Therapeutic Advances in Respiratory Disease

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COPD: a multifactorial systemic disease

Alice Huertas and Paolo Palange
Ther Adv Respir Dis 2011 5: 217 originally published online 23 March 2011
DOI: 10.1177/1753465811400490

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 Therapeutic Advances in Respiratory Disease Review

Ther Adv Respir Dis

COPD: a multifactorial systemic disease (2011) 5(3) 217—224
DOI: 10.1177/
1753465811400490
Alice Huertas and Paolo Palange
! The Author(s), 2011.
Reprints and permissions:
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Abstract: Chronic obstructive pulmonary disease (COPD) has traditionally been considered a journalsPermissions.nav
disease of the lungs secondary to cigarette smoking and characterized by airflow obstruction
due to abnormalities of both airway (bronchitis) and lung parenchyma (emphysema). It is now
well known that COPD is associated with significant systemic abnormalities, such as renal and
hormonal abnormalities, malnutrition, muscle wasting, osteoporosis, and anemia. However, it
is still unclear whether they represent consequences of the pulmonary disorder, or whether
COPD should be considered as a systemic disease. These systemic abnormalities have been
attributed to an increased level of systemic inflammation. Chronic inflammation, however, may
not be the only cause of the systemic effects of COPD. Recent data from humans and animal
models support the view that emphysema may be a vascular disease. Other studies have
highlighted the role of repair failure, bone marrow abnormality, genetic and epigenetic factors,
immunological disorders and infections as potential causes of COPD systemic manifestations.
Based on this new evidence, it is reasonable to consider COPD, and emphysema in particular,
as ‘a disease with a significant systemic component’ if not a ‘systemic disease’ per se. The aim
of this review is to give an overview of the most relevant and innovative hypothesis about the
extrapulmonary manifestations of COPD.

Keywords: chronic obstructive pulmonary disease, inflammation, oxidative stress, systemic

manifestations

Introduction the last two decades, including renal and hor- Correspondence to:
Paolo Palange, MD
The American Thoracic Society and the monal abnormalities [Palange, 1998], muscle Department of Public
European Respiratory Society define chronic wasting [Remels et al. 2007], osteoporosis Health and Infectious
Diseases, Sapienza
obstructive pulmonary disease (COPD) as ‘a pre- [Bolton et al. 2004], anemia [John et al. 2005] University of Rome, Rome,
ventable and treatable disease state characterized and reduction in circulating bone marrow pro- Italy
paolo.palange@
by airflow limitation that is not fully reversible. genitors [Palange et al. 2006]. Although these uniroma1.it
The airflow limitation is usually progressive and systemic manifestations have been described for Alice Huertas, MD
is associated with an abnormal inflammatory years in COPD patients, it is still unclear whether Department of Public
Health and Infectious
response of the lungs to noxious particles or they represent consequences of the pulmonary Diseases, Sapienza
gases, primarily caused by cigarette smoking. disorder, or whether COPD should be consid- University of Rome, Rome,
Italy
Although COPD affects the lungs, it also pro- ered as a systemic disease. The importance of INSERM U999 ‘‘Pulmonary
duces significant systemic consequences’ [Celli establishing the distinction between a respiratory Hypertension:
Pathophysiology and Novel
and MacNee, ATS/ERS Task Force, 2004]. It is disease with extrapulmonary manifestations and Therapies’’ Centre
interesting to point out how the definition of a systemic inflammatory state with multiple com- Chirurgical Marie
Lannelongue, Le Plessis-
COPD has evolved including the ‘systemic con- promised organs is justified by different thera- Robinson, France;
sequences’ of the disease. peutic options: in the first definition, therapy is University Paris-Sud 11,
Orsay, France
primarily centered on the lungs, whereas in the
The natural history of the disease reveals numer- second, therapy could aim at the systemic inflam-
ous extrapulmonary manifestations and comor- matory state.
bidity factors that complicate the evolution of
COPD, thereby altering the prognosis and qual- Furthermore, since COPD represents a group of
ity of life of patients [Barnes and Celli, 2009; pulmonary abnormalities of either airways (bron-
Agusti and Soriano, 2008]. Many extrapulmon- chitis) or lung parenchyma (emphysema), it is
ary effects of COPD have been described over reasonable to raise the question: does the

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Therapeutic Advances in Respiratory Disease 5 (3)
systemic involvement of the disease vary depend-
ing on the etiology and pathophysiology of each
of the two different COPD phenotypes?
The aim of this review is to give an overview of
the most relevant and innovative hypotheses
regarding the extrapulmonary manifestations of
COPD.
Systemic inflammation
Among the numerous extrapulmonary effects of
COPD, systemic inflammation has been widely
studied and considered as an important key
between the pulmonary disease and the related
systemic manifestations. Many studies have
reported changes in various inflammatory cells
and mediators, including neutrophils, lympho-
cytes, acute-phase reactants, and cytokines.
Gan and colleagues recently performed a meta-
analysis that showed systemic inflammation is pre-
sent during COPD exacerbations and stable
phases of the disease: increased numbers of leuko-
cytes, levels of acute-phase response proteins
(C-reactive protein and fibrinogen), cytokines
such as interleukin (IL)-6, and tumor necrosis
factor (TNF)-a are present in the peripheral
blood of COPD patients [Gan et al. 2004].
Systemic inflammation has been implicated in
the pathogenesis of the majority of COPD sys-
temic effects, including weight loss [Wouters,
2002], skeletal muscle dysfunction [Langen et al.
2001], cardiovascular diseases [Sin and Man,
2003], and osteoporosis [Biskobing, 2002],
although it is still controversial whether this so-
called low-grade systemic inflammation represents
the consequence of pulmonary inflammation into
the systemic vascular bed [Agustı̀ et al. 2003], or
whether it is a systemic inflammation. Vernooy
and colleagues, as well as Hurst and colleagues,
failed to show a relationship between TNF-a and
IL-8 values in induced sputum and plasma, sug-
gesting that the systemic inflammation in COPD
is not linked to the pulmonary inflammation in
these patients [Hurst et al. 2005; Vernooy et al.
2002]. Although inflammation is certainly one of
the major features of COPD, we still need to
understand whether the local inflammation is suf-
ficient to induce systemic effects, or whether a
second pathogenetic event is required.
Therefore, further studies are needed to elucidate
the origin of the systemic inflammation in COPD.
Malnutrition
Several studies have demonstrated an association
between poor nutrition and COPD, where weight
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loss and low body mass index (BMI) are associ-
ated with increased mortality [Schols et al. 1998;
Gray-Donald et al. 1996]. Interestingly, a ran-
domized, controlled trial showed that nutritional
supplementation resulted in improved exercise
capacity in well nourished, but not in undernour-
ished patients [Steiner et al. 2003]. It is also
known that patients with low BMI have higher
levels of inflammation than normal BMI patients
[Huertas et al. 2010]. On the other hand, it has
been shown that patients who have relative anor-
exia and high levels of inflammation are least
likely to respond to nutritional supplementation
[Creutzberg et al. 2000]. Therefore, it is reason-
able to wonder whether the inflammation causes
the reduction in BMI, whether the low BMI
induces a higher level of inflammation, or
whether a factor causing both inflammation and
low BMI could exist in these patients.
Understanding this aspect is important in order
to choose whether to treat the inflammation or
the outcome.
Vascular abnormalities
The loss of alveolar capillary endothelial cells has
been observed in emphysema for almost 50 years
[Liebow, 1959], but new data derived from inves-
tigations on the vascular nature of emphysema
suggest a systemic involvement of the disease
[Voelkel and Taraseviciene-Stewart, 2005; Santos
et al. 2002; Shapiro, 2000; Yamato et al. 1996].
The vascular endothelial growth factor (VEGF)
plays an important role in the vascular pathogen-
esis of COPD, particularly in emphysema. The
VEGF has a fundamental role in physiological
and pathophysiological angiogenesis and regula-
tion of endothelial cell differentiation. This has
been demonstrated by the lethality of VEGF
knockout mice and by the abnormal vasculogen-
esis of the heart and large vessels following the loss
of a single copy of the VEGF gene [Carmeliet et al.
1996]. The VEGF, also known as the vascular per-
meability factor, displays several key functions in
the lung, such as migration and proliferation of
endothelial cells, monocyte adhesion, angiogene-
sis, vasodilatation, and enhanced permeability, as
well as early hemangioblast development. Above
all, a crucial role in the genesis of emphysema
has been developed based on the observation
that blockade of VEGF receptor (VEGFR) -1
and -2 arrests lung growth and leads to an emphy-
sematous phenotype in a murine model
[McGrath-Morrow et al. 2005]. Therefore, an
interesting model of VEGFR blockade with
SU5416 results in endothelial cell apoptosis
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causing apoptosis-dependent emphysema in
rodents [Tang et al. 2004; Kasahara et al. 2000].
Alveolar maintenance is defined as the preserva-
tion of the alveolar gas-exchange area by limiting
the destruction of alveoli and airspace enlarge-
ment, the hallmark of emphysema. The finding
that decreased VEGF or VEGF signaling causes
experimental emphysema leads to the concept
that alveolar maintenance is required for struc-
tural preservation of the lung. This structure,
when disrupted by cigarette smoke, for example,
causes emphysema [Taraseviciene-Stewart and
Voelkel, 2008; Tuder and Voelkel, 2001].
Therefore, it appears quite legitimate to raise
the question whether maintaining cell homeosta-
sis by growth factors, such as VEGF, could
rescue emphysema. Unfortunately, no data are
so far available on the potential benefits of
VEGF gene therapy in emphysematous lung.
VEGF is a tightly regulated gene in the lung,
playing specific roles in different structural and
cellular compartments. While the VEGF protein
and mRNA contents in the lung are reduced in
severe emphysema, VEGF gene expression is
increased in the pulmonary arteries of smokers
and patients with moderate COPD, and corre-
lates with medial thickening of the pulmonary
vascular walls [Santos et al. 2003]. These data
confirm the systemic pathogenesis of emphy-
sema, but also underlie the multifactorial aspect
of the disease [Yoshida and Tuder, 2007].
Repair failure
The destruction of the alveolar walls leading to
enlargement of the alveolar spaces, which is a
well known characteristic of emphysema, could
also be considered as the result of an impaired
repair capacity. In addition to this, there is an
indication that lung repair, as evidenced by de
novo synthesis and tissue accumulation of elastin
and collagen, is inhibited by cigarette smoke
[Rennard et al. 2006]. Exposure to cigarette
smoke extract also inhibits fibroblast proliferation
[Nakamura et al. 1995], and fibroblasts isolated
from patients with emphysema exhibit decreased
proliferative capacity [Holz et al. 2004; Nobukuni
et al. 2002]. Exposure to cigarette smoke extract
induces cell-cycle arrest in fibroblasts, mediated
through the activation of p53 and p16, which
inhibit the cell cycle, leading to cellular senes-
cence [Nyunoya et al. 2006]. This may represent
a response of fibroblasts to DNA damage by cig-
arette smoke extract [Bartek et al. 2004]. This
may result in abnormal wound healing and
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A Huertas and P Palange
prevention of repair of lung injury. In addition,
cigarette smoke can kill endothelial cells and
endothelial cell precursors [Hoshino et al.
2005], and inhibit airway epithelial cell chemo-
taxis and proliferation [Wang et al. 2001].
Abnormal mesenchymal repair functions have
been observed in fibroblasts obtained from
emphysematous human lung. Holz and col-
leagues have demonstrated that fibroblasts cul-
tured from lungs of emphysematous patients
proliferate more slowly than fibroblasts obtained
from age-matched control lungs [Holz et al.
2004]. Rennard and colleagues have extended
these results to demonstrate that fibroblasts
from emphysematous patients are also less capa-
ble of responding to a chemotactic stimulus and
are less potent in contracting three-dimensional
collagen gels [Rennard et al. 2006].
It is unclear whether the differences between
fibroblasts obtained from normal or emphysema-
tous individuals represent underlying genetic dif-
ferences and hence susceptibility to develop
emphysema, or if they are an acquired defect.
Bone marrow-derived cells
Circulating bone marrow-derived progenitors
have been shown to be decreased in COPD
patients and to correlate with disease severity
[Huertas and Palange, 2011; Huertas et al.
2010; Palange et al. 2006; Fadini et al. 2006].
Several clinical factors have been implicated in
the mobilization of endothelial progenitor cells
(EPCs), and mechanisms have begun to be elu-
cidated. Defective lung development or defective
lung repair in the setting of protracted inflamma-
tion and injury may result in part from an inad-
equate contribution of local or circulating EPCs.
Age has previously been reported to be inversely
correlated with EPC number [Chang et al. 2007].
Newer data suggest that there are also differences
in the ability of EPCs to home to ischemic tissues
based on age, and that this may be mediated
through the inability of aged tissues to activate
normally the hypoxia-inducible factor-
1a-mediated hypoxia response [Llevadot et al.
2001].
It has also been shown that in COPD patients,
bone marrow dysfunction is related to lung func-
tion impairment, poor nutritional state, and
levels of systemic inflammation [Huertas et al.
2010]. In this study, patients with low BMI had
reduced circulating hemopoietic and endothelial
progenitor counts, suggesting lower progenitor
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Therapeutic Advances in Respiratory Disease 5 (3)
release from the bone marrow, pronounced sys-
temic inflammation with high levels of proangio-
genetic growth factors, and proinflammatory
markers, compared with normal BMI patients.
Interestingly, these growth factors and cytokines,
as well as BMI, were inversely correlated with
markers of disease severity. Furthermore,
among patients with similar pulmonary impair-
ment, those who displayed low BMI had a greater
bone marrow dysfunction.
All together, these data suggest that, in addition
to disease progression in terms of airflow obstruc-
tion, systemic involvement in COPD leads to a
more pronounced bone marrow impairment.
Whether this pool of precursor cells is reduced
as a consequence of the pulmonary disease or
whether the bone marrow involvement represents
a systemic disease needs to be defined.
Genetics and epigenetics
The genetic etiology of COPD is certainly in favor
of considering the disease as a systemic syndrome:
although smoking is considered to be the major
risk factor for COPD, only 15% to 20% of smo-
kers develop the clinically relevant disease [Celli
and MacNee, ATS/ERS Task Force, 2004;
Ouellette, 2004]. Genetic susceptibility to
COPD has been investigated in recent years and
numerous candidate genes have been found to
encode proteins that regulate: proteases and anti-
proteases (i.e. 1-antitrypsin, Serpine2, 1-antichy-
motrypsin, 2-macroglobulin, secretory leukocyte
proteinase inhibitor, matrix metalloproteinases
(MMP), ADAM33, protease-activated receptor-2);
mucociliary clearance (i.e. cystic fibrosis transmem-
brane regulator, mucins); antioxidants (i.e. micro-
somal epoxide hydrolase, glutathione-S-transferases,
cytochrome P450, extracellular superoxide dismut-
ase); inflammatory mediators (i.e. TNF-, IL-11,
IL-1 family). Interestingly, the MMP-1 promoter
has been shown to be a direct target of cigarette
smoke in lung epithelial cells and regions of the
human MMP-1 promoter have been recently
defined [Mercer et al. 2009]. This extensive list
of candidate genes attests to the relevance of the
genetic pathophysiology of COPD and, in partic-
ular, emphysema. Many animal models have
helped in defining the genes involved in the path-
ogenesis of this latter disorder, strongly suggesting
the systemic origin of the disease. Recently, cellu-
lar senescence has also been shown in a mouse
model of emphysema, where knocking out the
senescence marker protein-30, which protects
against aging, leads to airspace enlargement
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[Sato et al. 2006]. Interestingly, in experimental
models of emphysema, genes that encode proteins
important for the systemic immune response have
been shown to be involved. Mice lacking toll-like
receptor 4, which is activated during the innate
immune response, spontaneously developed
emphysema associated with an oxidative stress
imbalance (i.e. increased Nox3 gene expression,
a novel NAPDH oxidase, and elastin degradation)
[Zhang et al. 2006], but without any inflammatory
infiltration of the lung parenchyma.
Lung gene expression studies from endstage
COPD patients have shown impaired mitochon-
drial energy metabolism and protein synthesis
[Golpon et al. 2004], suggesting DNA damage
and posttranscriptional modifications, but little
is known about epigenetic marks in respiratory
diseases. Interestingly, it has been shown in
COPD that the expression and activity of histone
deacetylase (HDAC)-2 are markedly reduced in
lung parenchyma, bronchial biopsies, and alveo-
lar macrophages. This decrease is correlated with
disease severity and intensity of the inflammatory
response [Ito et al. 2005]. Overexpression or
knockdown of HDAC2 in alveolar macrophages
from COPD patients affects not only the inflam-
matory response but also corticosteroid respon-
siveness, suggesting an additional role for
HDAC2 in the anti-inflammatory actions of the
corticosteroid [Ito et al. 2006].
The clinical impact of cigarette smoking, which
ranges from negligible to endstage lung disease,
is, in part, determined by individual susceptibility
factors. Understanding the factors that lead to
emphysema is useful for predicting high-risk
individuals. Except for a1-antitrypsin, a defi-
ciency of which results in a predisposition to
smoking-induced emphysema, few other suscep-
tibility factors are defined. Genetic susceptibility
and epigenetic modifications strongly suggest a
systemic etiology of COPD, but further data are
needed to define better the precise etiopathology
of the disease.
Immunology
An interesting characteristic of emphysema is the
lack of attenuation in inflammatory and disease
parameters years after the cessation of smoking:
tobacco smoke seems to contain antigens that
induce immunological responses in susceptible
individuals. It might also be a more complex
pathogenesis in which smoking induces an auto-
immune response to an endogenous lung antigen.
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This alternative concept of emphysema patho-
genesis has been raised by Voelkel and colleagues,
who showed that humoral and CD4þ cell-
dependent mechanisms are sufficient to trigger
emphysema development, suggesting that alveo-
lar septal cell destruction might result from
immune mechanisms [Taraseviciene-Stewart
et al. 2005]. Using a murine model, they
showed that intraperitoneal injection of endothe-
lial cells causes emphysema, leading to alveolar
septal cell apoptosis, and the activation of
MMP-9 and MMP-2. Furthermore, naı̈ve
immunocompetent animals developed emphy-
sema following the administration of CD4þ T
cells. This hypothesis has also been investigated
in humans: by isolating peripheral blood CD4þ
T cells from emphysematous patients, Lee and
colleagues were able to show that exposure to cig-
arette smoke induces secretion of proteolytic
enzymes from cells of the innate immune
system. These cells liberate lung elastin fragments
which, in susceptible individuals, could initiate T
cell and B cell-mediated immunity against elastin
[Lee et al. 2007]. These data strongly suggest an
autoimmune pathogenesis of emphysema, charac-
terized by the presence of antielastin antibody and
T helper type 1 (Th1) responses that correlate
with emphysema severity.
It is interesting to point out that elastin is abun-
dant in various tissues, in particular in arteries,
arterioles, and skin. In addition to emphysema,
tobacco smokers are at high risk for coronary
artery disease, aortic aneurysms, and elastolytic
changes of the skin [Patel et al. 2006; Pepine et al.
2006]. These findings link emphysema to adap-
tive immunity against a specific lung antigen and
suggest the risk for smokers of developing auto-
immune diseases in other elastin-rich tissues,
such as arteries and skin. Findings of antielastin
autoimmunity in emphysema therefore suggest a
broader, systemic autoimmune process involving
the major elastin-bearing organs that may explain
these diverse clinical observations.
On the other hand, several clinical reports have
described cases of emphysema in patients with
hypocomplementemia, and in particular, those
with a history of hypocomplementemic urticarial
vasculitis. Although we need to better define this
possible pathogenesis, these reports suggest that
an impaired immunological condition could lead
to the development of emphysema [Jamison et al.
2008; Ghamra and Stoller, 2003], underlying the
systemic pattern of the disease.
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A Huertas and P Palange
Infections
Other observations keep the question of COPD
as a systemic disease open: emphysematous lung
destruction has been reported in other nonsmok-
ing-related disorders or hypersensitivity pneumo-
nitis [Tuder and Voelkel, 2001], and recent data
indicate that starvation causes lung cell apoptosis
in mouse lung [Massaro et al. 2004].
Furthermore, in a recent observational study,
HIV was identified as an independent risk
factor for COPD after adjusting for age, race,
pack-years of smoking, intravenous drug abuse,
and alcohol abuse. HIV subjects were 50—60%
more likely to receive a diagnosis of COPD
when these risk factors were taken into accounted
[Crothers et al. 2011, 2006]. A series of 114
HIVþ patients, when compared with 44 HIV—
controls, revealed a significantly higher rate of
emphysema among the HIVþ individuals [Diaz
et al. 2000]. When controlled for tobacco expo-
sure, the HIVþ subjects again had significantly
more emphysematous damage for a given level
of tobacco use. HIV is now frequently cited as a
susceptibility factor for the development of
emphysema, independently of cigarette smoking
status. The presence of common coexistent fac-
tors that may predispose patients to chronic lung
injury such as drugs, opportunistic infections,
and malnutrition, limits the scope of studies of
direct mechanisms involved in HIV-associated
emphysematous lung disease. Adding to the com-
plexity of HIV-associated COPD, several risk fac-
tors associated with HIV infection may
themselves play a pathogenic role in the develop-
ment of emphysema, such as infection or coloni-
zation with Pneumocystis, intravenous drug use,
malnutrition, etc. In the non-HIV infected pop-
ulation, Pneumocystis colonization has been asso-
ciated with increased severity of airway
obstruction in COPD [Morris et al. 2004;
Palange et al. 1994]. In the studied cohort of
patients, 36.7% of patients with GOLD stage
IV were colonized with Pneumocystis compared
with only 5.3% of patients with less severe
COPD or normal lung function. These data led
to the hypothesis that Pneumocystis colonization
may accelerate the development of airway
obstruction. Further studies of the pathogenic
role of fungal colonization in the development
of airspace enlargement in emphysema are
needed to understand better the role of coloniza-
tion by Pneumocystis and infection in the patho-
genesis of HIV-related emphysema. HIV-
seropositive individuals have a propensity to
develop emphysematous changes in their upper
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Therapeutic Advances in Respiratory Disease 5 (3)
lobes at an accelerated rate independently of their
smoking status. Confounding factors in HIV-
infected individuals, including Pneumocystis colo-
nization, drug use, and malnutrition, may play a
role in predisposition for emphysema. However,
HIV itself is emerging as an independent factor in
the pathogenesis of emphysema. A recent review
[Petrache et al. 2008] emphasized how HIV
infection may affect cytotoxic lymphocyte activa-
tion, lung capillary endothelial cell injury and
apoptosis, sphingolipid imbalance, and oxidative
stress in the lung. A better understanding of the
pathogenesis of HIV-associated pulmonary
emphysema may provide clues and therapeutic
targets that have broader application in this dis-
ease, including cigarette smoke-induced
emphysema.
Conclusion
Many extrapulmonary effects of COPD have
been described in the last two decades: some of
these manifestations have been extensively stud-
ied, but it is still unclear whether they represent
consequences of the pulmonary disorder, or
whether COPD should be considered as a sys-
temic disease. In this review, we have tried to
give an overview of the most relevant and inno-
vative hypothesis about the extrapulmonary
effects of COPD. Even if precise cellular and
molecular mechanisms are still unclear, evidence
has been provided suggesting that COPD, and
emphysema in particular, might be considered
as a systemic disease.
Further studies are needed to understand better
this complex and multifaceted disease in order to
treat patients with more specific tools.
Funding
This research received no specific grant from any
funding agency in the public, commercial, or not-
for-profit sectors.
Conflict of interest statement
The authors declare that there are no conflicts of
interest.
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