright cells were increased in smokers and patients
Regulatory T cells (Treg) are subsets of CD4+ T cells with with COPD compared with healthy people who had never
immunoregulatory functions, which inhibit autoimmunity smoked in another study.46 Because these cells encompass
and suppress inflammation. The two most abundant both FOXP3+ Treg and non-regulatory activated Th cells,
subsets of Treg are the natural Treg and the adaptive or additional multicolour flowcytometric and functional
inducible Treg. Natural Treg leave the thymus as effector studies of bronchoalveolar lavage fluid and lung digests
cells and are essential in maintaining self-tolerance, are warranted to resolve this discrepancy. T cells that are
whereas induced Treg mature in the periphery and are FOXP3+ and CD4+ are raised in lymphoid follicles of
activated by exogenous antigens. Treg exert their patients with moderate COPD compared with control
suppressive effect on other T cells or on antigen-presenting smokers,47 suggesting that Treg might regulate inflam-
dendritic cells via contact-dependent mechanisms or the matory responses to prevent autoimmunity.11 Treg that are
production of anti-inflammatory cytokines such as inter- CD4+, CD25+, and FOXP3+ resolve experimental lung
leukin 10 and transforming growth factor β (TGFβ).43 They injury in mice after intratracheal lipopolysaccharide
are characterised by expression of the transcription factor administration and are present in the bronchoalveolar
FOXP3 (forkhead box P3) and bright expression of the lavage fluid of patients with acute lung injury, suggesting
surface marker CD25, the interleukin 2 receptor α chain. that Treg modify innate immune responses during
Smokers with COPD and emphysema had significantly resolution of lung injury.48
fewer Treg cells in the lungs, less messenger RNA (mRNA)
for FOXP3, and less interleukin 10 secretion from the B cells
whole lung than controls.44 CD4+ CD25-bright cells were B cells are increased in large airways of patients with
significantly increased in bronchoalveolar lavage fluid in COPD, as shown in central bronchial biopsy specimens.

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The compartmentalisation of lymphoid follicles in


CXCR3
MHCI TCR CD8+ cytotoxic T cell B-cell and T-cell areas is—as in lymph nodes—regulated
CD8 Perforins, granzymes by homoeostatic chemokines, which dictate homing and
motility of lymphocytes and dendritic cells in lymphoid
CD80 CD28
CD86 tissues.55 CCL19 and CCL21 attract naive T lymphocytes
CD4+ T helper cell IL 12R expressing CCR7 and mature dendritic cells into the
IL 18R T-cell areas, whereas the CXC chemokine CXCL13
Th1 CXCR3 INFγ, TNFα
T-bet CCR5 attracts B cells expressing CXCR5 (table 3). Whereas in
lymph nodes lymphotoxin α induces the expression of
18 IL 4R
, IL CCR3
the chemokines CCL19 and CXCL13, interleukin 17 is
12 in
IL lept Th2 CCR4 needed for the induction of these chemokines in iBALT.56
IL 4, IL 5, IL 13
GATA-3 CCR8
MHCII TCR IL 4 2A Once formed, iBALT is longlasting and participates in
P
virus
CD4 rhino CD25 local immune responses.52
TGFβ
IL
1β CTLA4 In these lymphoid follicles—especially in germinal
CD80 CD28 , IL RA Treg GITR
CD86 6,
TG FOXP3 CCR7
IL 10, TGFβ centres of secondary lymphoid follicles—antigen
Fβ retention, immunoglobulin class switching, and affinity
; IL
23
IL 23R maturation occur.52 The B cells are oligoclonal in nature,
CCR4
Th17 CCR6 suggesting antigen-specific induction of the B-cell
IL 17A, IL 17F, IL 21, IL 22
RORyT follicles.50 Which antigens might be involved is not
known, but microbial antigens, cigarette smoke-derived
Figure 3: Dendritic cells driving CD4+ T helper cell differentiation and CD8+ T-cell cytotoxicity antigens, breakdown products from extracellular matrix,
MHC I-restricted dendritic cells present antigenic peptides to CD8+ T cells, whereas MHC II-restricted dendritic and autoantigens have been suggested.51 Therefore, the
cells drive the differentiation of naive CD4+ T cells towards T helper (Th) 1, Th2, Th17 cells or regulatory T cells pathogenic role of the follicular B-cell response is
(Treg) depending on the cytokine balance in the local microenvironment. The different Th cell subsets and
Treg cells are characterised by different transcription factors and membrane-bound receptors (eg, chemokine
controversial; it might be beneficial, if protective against
receptors) and produce different cytokines. IL=interleukin. CXCR=chemokine (c-x-c motif) receptor. microbial colonisation and infection of the lower
CCR=chemokine (c-c motif) receptor. INF=interferon. TNFα=tumour necrosis factor α. GATA-3=GATA binding respiratory tract; or by contrast, it could be detrimental, if
protein 3. GITR=glucocorticoid-induced tumour necrosis factor-related protein. CD=cluster of differentiation. directed against lung tissue antigens, suggesting an
CTLA=cytotoxic T-lymphocyte antigen. TGFβ=transforming growth factor β. FOXP3=forkhead box P3.
RORγT=retinoid related orphan receptor gamma T.
autoimmune component in the pathogenesis of COPD
and especially emphysema.11

Moreover, B cells organised into lymphoid follicles have Infection in COPD


been shown around small airways49 and in lung Infections of the respiratory tract contribute to the
parenchyma50 of patients with COPD, especially in severe pathogenesis and course of COPD in at least two different
and very severe disease. As seen in other tissues that are ways.57 First, viral and bacterial infections are the most
affected by chronic inflammation, lymphoid follicles in important cause of acute exacerbations of COPD. As
patients with COPD result from lymphoid neogenesis51 airflow obstruction progresses in COPD, the frequency
and belong to the inducible Bronchus-Associated of exacerbations greatly increases.58 Second, colonisation
Lymphoid Tissue (iBALT), an ectopic lymphoid tissue and chronic infection of the lower airways by respiratory
that is formed on infection or inflammation in both mice pathogens can amplify and perpetuate chronic inflam-
and man.52 iBALT acquires antigens from the airways, mation in stable COPD. The frequency of chronic
initiates local immune responses, and maintains memory bacterial colonisation and infection increases progres-
cells in the lungs. sively with disease severity.59,60
Lymphoid follicles are anatomically and functionally Importantly, in COPD, phagocytosis of bacteria such
well organised, consisting of a specific arrangement of as Haemophilus influenzae and Streptococcus pneumoniae
memory and naive B cells, T cells, dendritic cells, and by alveolar macrophages is impaired.61,62 Monocyte-
follicular dendritic cells, which allow for T-cell and B-cell derived macrophages and alveolar macrophages from
priming and clonal expansion.51 Plasmacytoid dendritic patients with COPD showed significantly decreased
cells have been recorded in peribronchiolar lymphoid phagocytic responses to bacteria compared with non-
follicles of patients with COPD.53 B-cell activating factor smokers and smokers.63 The impairment of phagocytosis
of tumour necrosis factor family (BAFF) is overexpressed of bacteria by alveolar macrophages in COPD
in lymphoid follicles in lungs of patients with COPD, contributes to chronic bacterial colonisation and to
compared with controls, suggesting that the BAFF to acute infectious exacerbations.
BAFF-receptor pathway contributes to the development Bacteria such as H influenzae, S pneumonia, and
and maintenance of lymphoid follicles in COPD.54 Moraxella catarrhalis are detected in about 25% of patients
Moreover, pulmonary BAFF expression correlates to the with stable COPD and in more than 50% of patients
degree of airflow limitation and hypoxia, two important during COPD exacerbations.64 Bacterial exacerbations
markers of disease severity. lead to increased airway and systemic inflammation, as a

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result of direct effects of bacteria and of the host response.57 A B


Several PAMPs of bacteria, including lipopolysaccharides,
peptidoglycans, and outer-membrane proteins, are sensed
by specific PRRs on epithelial cells and innate immune
cells (table 4), triggering the nuclear factor-κB pathway
and other signal transduction pathways such as p38
mitogen-activated protein kinase and interferon regulatory
factors, resulting in the production of pro-inflammatory
cytokines and chemokines (figure 2). TLR signalling in
100 μm 100 μm
macrophages seems to link phagocytosis, a biological
process to remove extracellular organisms, to autophagy,
(webappendix p 3).65,66 Not only an increase in the C D
concentration of bacteria that colonise the lower airways
in patients with COPD, but also the acquisition of a new
bacterial strain is crucial in the pathogenesis of
exacerbations.67 In patients with severe COPD, exacer-
bations can be caused by Pseudomonas aeruginosa.
Viruses can be detected in 10–15% of sputum samples
in patients with stable COPD, and in 30–60% of those
with COPD exacerbations, dependent on the sensitivity of 100 μm 100 μm
the detection method.68 Rhinoviruses and influenza virus
are the respiratory viruses that are most frequently Figure 4: Dendritic cells in chronic obstructive pulmonary disease (COPD)
(A and B) Accumulation of dendritic cells in small airways of patients with COPD. Langerin+ dendritic cells (brown) in
associated with exacerbations of COPD. Rhinoviruses are
human lung tissue cryosections of (A) a smoker without COPD and (B) a patient with stage II COPD according to the
isolated from nasal and lung fluid from patients with global initiative for chronic obstructive lung disease (GOLD) scale. (C) Immunohistochemical double staining for
acute exacerbations of COPD,69 indicating that rhino- dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin+ (DC-SIGN+) interstitial-type
viruses infect upper and lower airway epithelial cells. dendritic cells (red) and langerin+ Langerhans type dendritic cells (blue) in small airways of human lung. Langerin+
cells are mainly present in the epithelium, whereas DC-SIGN+ cells are localised in the lamina propria and adventitia.
In induced rhinovirus infection in volunteers with There are no double positive cells, confirming the segregation of these two dendritic cell subsets in human lung.
COPD, Johnston and colleagues70 showed a causal relation (D) Identification of plasmacytoid dendritic cells in a lymphoid follicle of a patient with COPD GOLD stage II. Triple
between rhinovirus infection and COPD exacerbations. staining of a cryosection of human lung tissue for CD3 (blue colour indicates the T-cell zone), CD20 (red-pink colour
After rhinovirus infection, patients with COPD developed indicates the B-cell zone) and BDCA-2 (brown colour indicates plasmacytoid dendritic cells). Plasmacytoid dendritic
cells (arrows) are mainly found in the T-cell zone of lymphoid follicles.
lower respiratory symptoms, airflow obstruction, and
systemic and airway inflammation that were greater and
Ligands Target cells
lengthier than in controls; virus load was higher in
patients with COPD, whereas interferon production by CC-motif chemokine receptors

bronchoalveolar lavage cells was impaired.70 CCR2 CCL2/MCP-1 Monocytes, immature dendritic cells, T cells

Severe COPD exacerbations needing hospitalisation CCR5 CCL3/MIP-1α, CCL4/MIP-1β, CCL5/RANTES Monocytes, immature dendritic cells, T cells
were associated with increased sputum neutrophilia, CCR6 CCL20/MIP-3α Immature dendritic cells, T cells
irrespective of viral or bacterial infections, whereas CCR7 CCL19/MIP-3β, CCL21/SLC Mature dendritic cells, T cells, B cells
sputum eosinophils were increased during viral CXC-motif chemokine receptors
exacerbations.71 CD4+ T cells from bronchoalveolar lavage CXCR1 CXCL8/IL 8 Neutrophils, monocytes
fluid from patients with COPD showed a mixed Th1 and CXCR2 CXCL8/IL 8, CXCL1/GRO-α Neutrophils, monocytes
Th2 cell cytokine phenotype during acute rhinovirus CXCR3 CXCL9/Mig, CXCL10/IP-10, CXCL11/I-TAC T cells
infection.69 Human rhinovirus-encoded proteinase 2A CXCR5 CXCL13/BCA-1 B cells
induced strong Th1 and Th2 immune responses from
Simplified and non-limiting table of chemokines and chemokine receptors implicated in COPD. CCL=chemokine
CD4+ T cells, implicating this microbial proteinase as an (c-c motif) ligand. CXCL=chemokine (c-x-c motif) ligand. MCP 1=monocyte chemoattractant protein 1.
adjuvant factor during respiratory tract infections in MIP=macrophage inflammatory protein. RANTES=regulated on activation normal T-cell expressed and secreted.
patients with COPD69 (figure 3). SLC=secondary lymphoid tissue chemokine. IL 8=interleukin 8. GRO-α=growth related oncogene α. Mig=monokine
induced by interferon γ. IP-10=interferon-γ inducible protein of 10 kDa. I-TAC=interferon-inducible T-cell-α
Studies of sputum and bronchoalveolar lavage showed chemoattractant. BCA-1=B-cell attracting chemokine.
increased concentrations of neutrophils, CXCL8, TNFα,
and proteases (neutrophil elastase and MMP-9) in Table 3: Chemokines and chemokine receptors in chronic obstructive pulmonary disease (COPD)
COPD patients and bacterial colonisation compared
with those without bacterial pathogens.57 The locally to the development of B-cell lymphoid follicles
colonisation-induced triggering of PRR by microbial and mucosal IgA production, and systemically to the
PAMPs thus amplifies the chronic neutrophilic airway production of IgG antibodies in serum. Strain-specific
inflammation in COPD. Patients with COPD develop immunoglobulin responses reduce the risk of
specific adaptive immune responses to colonising exacerbation after acquisition of a new bacterial strain
bacteria. These adaptive immune responses contribute and contribute to clearance of the pathogen.72

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slgA
Antigen

Epithelium

Lymphoid follicle
IgA
Plasma cell
IL 1β CCL3,4,5
CXCL9,10,11 IL 18/IL 23 ECM breakdown fragments
FDC
CXCR3
CCR5 IL 18R

IL 23R IgM, IgG


Antibody
CD8+ cytotoxic BAFF
LTβR
T cell
BAFF-R
Th17 cell
Th1 cell CXCL12
B cell CXCL13
CXCR5 LTα1β2
T cell CCL19
CCL21
Perforins
Granzymes CCR7
IFNγ
TNFα
IL 17A
IL 17F
IL 21 HEV
IL 22
Smooth muscle cell Dendritic cell

Figure 5: Adaptive immune responses in chronic obstructive pulmonary disease (COPD)


Cigarette smoke-derived antigens, microbial antigens (from viral or bacterial colonisation and infection of the lower respiratory tract), breakdown products from extracellular matrix (such as collagen
and elastin fragments) and possibly lung tissue autoantigens (eg, epithelial antigens or smooth muscle antigens) can elicit adaptive immune responses in the lungs of patients with COPD,
encompassing cytotoxic CD8+ T cells, T helper (Th)1 and Th17 CD4+ T cells, and B-cell responses with antibody production. Peribronchiolar lymphoid follicles are organised in T-cell and B-cell
compartments through the lymphoid homoeostatic chemokines CCL19 and CCL21 (attracting CCR7+ naive T cells and dendritic cells) and CXCL12 and CXCL13 (binding to CXCR5 on B cells),
respectively. In these lymphoid follicles—which belong to the inducible Bronchus-Associated Lymphoid Tissue—local immunoglobulin production, including production of protective mucosal
immunoglobulin (Ig) A, occurs rapidly and efficiently. sIgA=secretory immunoglobulin A. FDC= follicular dendritic cells. BAFF=B-cell activating factor of tumour necrosis factor family.
BAFF-R=B-cell activating factor of tumour necrosis factor family-receptor. CCL=chemokine (c-c motif) ligand. CCR=chemokine (c-c motif) receptor. CXCL=chemokine (c-x-c motif) ligand.
CXCR=chemokine (c-x-c motif) receptor. HEV=high endothelial venules. LT=lymphotoxin. ECM=extracellular matrix. TNFα=tumour necrosis factor α. CD=cluster of differentiation.

Is COPD an autoimmune disease? epithelial cells, including anti-Hep-2 epithelial cell IgG
On the basis of the presence of B-cell lymphoid follicles autoantibodies, were recorded more frequently in patients
in patients with advanced COPD and the detection of with COPD than in controls.73 Serum concentrations of
diverse autoantibodies in serum of a subgroup of patients antitissue antibodies, especially antismooth muscle-
with COPD,44,73,74 COPD has been regarded as an auto- antigen antibodies, were present in a fifth of patients with
immune disease.11 Lee and colleagues44 showed the COPD with a recent history of hospitalisation for
presence of antielastin antibody and Th1 responses in exacerbation of COPD, and correlated with the severity of
patients with COPD, which correlated with severity of airflow limitation.74 Finally, antinuclear autoantibodies
emphysema. However, several other research groups were more prevalent in patients with COPD than in
could not detect increased antielastin antibody titres in healthy controls, but these molecules were not associated
patients with COPD. Greene and colleagues75 reported no with smoking status or FEV1, hence the pathological
significant differences in the levels of antielastin or importance of these observations is unclear.74,75
anti-N-acetylated proline-glycine-proline (Pro-Gly-Pro)
autoantibodies in three groups of patients with chronic Why does pulmonary inflammation persist
inflammatory lung disease (cystic fibrosis, α1-antitrypsin despite smoking cessation?
deficiency, and COPD) compared with healthy controls. Airway inflammation in patients with COPD persists
Moreover, smoke exposure but not disease state seemed after smoking cessation.76 Although autoimmunity might
to be the main determinant of antielastin antibody contribute to the perpetuation of pulmonary inflammation
concentrations.76 Antibodies against primary pulmonary in a subgroup of patients with advanced COPD and

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emphysema, several other mechanisms are likely to be


PAMP PRR (cellular [soluble])
involved in persistence of the inflammatory response
despite smoking cessation. These mechanisms are not Bacteria

mutually exclusive and encompass self-perpetuating Streptococcus pneumoniae Lipoteichoic acid, pneumolysin TLR2, TLR4, PAFR
Peptidoglycan NOD1, NOD2, [LBP]
innate immune responses, airway wall remodelling, CpG dinucleotides TLR9
impaired macrophage clearance, chronic colonisation Phosphorylcholine [CRP]
and infection of the lower airways, oxidative stress, tissue Haemophilus influenzae LPS TLR4 and CD14, [LBP]
hypoxia, genetic susceptibility, and epigenetic changes.21 OMP P6, OMP P2 TLR2
Peptidoglycan NOD1, NOD2
First, destruction of extracellular matrix (collagen,
Moraxella catarrhalis LPS TLR4 and CD14, [LBP]
elastin, and hyaluronan), releases proinflammatory
Usp A1 NOD1, NOD2, CAECAM1
fragments that are chemotactic for neutrophils and Usp A2 PAFR
monocytes, sustaining inflammation even when the Pseudomonas aeruginosa LPS TLR4 and CD14, [LBP]
initial stimulus is gone.77 CXC chemokines mediate Flagellin TLR5
neutrophil attraction to sites of tissue injury, and matrix Viruses
fragments of collagen—including the tripeptide N-acetyl Rhinovirus dsRNA TLR3, MDA5
Pro-Gly-Pro—are important neutrophil chemoattrac- Influenza dsRNA TLR3, RIG-I, MDA5
tants.78 Furthermore, fragments of elastin have major ssRNA TLR7, TLR8
chemotactic activity, inducing recruitment of monocytes TLR=Toll-like receptor. PAFR=plateled-activating factor receptor. NOD=nucleotide-binding oligomerisation
and macrophages in experimental models of emphysema. domain-containing protein. LBP=lipopolysaccharide-binding protein. CRP=C-reactive protein. LPS=lipopolysaccharide.
Additionally, other constituents or fragments of the OMP=outer membrane protein. Usp=ubiquitous surface protein. CAECAM1=carcinoembryonic antigen-related cell
adhesion molecule 1. dsRNA=double stranded RNA. ssRNA=single stranded RNA. MDA5=melanoma
extracellular matrix such as tenascin C, biglycan, and low
differentiation-associated gene 5. RIG-I=retinoic acid-inducible gene I.
molecular weight hyaluronan contribute to the
perpetuation of the inflammatory response, partly Table 4: Microbial pathogens, pathogen associated molecular patterns (PAMP), and pattern recognition
through activation of TLR2, or TLR4, or both (table 2). receptors (PRR) in chronic obstructive pulmonary disease

Second, the removal of apoptotic cells (termed


efferocytosis) is a highly conserved process, and is inflammatory genes and HIF-1α.80 Fifth, expression of
essential for the resolution of inflammation and the several microRNAs—which negatively regulate protein
maintenance of lung integrity.13 In COPD, apoptotic cells expression (webappendix p 4)—is significantly decreased
are increased because of enhanced induction of apoptosis in induced sputum of patients with COPD.81 Of particular
and deficient phagocytosis of apoptotic cells by alveolar interest is the decreased expression of microRNA let-7c in
macrophages, which lead to impaired resolution of sputum of smoking patients with COPD, because let-7c
inflammation. In a murine model of COPD, acute and not only regulates several inflammatory genes such as
subacute cigarette exposure suppresses efferocytosis by TNFR-II, but has also been implicated in oncogenesis
alveolar macrophages.79 Moreover, apoptosis of neutrophils (eg, lung cancer).82,83
followed by efferocytosis not only prevents damage, but Importantly, in patients with COPD oxidative stress
also induces an anti-inflammatory macrophage phenotype persists after smoking cessation, and has a crucial role in
(M2 or alternatively activated macrophages). By contrast, perpetuation of pulmonary inflammation (webappendix
failed efferocytosis of apoptotic neutrophils leads to p 2). The reduced histone deacetylase 2 activity in COPD
secondary necrosis, which results in the release of has been linked to increased acetylation of the central
DAMPs, neutrophil elastase, and other toxic components antioxidant transcription factor Nrf 2, impairing Nrf 2
into the extracellular space (figure 2). activity and the upregulation of antioxidant enzymes in
Third, impaired innate lung defences predispose response to oxidative stress.84 Impairment of Nrf2-
patients to microbial colonisation and infection of the mediated antioxidant defences and epigenetic changes
lower respiratory tract, which causes additional airway induced by reactive oxygen species (eg, histone
epithelial injury. This cyclical sequence of events amplifies modifications) contribute to the persistence of oxidative
chronic inflammation and perpetuates microbial stress in COPD.9,85,86
infections that are characteristic of severe COPD.57 Fourth,
local tissue hypoxia in patients with COPD can perpetuate Therapeutic implications
lung inflammation, because of an important bidirectional Smoking cessation attenuates the accelerated decrease
communication between hypoxia and inflammation.80 In in lung function in patients with COPD.87,88 A pooled
hypoxic conditions, hypoxia-inducible factor 1α (HIF1α) analysis of three bronchial biopsy studies showed that,
translocates frFom the cytoplasm to the nucleus, inducing in established COPD, the numbers of inflammatory
transcription of multiple genes, including those of TLRs cells in the bronchial mucosa are much the same as in
and nuclear factor-κB. HIF-1α prolongs the lifespan of former smokers and in persistent smokers.76 How-
neutrophils by inhibiting apoptosis. Conversely, inflamed ever, analysis of bronchoalveolar lavage fluid of
tissues often become hypoxic and activation of the COPD patients suggests that smoking cessation
nuclear factor-κB pathway leads to the transcription of partly changes the macrophage polarisation from a

www.thelancet.com Vol 378 September 10, 2011 1023


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proinflammatory M1 towards an anti-inflammatory mannose receptor on alveolar macrophages, which


M2 macrophage phenotype.89 improves the phagocytosis of apoptotic cells.100
Regular treatment with long-acting bronchodilators is Several molecular and cellular mediators of the innate
the mainstay of therapy in symptomatic patients with and adaptive immune responses, are regarded as new
For more on clinical trials for moderate to severe COPD, but only a few randomised therapeutic targets. Possible new drugs for COPD
COPD see http://clinicaltrials. controlled trials have investigated the effects of pharma- encompass modulators of TLRs, chemokine receptor
gov/ct2/results?term=COPD
cological treatment on the underlying bronchial and antagonists, protease inhibitors (eg, small-molecule
pulmonary inflammation.90–92 3-month treatment with the neutrophil elastase inhibitors and inhibitors of MMP-9
inhaled corticosteroid fluticasone-propionate did not and MMP-12) and anti-interleukin-17 targeted therapies
reduce numbers of CD8+ T cells, macrophages, or (including anti-interleukin-17 monoclonal antibodies and
neutrophils in bronchial biopsy samples,91 whereas tocilizumab, which targets the interleukin-6 receptor and
combination therapy of salmeterol xinafoate and thereby favours the differentiation towards Treg instead of
fluticasone was associated with a reduction in CD8+ cells Th17 cells). However, specific targeted anti-inflammatory
on biopsy samples.92 Whereas—especially mild to therapy with the anti-TNFα monoclonal antibody
moderate—asthma is usually highly responsive to inhaled infliximab has failed in COPD.101 An alternative approach
corticosteroid therapy, COPD patients respond poorly to is to try to restore glucocorticoid sensitivity in patients
such treatment. The differences in corticosteroid with COPD.85 Dependent on the underlying molecular
responsiveness between asthma and COPD are due to mechanism of glucocorticoid resistance, patient-specific
several molecular mechanisms, including oxidative stress.83 therapies need to be investigated, encompassing anti-
Cigarette smoke and stress from reactive oxygen species oxidants, theophylline, or kinase inhibitors such as
can prevent nuclear translocation of the glucocorticoid mitogen-activated protein kinase inhibitors or phos-
receptor or decrease the activity of the co-repressor protein phatidylinositol-3 kinase inhibitors.86,102,103
histone deacetylase 2, reducing the ability of corticosteroids Contributors
to switch off inflammatory gene expression.85,93 Additionally, GGB contributed to the literature search, writing and revision of the report.
differences in the type of the underlying immune responses GFJ co-supervised the preclinical and clinical work that is the basis of this
report and reviewed and edited the report. KRB contributed to the literature
between asthma and COPD, might contribute to search, created the tables and figures, and reviewed and edited the report.
differential corticosteroid responsiveness.93,94 The Th2-
Conflicts of interest
driven eosinophilic airway inflammation in mild allergic GGB is a member of advisory boards for AstraZeneca,
asthma is highly responsive to inhaled corticosteroids, Boehringer-Ingelheim, GlaxoSmithKline, and Novartis; has been a
implicating this drug class as the mainstay treatment in consultant for Amakem; and has received speaker’s fees from
persistent asthma. By contrast, the chronic neutrophilic AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Merck,
Novartis, Pfizer, and UCB. GFJ is a member of advisory boards for
airway inflammation in COPD is resistant to steroids.95 AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck, Novartis,
Short-term courses of oral corticosteroids are effective for and Nycomed; has received grants or has grants pending from
acute exacerbations of COPD. However, chronic treatment AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, and
with systemic corticosteroids should be avoided in patients UCB; and has received speaker’s fees from Almirall, AstraZeneca,
Boehringer-Ingelheim, GlaxoSmithKline, Merk Novartis, Pfizer, and
with stable COPD.96 UCB. KRB declares that he has no conflicts of interest.
In patients with COPD, the specific phosphodiesterase-4
Acknowledgments
inhibitor roflumilast significantly reduced the absolute We thank all collaborators at the Laboratory for Translational Research of
number of neutrophils in sputum and the concentrations Obstructive Pulmonary Disease, Department of Respiratory Medicine,
of CXCL8 and neutrophil elastase in sputum super- Ghent University Hospital and Ghent University, Ghent, Belgium;
Professor Patrick Venables for helpful insights into autoantibodies; and
natants.97 This anti-inflammatory effect of roflumilast
the Interuniversity Attraction Poles Program (Belgian State, Belgian
might correlate with its reduction of exacerbations in Science Policy, Project P6/35), the Fund for Scientific Research Flanders
severe COPD patients with chronic bronchitic symptoms and the Concerted Research Action of Ghent University for funding.
and a history of COPD exacerbations.98 In this COPD References
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