Hindawi Publishing Corporation
Mediators of Inflammation
Volume 2013, Article ID 769214, 19 pages
Macrophage Heterogeneity in Respiratory Diseases
Carian E. Boorsma,1,2Christina Draijer,1,2and Barbro N. Melgert1,2
1Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen,
Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
2GRIAC Research Institute, University Medical Center Groningen, University of Groningen,
Hanzeplein 1, 9713 GZ Groningen, The Netherlands
Correspondence should be addressed to Barbro N. Melgert; email@example.com
Received 12 October 2012; Accepted 15 January 2013
Academic Editor: Chiou-Feng Lin
Copyright © 2013 Carian E. Boorsma et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Macrophages are among the most abundant cells in the respiratory tract, and they can have strikingly different phenotypes within
this environment. Our knowledge of the different phenotypes and their functions in the lung is sketchy at best, but they appear
to be linked to the protection of gas exchange against microbial threats and excessive tissue responses. Phenotypical changes of
macrophages within the lung are found in many respiratory diseases including asthma, chronic obstructive pulmonary disease
(COPD), and pulmonary fibrosis. This paper will give an overview of what macrophage phenotypes have been described, what
their known functions are, what is known about their presence in the different obstructive and restrictive respiratory diseases
(asthma, COPD, pulmonary fibrosis), and how they are thought to contribute to the etiology and resolution of these diseases.
Most tissue macrophages are derived from hematopoietic
stem cells and their local expansion within tissues can be
due to local proliferation of existing macrophages or due
to infiltration of blood-derived monocytes, depending on
the circumstances. Traditionally characterized as the first
line of defense against foreign invaders, research in the past
decade has shown that their role extends to developmental
processes and maintenance of tissue homeostasis in many
ways [1, 2]. To fulfill these many different roles in tissue,
macrophages can adopt a myriad of phenotypes based on
signals they receive from their environment. From in vitro
studies a nomenclature was proposed similar to the Th1/Th2
dichotomy, with M1 macrophages being known as classically
activated macrophages induced by interferon gamma (IFN훾)
interleukin (IL)-4 and IL-13 [3, 4]. The M2 concept already
had to expand to M2a, M2b, and M2c to encompass the
these in vitro concepts have been hard to match to in situ
and tumor necrosis factor alpha (TNF훼) and M2 being
known as alternatively activated macrophages induced by
markers for the different phenotypes within tissue and by the
observation that in situ macrophage phenotypes appear as a
continuum rather than discrete entities [5, 6].
Macrophages are among the most abundant cells in
the respiratory tract and can be broadly divided into
two populations depending on their localization: alveolar
macrophages (AMs) that line the surface of alveoli and inter-
stitial macrophages (IMs) that reside in the space between
suggested that AM do not originate directly from blood
Compared with AMs, IMs are less efficient in phagocytosing
but are better at stimulating T-cell proliferation in vitro .
In addition, IMs as opposed to AMs, were also found to
. Although IMs and AMs have distinct functions, they
both are among the first to encounter allergens and other
threats to the lung homeostasis [8, 10, 11]. They are both
capable of quickly dealing with those without perturbing
normal gas exchange because they can adopt the most
effective phenotypes based on signals from surrounding
tissue. These phenotypical changes are also linked to many
2 Mediators of Inflammation
restrictive respiratory diseases (pulmonary fibrosis) changes
found. In this paper we will first briefly discuss the in vitro
generated phenotypes and then compare this with their role
in the pathogenesis of obstructive and restrictive respiratory
2. M1, M2, and Beyond
2.1. M1 Macrophages. Classically activated or M1 macropha-
ges develop after being exposed to IFN훾 and TNF훼 or
regulatory factor 5 (IRF5) . They are essential in host
defense against intracellular pathogens by generating reac-
tive oxygen species (ROS) and nitric oxide (NO) through
upregulated expression of inducible nitric oxide synthetase
(iNOS) and amplifying Th1 immune responses by producing
lipopolysaccharide (LPS, which induces TNF훼 production)
under the influence of the transcription factor interferon-
proinflammatory cytokines like IL-12, IL-1훽, and TNF훼
bilities, and enhanced production and secretion of matrix
metalloproteinases (MMPs) such as MMP7 and MMP9 [14–
17]. The secretion of MMPs enables macrophage migration
duringinflammatoryresponses, but excessive orunregulated
production results in tissue damage [5, 17].
(see also Figure 1) . In addition, they show enhanced
phagocytosis of microorganisms, antigen-presentation capa-
2.2. Alternative Activation. Alternatively activated or M2
macrophages were named to indicate that their activation
status was distinctly different from the classically activated
macrophages. First discovered to be induced by IL-4 and
IL-13 [18, 19], this phenotype was soon found to have more
in function [5, 20]. A variety of different names have been
suggested, but for the purpose of this paper we will adopt the
names suggested by Mosser and Edwards  and Sica and
Mantovani . They have suggested alternatively activated
or M2 macrophages for the phenotype induced by IL-4/IL-
13 and regulatory macrophages or M2-like cells for the
phenotype characterized by high IL-10 production that are
induced by a variety of stimuli (see also Figure 1).
13 under the influence of the transcription factor IRF4 ,
wound-healing macrophages because of their association
receptors and transglutaminase 2 in man and mice [19, 23]
and by upregulated expression of arginase-1, chitinase-3-
like protein-3 (Chi3l3, also known as Ym1), and resistin-
like molecule-훼 (Relm훼, also known as FIZZ1) in mice only
and clearance of apoptotic cells and extracellular matrix
components (efferocytosis) [26–28].
(see also Figure 1) [22, 24, 25]. They have poor antigen
presenting capabilities and exhibit increased release of iron
ulate mannose receptors and in addition produce high
levels of IL-10 (see also Figure 1). They are induced by a
number of stimuli that need to be combined with a second
signal, which is Toll-like receptor (TLR) stimulation. The
initial signals include glucocorticosteroids, prostaglandin E2
(PGE2), antibody immune complexes, transforming growth
factor beta (TGF훽), and IL-10 itself . They may also be the
between M2 and M2-like macrophages [29–32].
Transcriptional control of this phenotype is unclear
but may involve peroxisome proliferator-activated recep-
훽 (C/EBP훽)-axis . As a result of their high IL-10 produc-
responses to limit inflammation but may also permit tumor
been difficult to distinguish genuine M2 macrophages from
M2-like macrophages because they share many markers,
most notably the mannose receptor. Only IL-10 production
would be a reliable marker but is used seldomly to identify
M2-like macrophages . The exact differences in tissue
distribution and function of these two phenotypes are there-
fore difficult to establish from the studies published to date.
M2-like macrophages in the context of respiratory diseases.
tor gamma (PPAR훾) and the cAMP-responsive element-
tion, M2-like macrophages have strong anti-inflammatory
activity. This can be beneficial during later stages of immune
has not been rigorously shown due to the overlap in markers
3. Macrophages and Asthma
3.1. Asthma. Over the last few decades the prevalence of
asthma has rapidly increased, and currently more than half
a million people suffer from asthma in The Netherlands
(Annual Report 2011 Dutch Lung Fund). More women are
affected by this underdiagnosed and undertreated airway
disease than men. Asthma is a heterogeneous disorder of
the airways, which are chronically inflamed and contract
and airway wall remodeling, which leads to symptoms such
as wheezing, coughing, and chest tightness .
Several distinct forms of asthma have been recognized
and can roughly be divided into atopic and the less-studied
which is a predisposition to mount an immunoglobulin type
E (IgE) response. This type is characterized by infiltration of
eosinophils in the lungs. In nonatopic asthma there is no evi-
dence of allergen-specific IgE, and this type is characterized
of asthma patients suffer from severe asthma, which includes
both atopic and nonatopic characteristics. Severe asthma
is defined as being unable to control asthma symptoms
despite taking high-dose corticosteroids, also referred to as
corticosteroid-resistant asthma .
3.2. Pathogenesis of Asthma. Asthma is traditionally consid-
ered a T-helper-2- (Th2-) cell driven inflammatory disorder.
Activation of a Th2-response is characterized by the release
Mediators of Inflammation3
MHC class II
MHC class II
Figure 1: Schematic representation of the three macrophage phenotypes and their characteristics. IFN훾: interferon gamma; TNF훼: tumor
interferon regulatory factor 5; Fe: iron; TGM2: transglutaminase 2; YM1: chitinase-3-like protein-3; FIZZ1/Relm훼: resistin-like molecule-훼;
activated receptor gamma.
of the cytokines IL-4, IL-5, IL-9, and IL-13. These Th2-
cytokines are responsible for the recruitment of effector
cells resulting in eosinophil infiltrates, IgE production, and
histamine release among other typical asthma symptoms.
The innate immune system is increasingly being recognized
as an additional important disease mechanism in asthma
. Cells of the innate immune system actively orchestrate
cells (DC) in the lung taking up allergens and pathogens
and presenting those to the adaptive immune system, other
cells important for innate immune responses in the lung are
mostly unexplored .
3.3. Macrophage Phenotypes and Asthma. In asthma it
appears that effective phenotype switching is impaired and
macrophages can actually contribute to the pathogenesis of
this disease. The next part will focus on the roles of each
known phenotype in the pathogenesis of asthma.
3.4. M1 Macrophages in Asthma. Althoughtheinflammatory
process in asthma is dominated by a Th2 inflammation,
increasing evidence supports the parallel development and
involvement of both M1 and M2 macrophages in this dis-
ease. We have recently shown that during the develop-
ment of house-dust-mite-induced asthma numbers of M1
macrophages are high in a short model as compared to
control mice and decrease with longer exposure . Levels
severe forms of the disease [40–42]. Elevated serum IFN훾
that induce airway hyperreactivity [43, 44]. In agreement
with the findings in human asthma, it was shown that both
of M1 inducers (IFN훾 and LPS or TNF훼) were found to be
correlates with the severity of airway inflammation in atopic
asthma, and this cytokine has been linked to mechanisms
IFN훾 and LPS contribute to airway inflammation and airway
development of airway hyperreactivity and attraction of
eosinophils and neutrophils [47, 48].
In both atopic and nonatopic asthmatics, the amount of
LPS in house dust has been related to the severity of airway
inflammation [49, 50]. Inhalation of pure LPS by asthmatics
is associated with bronchoconstriction and a change in
airway hyperreactivity [51, 52]. Administration of high doses
of LPS into the lungs of allergic mice promotes airway
significantly higher in asthmatics, especially in those with
hyperreactivity in a mouse model of asthma [45, 46]. TNF훼
is implicated in many aspects of asthma pathology, including
bothIFN훾 andLPSinducedhighernumbers ofmacrophages
transcription factor IRF5. It was shown that a common
IRF5 gain-of-function haplotype is associated with asthma
and the severity of asthmatic symptoms. These associations
were more pronounced in nonatopic asthmatics, and it was
suggested that IRF5 may only have a profound impact on
the pathogenesis and severity of nonatopic asthma and not
on atopic asthma . An explanation could be that M1
macrophages are responsible for the recruitment of neu-
trophils, which are the major effector cells in nonatopic
asthma. Neutrophils are also dominant in more severe phe-
notypes of asthma, and the most commonly used therapy for
asthma, corticosteroids, is not effective against neutrophilic
inflammation . This is in accordance with recent find-
ings that corticosteroid-resistant asthmatics have increased
expression of M1 markers on macrophages in bronchoalveo-
lar lavage fluid (BALF) compared to corticosteroid-sensitive
asthmatics, suggesting that M1 macrophages also play a key
role in the development of severe corticosteroid-resistant
A few studies have shown that M1 macrophages act
preventively in the onset of allergic airway inflammation in
12 during the sensitization phase aggravated development of
allergic airway inflammation but neutralization of IL-12 dur-
ing challenges abolished the development of allergic airway
inflammation. These data demonstrate a dual role of IL-12: it
acts preventive during Th2 sensitization, but it contributes to
allergic airway disease during allergen challenges. The effects
Mediators of Inflammation
in the lungs .
M1 macrophages polarize under the influence of the
of IL-12 neutralization were not shown in IFN훾 knockout
mice, suggesting that IFN훾 plays an essential role in the IL-
12-induced effect .
Thus, both the presence of M1 skewing factors (IFN훾,
imply that M1 macrophages may be beneficial to prevent
allergic sensitization, but in already established disease they
promote the development of M2 macrophages and induce
corticosteroid resistance. Besides a role in severe asthma,
markers of M1 macrophages have also been implicated in
TNF훼, or LPS) and the proinflammatory mediators released
by M1 macrophages can contribute to asthma. The data
3.5. M2 Macrophages in Asthma. The cytokines IL-4 and
IL-13 are abundantly present in the lungs of asthmatics,
and it may therefore not come as a surprise that mark-
ers expressed by M2 macrophages have been associated
with asthma. Elevated levels of chitinase family members
have been found in the serum and lungs of patients with
numbers [60, 61]. Indeed, we showed that asthmatics have
higher percentages of macrophages expressing mannose
receptor and transglutaminase 2 in bronchial biopsies than
in healthy subjects [23, 62]. In addition Kim et al. showed
that severe asthmatics had higher numbers of IL-13-positive
M2 macrophages in BALF as compared to healthy controls
. Both chitinase levels and the percentage of mannose
receptor-positive macrophages also correlated with asthma
severity [60, 62]. Higher numbers of M2 macrophages were
also found in children undergoing severe exacerbations of
asthma . In addition, we have recently shown in several
models of house-dust-mite-induced asthma that the number
of M2 macrophages positively correlated with the severity of
airway inflammation . These clinical and animal model
findings demonstrate a correlation between asthma severity
M2 macrophages actively contribute to the induction and
exacerbation of the disease or are just bystanders in allergic
airway inflammation responding to the high IL-4 and IL-13
Credit to the role of M2 macrophages in the exacer-
bation of the disease was given by adoptive transfer stud-
ies. The transfer of in vitro differentiated M2 macrophages
into the airways of male asthmatic mice aggravated airway
inflammation . Another study using IL-4R훼-positive
inflammatory response in the lung . In a different model
of M2 macrophages into the lungs of mice enhanced both
inflammation and collagen deposition  as compared to
asthmatic mice not treated with macrophages. Since M2
macrophages and their products have been reported in
asthma patients, M2 macrophages may be a target to reduce
asthma symptoms. Indeed, the study by Moreira et al. in
with an inhibitor of M2 macrophage generation resulted
in lower airway hyperreactivity, mucus cell proliferation,
mice . In support of these results, inhibition of M2-
expressed transglutaminase 2 reduced ovalbumin-induced
airway hyperreactivity, ovalbumin-specific IgE levels, and
infiltration of inflammatory cells in lung tissue . These
studies substantiated previous circumstantial evidence con-
cerning a role for M2 macrophages in the pathogenesis of
asthma [69, 70].
Unfortunately, the previous studies did not conclu-
sively prove that M2 macrophages play a causative role
in the development of allergic airway inflammation. In
contrast to what has just been described, Nieuwenhuizen
et al. recently demonstrated that M2 macrophages are not
necessary for allergic airway disease and may only be a
consequence of the elevated Th2 response. They studied
the contribution of M2 macrophages to acute, chronic,
and house-dust-mite-induced allergic airway inflamma-
M2 macrophages showed that intraperitoneal injection of
these macrophages was sufficient to increase the allergic
tion by using mice with abrogated IL-4R훼 signaling on
eosinophils, and collagen deposition were not significantly
affected by decreased development of M2 macrophages.
However, the expression of M2 markers was still higher in
macrophages. It was demonstrated that airway hyperre-
activity, Th2 responses, mucus hypersecretion, number of
mice with macrophage-restricted IL-4 receptor-훼 (IL-4R훼)
Mediators of Inflammation5
small numbers of M2 macrophages may still have been able
to reinforce the Th2 response .
To sum up, M2 markers are correlated with severity
of allergic airway disease in humans and mice, suggesting
that M2 macrophages contribute to the disease. Indeed,
elimination of M2 macrophages in established disease by
pharmacological interventions remarkably decreased the
degree of airway inflammation. However, new data suggest
that M2 macrophages are not essential for the development
as a consequence of the Th2 response.
3.6. M2-Like Macrophages in Asthma. Reports on the role of
M2-like macrophages in asthma are few. These macrophages
could play an important role in the resolution of asthma
because of their production of IL-10. Interestingly, a lower
level of IL-10 production was found in lung macrophages
macrophages from severe asthmatics produce high levels
of IL-6 and IL-8, but IL-10 was undetectable in these cells
compared to macrophages from patients with moderate
Studies in mouse models of allergic airway inflammation
have investigated the role of IL-10 intensively and found it
to be an important mediator in the resolution of airway
10 by macrophages. We have just shown that the number of
mite-induced asthma as compared to control mice , and
recently it was also shown that lung interstitial macrophages
and TLR ligands induced increased production of IL-10
by these macrophages, and this resulted in lower levels of
IL-5 and ovalbumin-specific IgE and a lower number of
eosinophils in a mouse model of asthma .
Although evidence for a role of M2-like macrophages in
asthma is scarce, these findings suggest a protective effect
asthma and absent in severe asthma. In a mouse model of
asthma IL-10 was shown to act as an anti-inflammatory.
Studies on the resolution of asthma may reveal whether
an increased production of IL-10 by these macrophages is
Combining the data available for the different subsets in
asthma (see also Figure 2) suggests that M1 macrophages
can prevent the induction of asthma but during established
disease can cause severe corticosteroid-resistant asthma. M2
macrophages are associated with asthma and their presence
correlates with more severe disease. However, it is still
a matter of debate whether they genuinely contribute to
asthma pathogenesis or are just innocent bystanders of the
inflammation. M2-like macrophages seem to be beneficial to
the resolution of asthma through production of IL-10 but are
inflammation can progress.
Contribution to disease
Figure 2: Schematic representation of the presence of M1, M2, and
M2-like macrophages in lung tissue during homeostatic conditions,
induction of asthma, and during moderate and severe asthma.
4. Macrophages and Chronic Obstructive
Pulmonary Disease (COPD)
4.1. COPD. COPD is one of the most common respiratory
diseases and affects around 320,000 people in The Nether-
lands (Annual Report 2011 Dutch Lung Fund). It is projected
to be the fourth leading cause of death worldwide by 2030
and places a huge economic burden on society . COPD
is caused by lung inflammation due to inhalation of noxious
gasses and particles: in the Western World most commonly
from cigarette smoking and in developing countries from
indoor biomass cooking and heating . The disease is
characterized by airflow limitation that is not fully reversible,
(also known as chronic bronchitis) and destruction of alveoli
resulting in airspace enlargement (also known as emphy-
sema) . The relative contributions of chronic bronchitis
and emphysema to the COPD phenotype can vary from
person to person.
4.2. Pathogenesis of COPD. Exposure to smoke and particles
leads to an exaggerated chronic inflammation in lungs of
people susceptible to the development of COPD. Excess
mucus production and progressive narrowing of the res-
piratory bronchioles characterize chronic bronchitis. The
mucosa, submucosa, and glandular tissue become infiltrated
with inflammatory cells and the walls of the respiratory
bronchioles become thickened because of edema and fibrosis
. Chronic mucus hypersecretion is induced by goblet
cell hyperplasia and hypertrophy of submucosal glands ,
which further contributes to occlusion of small airways. This
progressive narrowing leads to obliteration or even complete
about the role of macrophages in this part of the disease,
but pigmented macrophages were found to cluster around
6 Mediators of Inflammation
The alveolar destruction that characterizes emphysema
is the result of infiltration of inflammatory cells with a
prominent role for macrophages. Both neutrophils and
macrophages are being recruited to the lung because
smoke/particle exposure injures epithelial cells that subse-
83]. They have been postulated to be the main effector cells
contributing to the excess tissue damage seen in emphysema
because of their ability to produce proteolytic MMPs like
neutrophil elastase and macrophage elastase (MMP12) [83,
been found in airways and lung parenchyma of patients with
COPD [85–87]. However, only the number of parenchymal
alveolar macrophages was directly proportional to the sever-
ity of lung destruction in emphysematous lung tissue from
role for macrophages, because deletion of neutrophils in
emphysema, whereas deletion of macrophages did . In
addition, mice deficient in MMP12 (mainly produced by
macrophages) were completely protected from cigarette-
duce neutrophil elastase . Similarly, inhibiting MMP12
reduced smoke-induced airway inflammation in mice .
4.3. Macrophage Phenotypes and COPD. The role of the
different macrophage phenotypes in COPD is the topic of
quite a few studies recently and the subject of much debate
studies in mice and results from patient studies, M1 polar-
ization is expected to play an important role in the patho-
genesis of COPD. However, the results of other studies have
questioned this view, and this is nicely illustrated by studies
from Shaykhiev et al. and Hodge et al. [92, 93]. The first ones
recently studied the transcriptome of alveolar macrophages
from healthy smokers and nonsmokers and compared them
to alveolar macrophages from COPD smokers . Their
results showed a mixed phenotype for alveolar macrophages
after smoking with downregulation of M1 genes and partial
upregulation of M2 genes, which was progressively worse
in COPD. Hodge et al. showed a mixed phenotype in
alveolar macrophages of smoking COPD patients with some
M1 (MHC II expression) and M2 (efferocytosis) markers
going down and some going up (proinflammatory cytokine
production and DC-SIGN expression) . In the next part
we will touch upon this debate as we discuss the separate
phenotypes in the pathogenesis of COPD.
4.4. M1 Macrophages in COPD. Several lines of evidence
support not only a role for M1 macrophages but also a role
for dysregulated M1 macrophages in the development of
to induce M1 polarization of macrophages. Smoking is the
most important risk factor for COPD and cigarette smoke
contains many thousands of compounds, including LPS that
can activate macrophages in the lung . Indeed, increased
expression of iNOS in alveolar macrophages was found in
COPD patients [95–97], indicating a polarization towards an
M1 phenotype. Upregulation of iNOS increases ROS and NO
production and can then cause oxidative stress. Oxidative
stress has been shown to be an important contributor to the
pathogenesis of COPD . Smoking itself of course causes
oxidative stress, and increased iNOS activity through M1
polarization can add to this stress [99–101].
Furthermore, many studies have shown that smoke
exposure enhances the release of the M1 proinflammatory
1훽, IL-6, IL-8, and TNF훼 have all been found to be elevated
inflammation, emphysema, and mucus production [102, 119–
and airway fibrosis in mice . Taken together these data
suggest cytokines produced by M1 macrophages at least play
a role in the pathogenesis of COPD.
Another important M1-related cytokine with a role in
polarization. Inducible overexpression of IFN훾 in lungs of
cytokines IL-1훽, IL-6, IL-8, and TNF훼 [102–107]. M1-derived
in COPD [108–118] and in experimental settings have been
found to contribute to the development of persistent airway
cytokines also play a role in the pathogenesis of COPD. IL-
humans antibodies against TNF훼 seem to be ineffective in
mice overexpressing TNF훼 in lung tissue develop chronic
COPD, questioning the relevance of this cytokine for human
inflammation and emphysema [119, 125, 126]. However, in
COPD is IFN훾. It is produced by CD8+ T cells that infil-
mice caused emphysema with alterations in the balance of
MMPs and antiproteases . However, in human alveolar
caused lung inflammation, emphysema, mucus metaplasia,
trate the lungs in COPD [88, 128, 129] and can cause M1
macrophages from smokers reduced expression of IFN훾
course is in line with the above-cited finding by Shaykhiev et
al. that M1 genes are downregulated in alveolar macrophages
to nonsmokers .
presumably to enable macrophage migration during inflam-
matory responses [5, 17]. MMP9 is associated with the
breakdown of extracellular matrix in COPD as macrophages
from patients with COPD have a significantly higher pro-
duction of MMP9 as compared to control macrophages
Finally, an important property of M1 macrophages that
appears to be dysregulated is phagocytosis of microorgan-
of microbial threats and phagocytosis of microorganisms is
part of that function [14, 15]. COPD is often exacerbated
by infections , and there is accumulating evidence that
reduced macrophage phagocytosis in COPD may be respon-
sible for the persistence of microorganismsin the lungs [133–
135]. This dysfunction of phagocytosis is not restricted to
M1 polarization may be impaired after smoking. This of
Mediators of Inflammation7
phagocytic functions such as efferocytosis and mannose
receptor-mediated uptake [136, 137]. This overall inhibition
of phagocytosis irrespective of macrophage phenotype was
further confirmed by the later study of Hodge et al. that has
already been mentioned before .
Taken together, the available data suggest that a dysreg-
ulated M1 response plays a role in COPD rather than an
increased number of M1 macrophages. Some aspects of the
M1 activation signature are upregulated in COPD (ROS gen-
eration, proinflammatory cytokines, production of MMP9),
ical M1-inducer IFN훾 may be able to induce emphysema,
13 in lung tissue caused lung pathology mirroring human
COPD with macrophage- and lymphocyte-rich inflamma-
tion, emphysema, and mucus metaplasia . Unfortu-
nately, macrophages were not further characterized in this
study, so it is not known if IL-13 overexpression also induced
for a role for M2 macrophages came from a study by Kim
et al. who showed that viral infections could induce an
IL-13-producing M2 phenotype through interactions with
natural killer T cells leading to chronic airway inflammation
. They also showed higher numbers of IL-13-positive M2
macrophages in lung tissue of COPD patients.
In mice, M2 macrophages produce large amounts of
chitinases like Ym1 and Ym2 . Whether their human
counterparts are also induced by alternative activation
is unclear, but another member of this family, stabilin-1
interacting chitinase-like protein (SI-CLP), has been found
upregulated in M2 macrophages . Whether or not
pointing at alternative activation, many members of the
chitinase family associate with COPD. Chitotriosidase levels,
for instance, were increased in bronchoalveolar lavage of
smokers with COPD and they also had more chitotriosidase-
positive cells in bronchial biopsies and an elevated pro-
portion of alveolar macrophages expressing chitotriosidase
as compared to smokers without COPD or never smokers
. Furthermore, macrophage chitinase-1 was selectively
serum concentrations of YKL-40 were significantly higher
in smokers with COPD as compared to nonsmokers or
smokers without COPD and correlated negatively with lung
function [143–145]. Interestingly, YKL-40 also stimulated the
production of proinflammatory cytokines and MMP9 by
macrophages from COPD patients, suggesting YKL-40 itself
actually induces more of an M1 phenotype .
role for M2 macrophages. As mentioned above MMP12
plays an important role in mouse emphysema [90, 91], and
MMP12 was found specifically induced in IL-4-stimulated
increased M2 polarization of alveolar macrophages in
4.5. M2 Macrophages in COPD. Overexpression of prototyp-
but so does overexpression of prototypical M2 induced
IL-13. Zheng et al. showed that mice overexpressing IL-
Contribution to disease
Figure 3: Schematic representation of the presence of M1, M2, and
M2-like macrophages in lung tissue during homeostatic conditions,
during healthy smoking, and in COPD. Please note the dysfunc-
tional state of macrophages during COPD.
smokers using MMP12 as a marker for alternative activation
, and many others showed that smoke induces MMP12
in macrophages [148–154]. Interestingly, MMP12 production
by macrophages was also found to be necessary to terminate
both neutrophil and macrophage influx at the end of an
inflammatory response and may therefore be an instrument
of M2 macrophages to dampen inflammation to be able
to start remodeling of damaged tissue . How that
ties in with the potential proemphysematous role of M2
macrophages remains an open question.
Summarizing, there is some evidence for a role of M2
activation in COPD, and this evidence points at a role con-
tributing to the development of COPD. The data by Hodge
et al. suggest that, similar to dysfunctional M1 activation, M2
activation is also dysregulated with reduced efferocytosis but
increased expression of M2 marker DC-SIGN .
4.6. M2-Like Macrophages in COPD. No attempts have been
in lung tissue of COPD patients after LPS stimulation as
the number of IL-10-positive macrophages in sputum from
COPD patients and healthy smokers was decreased as com-
pared to healthy nonsmokers . This would suggest that
M2-like macrophages are impaired in smoking and COPD
and therefore cannot suppress the ongoing inflammation
induced by smoke.
Combining the data available for M1, M2, and M2-like
macrophages (see also Figure 3), it appears COPD is a
8 Mediators of Inflammation
one particular polarization state. Macrophages in COPD are
promoting ongoing inflammation and tissue damage but are
bodies and produce anti-inflammatory cytokines like IL-10.
5. Macrophages and Pulmonary Fibrosis
5.1. Pulmonary Fibrosis. Pulmonary fibrosis is a disease that
encompasses a collection of restrictive pulmonary disorders
characterized by progressive and irreversible destruction of
lung architecture by excessive deposition of extracellular
as an essential process of tissue healing after lung injury,
continuous damage may result in abnormal wound repair
and progress to fibrosis. Fibrosis of the interstitium ulti-
mately leads to organ malfunction because of the disturbed
architecture of the lung, causing impaired gas exchange and
fibrotic lesions remain localized to a limited area of the
lung because the initial trigger is removed, for example after
tuberculosis or a fungal infection, while in others such as
in sarcoidosis and idiopathic pulmonary fibrosis (IPF) the
fibrotic process continues to progress throughout the lungs
in a diffuse manner .
IPF is the most common and most dangerous of the
fibrotic lung diseases. The chronic and slowly progressing
character of the disease together with an unknown aetiology
makes it a difficult disease to diagnose and treat. The
incidence of IPF appears to be increasing and is currently
estimated at 7–16 cases per 100,000 persons . Patients
survival of 2–5 years . Currently there are no effective
therapies available for these patients, as no therapy has yet
been proven to cure or even halt the progression of fibrosis
5.2. Pathogenesis of Pulmonary Fibrosis. To describe the
pathogenesis of pulmonary fibrosis and to be able to unravel
the complex interactions of macrophages, tissue repair after
injury can be divided into four different stages: the clotting
phase for emergency tissue repair, then the inflammatory
tissue in the fibrotic phase for more permanent repair, and
eventually resolution of scar tissue and restoration of tissue
homeostasis in the resolution phase. During fibrosis some or
all of these stages are dysregulated as will be discussed below.
injury to the epithelial cell layer lining the alveoli. This
damage initiates a blood coagulation cascade to prevent
severe blood loss and to maintain some sort of homeostasis.
This includes platelet accumulation and production of fibrin
by epithelial cells, which is essential for fibrin-containing
clot formation . To restore the function of damaged
tissue, plasminogen activator (PA) eventually breaks down
this fibrin matrix again. In pulmonary fibrosis, changes in
both the coagulation cascade itself and the resolution of the
wound-healing clot can affect the disease. Impaired fibrin
cell survival . Impaired resolution of clots can be caused
by either the absence of PA  or by increased production
of PA inhibitors PAI-1 or PAI-2 .
Cell damage furthermore triggers an inflammatory reac-
tion in lung tissue. It has been difficult to investigate the
role of the former and this phase in fibrosis because patients
usually present with end-stage disease. Nevertheless, the
inflammatory response has been extensively studied in LPS-
induced inflammation in humans (reviewed by Rossol et al.
). It was shown that epithelial cell damage induces the
release of several cytokines and chemokines that triggers an
influx of neutrophils, closely followed by monocytes to fight
the inciting agent . Epithelial cells also release growth
factors like TGF훽, TNF훼, and epidermal growth factor alfa
proteins [168, 169].
Control of the inflammatory event, however, is essential
for a proper wound healing process . Dysregulation
of the inflammatory phase with a prominent role for M1
macrophages has long been thought to be important to the
process of fibrosis. The fact that anti-inflammatory drugs
such as corticosteroids have no therapeutic effects in patients
with pulmonary fibrosis has made this assumption unlikely
. Now the new prevailing hypothesis is that pulmonary
fibrosis probably develops when the fibrotic phase and/or
resolution phase become dysregulated .
To progress from the inflammatory phase to the next
phase of tissue repair, inflammation needs to be dampened.
the influence of TGF훽 and PDGF produced by damaged
which are the main producers of collagen and other ECM
The release of IL-10 and TGF훽 dampens inflammation and
epithelial cells and platelets, fibroblasts differentiate into
myofibroblasts, proliferate, and produce ECM proteins .
promotes ECM production by myofibroblasts . Under
Furthermore, they start producing their own TGF훽 to
myofibroblasts and increased production of ECM are found
in fibrotic lungs. Increased numbers of M2 macrophages
are also associated with this phase, and these macrophages
are therefore suggested to play an important role in the
development of fibrosis .
of excess ECM are essential to recover normal lung function.
alveolar epithelial type II cells (AEC II) become hyperplastic
and provisionally restore the epithelial cell layer along with
the ECM produced by myofibroblasts . Normally these
type II cells would revert back to AEC I and homeostasis
is restored. However, when injury is repetitive this does not
seem to occur; ECM is produced continuously and AEC
II continue to proliferate without reverting back to AEC
I. In a proper tissue healing response, the excess of ECM
products is removed to gain full function of the lungs again.
Macrophages are important cells in degrading and taking up
ECM components. In order to do so they produce MMPs
and their inhibitors (tissue inhibitors of metalloproteinases,
TIMPs). A balance between the activities of MMPs and
maintain tissue healing . In pulmonary fibrosis this
phase is probably dysregulated as increased numbers of
Mediators of Inflammation9
TIMPs is important to maintain tissue homeostasis .
Levels of both MMPs and TIMPs are elevated in patients and
mouse models of pulmonary fibrosis , but their balance
is clearly disrupted as the net result is an excess of ECM in
5.3. Macrophages in Pulmonary Fibrosis. Macrophages play
an important role in the pathogenesis of lung fibrosis, but
their role is complex. They are involved in many of the
dysregulated tissue healing responses in fibrosis, and they
can also adopt many phenotypes. This complexes studies
into their role in fibrosis tremendously. In the next part we
will discuss what is known about the contribution of each
macrophage phenotype to each stage of fibrosis.
5.4. M1 Macrophages in Pulmonary Fibrosis. We have found
no studies reporting on the presence of M1 macrophages in
pulmonary fibrosis except for one study by Nagai et al. show-
ing that folate-receptor-beta- (FR훽-) positive macrophages
were higher in patients with IPF as compared to controls
. These macrophages have previously been shown to
produce TNF훼 and oxygen radicals and are therefore very
may play a role in both the inflammatory phase as well as
the resolution phase of pulmonary fibrosis. As a reaction
site of inflammation and differentiate into M1 macrophages
under the influence of proinflammatory cytokines. Once
likely M1 macrophages .
Several lines of evidence suggest that M1 macrophages
activated, M1 macrophages themselves produce TNF훼, IL-
Many studies indicate that these proinflammatory cytokines
and oxygen radicals are associated with fibrosis development
1훽, and oxygen radicals to kill and phagocytose microbes
to fight an infection or remove an exogenous agent .
[180–188]. In the study by Nagai et al. ablation of the FR훽-
ment . However, the importance of the contribution
of inflammation to established fibrosis has been challenged
no therapeutic effects in patients with pulmonary fibrosis
. This view was confirmed by a study from Gibbons et
al. They studied newly recruited inflammatory macrophages
in a mouse model of bleomycin-induced lung fibrosis and
circulating inflammatory monocytes during the inflamma-
tory phase did not affect the onset or degree of fibrosis
that developed after this inflammatory phase . Another
expressing M1 macrophages during the inflammatory phase
of bleomycin-induced fibrosis abrogated fibrosis develop-
study pointed out that the M1 cytokine TNF훼 has beneficial
In the resolution phase, macrophages are involved in
the degradation of excess ECM and the uptake of matrix
components [189, 191]. Depletion of macrophages during
this recovery phase impaired the resolution of fibrosis by
slowing down the degradation of ECM . It is unclear
what type of macrophages is responsible for degradation of
ECM, but a case can be made for M1 macrophages as these
effects on alveolar epithelial cell recovery and therefore also
contributes to resolution .
in lungs of IPF patients and this may reflect a failing attempt
of the lungs to remove excess ECM and may be caused by a
simultaneous increase of the inhibitor TIMP-1 [192–194].
Macrophages are also important in the subsequent
mechanisms. Again it is unclear if this is restricted to
one particular phenotype, but the receptors involved would
suggest more of an M2 phenotype, and this will therefore be
discussed in the next part on M2 macrophages.
In summary, M1 macrophages are important in the
inflammatory phase, but their presence does not appear to
affect the subsequent fibrotic phase. During resolution of
scar tissue, macrophages are indispensable for degradation
of ECM. This may be related to an M1 phenotype, and it
may therefore be beneficial to stimulate recruitment of M1
macrophages to reverse fibrosis.
5.5. M2 Macrophages in Pulmonary Fibrosis. There is a great
deal of evidence that Th2 responses are important in the
development of fibrosis, and it appears that IL-13 is the
Levels of IL-13 are higher in patients with pulmonary fibrosis
as compared to controls, and macrophages isolated from
these fibrotic lungs produce more IL-13 than macrophages
from control lungs . It therefore comes as no surprise
although we could not find publications directly showing
numbers of M2 macrophages are increased in lung tissue
of patients with pulmonary fibrosis. We did find one study
showing higher numbers of M2 macrophages in BALF of IPF
patients as compared to controls and two studies showing
higher numbers of insulin-like growth factor-I (IGF-I)-
positive and PDGF-positive interstitial macrophages in lung
tissue of IPF patients as compared to controls [204–206].
Both these markers are important profibrotic mediators, and
a recent study by Chen et al. showed that expression of IGF-
I colocalized with arginase-1 and not with IL-10 expression
IGF-I and not the M2-like subset . This was a study in
mice; it therefore remains to be investigated whether this is
also true in humans.
Markers found on or produced by M2 macrophages
have also been found to be increased in pulmonary fibrosis.
Levels of galectin-3, a carbohydrate-binding lectin that is
necessary for alternative activation , were higher in
BALF of IPF patients as compared to control patients .
of the human M2 marker CCL18 than control macrophages,
and this correlated negatively with pulmonary function test
as compared to controls, although it is still unclear whether
macrophages . This is also the case for arginase-1, which
is a marker of M2 macrophages in mice but its specificity in
humans is debated . Nevertheless, lung tissue from IPF
patients had higher expression of arginase-1 in macrophages
10 Mediators of Inflammation
than normal lung tissue . Lastly, circulating monocytes
from systemic sclerosis patients with pulmonary fibrosis
sion of CD163, a marker of alternative activation in humans
more about the role of M2 macrophages in fibrosis of the
lung. Depletion of macrophages during the fibrotic phase of
lung fibrosis reduced the deposition of ECM in this organ
. To confirm a role for M2 macrophages, levels of Ym1
and arginase-1 were measured before and after macrophage
depletion. Both markers showed decreased expression in
the lungs after removal of macrophages. The M1 marker
iNOS did not show a reduction in expression, indicating
that M2 macrophages are predominantly responsible for the
development of fibrosis. Furthermore, M2 marker MMP12
was shown to be essential in the development of fibrosis
induced by excessive activation of Fas  and in a model
of IL-13 dependent fibrosis .
There is some evidence or how M2 macrophages would
contributes to the fibrosis development. The aforementioned
production of IGF-I and PDGF contribute to proliferation
of fibroblasts and their transformation to ECM-producing
myofibroblasts . Furthermore, FIZZ1 (also known as
duction in fibroblasts , but a recent paper by Pesce et al.
contradictory finding highlights other new findings that
also suggest that M2 macrophages could be antifibrotic. A
mechanistic study in a model of Schistosoma-induced liver
fibrosis with specific deletion of the IL-4R훼 on myeloid cells
. In addition, related studies with mice lacking arginase-
1 in M2 macrophages showed that the arginase-1-expressing
M2 macrophages were required for suppression and resolu-
tion of fibrosis . This correlates well with findings that
uptake of ECM components appears to be mediated by M2
macrophages. Uptake of these components is mediated by
globule epidermal growth factor 8 (Mfge8) . Mannose
receptors of course are a known M2 marker, and for Mfge8
this is unclear. Both mannose receptor 2 and Mfge8 were
shown to attenuate fibrosis in different models [219, 220].
To summarize, M2 macrophages are firmly associated
with fibrosis development, but new evidence suggests they
may actually contribute to resolution of fibrosis. Their pres-
ence during fibrosis may be explained as a failing attempt to
clear the excess ECM. The conflicting roles described in the
of M2 and M2-like macrophages simply because these two
be discussed below.
M2 macrophages are not required for fibrosis development
5.6. M2-Like Macrophages in Pulmonary Fibrosis. The spe-
during the transition from inflammation towards tissue
healing. The signature marker of M2-like macrophages is IL-
10, which is the canonical anti-inflammatory cytokine with
profibrotic actions. Elevated levels of IL-10 and enhanced
production of IL-10 by alveolar macrophages have been
reported in several fibrotic diseases, including IPF [221–
223] and in systemic sclerosis patients with interstitial lung
disease . Its anti-inflammatory actions in lung are
illustrated by a study from Armstrong et al., showing that
IL-10 inhibited TNF훼 production by alveolar macrophages
that IL-10 attenuates bleomycin-induced inflammation and
can thereby attenuate fibrosis development [182, 225, 226].
However, overexpression of IL-10 in lungs of mice was found
to be profibrotic . Sun et al. found that inducible IL-
10 overexpression in Clara cells induced fibrosis by fibrocyte
recruitment and activation of macrophages towards an M2
phenotype. The increased levels of IL-10 found in lungs
of IPF patients may therefore contribute to the fibrotic
macrophages. Whether TGF훽 production is restricted to the
In summary, M2-like macrophages are likely candidates
for promotion of fibrosis. They may be recruited or induced
by damage to the epithelium to dampen inflammation and
start repair. In the event of ongoing damage they are contin-
ually induced or recruited and may contribute to fibrosis by
of inducing M2-like macrophages, this would explain why
these drugs are not effective against fibrosis and may even be
disadvantageous. This is illustrated by our finding that when
in a model of liver fibrosis, fibrosis actually becomes worse
Overall, current data on the role of macrophages in the
development of pulmonary fibrosis show that macrophages
are important cells in the pathogenesis of this disease (see
also Figure 4). M1 macrophages are important in the inflam-
matory phase and may also be important for resolution
of the disease, although this hypothesis needs testing. M2
and M2-like macrophages are highly associated with fibro-
genesis. However, new data suggest that M2 macrophages
may actually protect against development of fibrosis while
M2-like macrophages contribute to fibrosis. Therefore, key
to understanding how these two phenotypes contribute to
pulmonary fibrosis are studies differentiating between M2
and M2-like macrophages.
after LPS stimulation . In addition, several studies in
mice using the model of bleomycin-induced fibrosis suggest
cytokine TGF훽 would also fit with this role of dampening
IL-10-producing M2-like macrophage subtype remains to be
inflammation and promoting tissue repair by this subset of
tissue homeostasis in the lung. Through their ability to
change phenotypes they are able to regulate responses to
Mediators of Inflammation11
Contribution to disease
Contribution to resolution
Figure 4: Schematic representation of the presence of M1, M2, and
M2-like macrophages in lung tissue during homeostatic conditions
and after injury to the lung. Normally after lung injury a process
of tissue repair is initiated with four distinct phases leading to
homeostatic conditions again. In lung fibrosis this normal tissue
repair response is dysregulated leading to deposition of excess
extracellular matrix and little resolution of scar tissue.
homeostatic threats without impairing the functionality of
the organ. The available literature also shows that when
phenotype switching becomes dysfunctional or when some
aspects of a particular phenotype become dysfunctional,
pathologies develop. However, data on the distribution of
is sorely lacking for humans as well as experimental models
of respiratory diseases.
In general, asthma, COPD, and pulmonary fibrosis are
diseases characterized by changes in macrophage subsets in
the lung (M1, M2, and M2-like). It seems likely that changes
in the interactions between the different subsets, that is, the
rather than the presence of one particular subset. The next
challenge will be to specifically improve a particular function
of a subset in vivo or specifically change a phenotype as a
novel therapeutic approach for obstructive and restrictive
Conflict of Interests
The authors have no conflict of interests to declare.
This work was supported by Grant 3.2.10.056 from The
Netherlands Asthma Foundation (BNM).
 J. A. Stefater III, S. Ren, R. A. Lang, and J. S. Duffield, “Metch-
nikoff’s policemen: macrophages in development, homeostasis
and regeneration,” Trends in Molecular Medicine, vol. 17, no. 12,
pp. 743–752, 2011.
 S. Gordon, “The macrophage: past, present and future,” Euro-
pean Journal of Immunology, vol. 37, no. 1, pp. S9–S17, 2007.
 S. Gordon and P. R. Taylor, “Monocyte and macrophage
heterogeneity,” Nature Reviews Immunology, vol. 5, no. 12, pp.
 F. O. Martinez, A. Sica, A. Mantovani, and M. Locati,
“Macrophage activation and polarization,” Frontiers in Bio-
science, vol. 13, no. 2, pp. 453–461, 2008.
 D. M. Mosser and J. P. Edwards, “Exploring the full spectrum
of macrophage activation,” Nature Reviews Immunology, vol. 8,
no. 12, pp. 958–969, 2008.
 F. Geissmann, S. Gordon, D. A. Hume, A. M. Mowat, and G.
J. Randolph, “Unravelling mononuclear phagocyte heterogene-
ity,” Nature Reviews Immunology, vol. 10, no. 6, pp. 453–460,
 D. Schneberger, K. Aharonson-Raz, and B. Singh, “Monocyte
and macrophage heterogeneity and Toll-like receptors in the
lung,” Cell and Tissue Research, vol. 343, no. 1, pp. 97–106, 2011.
 G. Franke-Ullmann, C. Pf¨ ortner, P. Walter, C. Steinm¨ uller,
M. L. Lohmann-Matthes, and L. Kobzik, “Characterization
of murine lung interstitial macrophages in comparison with
alveolar macrophages in vitro,” The Journal of Immunology, vol.
157, no. 7, pp. 3097–3104, 1996.
 D. Bedoret, H. Wallemacq, T. Marichal et al., “Lung interstitial
macrophages alter dendritic cell functions to prevent airway
allergy in mice,” Journal of Clinical Investigation, vol. 119, no. 12,
pp. 3723–3738, 2009.
 S. Prokhorova, N. Lavrikova, and D. L. Laskin, “Functional
of alveolar macrophages from rat lung,” Journal of Leukocyte
Biology, vol. 55, no. 2, pp. 141–146, 1994.
 L. Landsman, C. Varol, and S. Jung, “Distinct differentiation
potential of blood monocyte subsets in the lung,” The Journal
of Immunology, vol. 178, no. 4, pp. 2000–2007, 2007.
 T. Krausgruber, K. Blazek, T. Smallie et al., “IRF5 pro-
motes inflammatory macrophage polarization and T H1-TH17
responses,” Nature Immunology, vol. 12, no. 3, pp. 231–238, 2011.
 S. K. Biswas and A. Mantovani, “Macrophage plasticity and
interaction with lymphocyte subsets: cancer as a paradigm,”
Nature Immunology, vol. 11, no. 10, pp. 889–896, 2010.
 J. J. Wirth, F. Kierszenbaum, G. Sonnenfeld, and A. Zlotnik,
“Enhancing effects of gamma interferon on phagocytic cell
association with and killing of Trypanosoma cruzi,” Infection
and Immunity, vol. 49, no. 1, pp. 61–66, 1985.
 J. N. Higginbotham, T. L. Lin, and S. B. Pruett, “Effect of
macrophage activation on killing of Listeria monocytogenes.
Roles of reactive oxygen or nitrogen intermediates, rate of
phagocytosis, and retention of bacteria in endosomes,” Clinical
 E. Song, N. Ouyang, M. H¨ orbelt, B. Antus, M. Wang, and M.
S. Exton, “Influence of alternatively and classically activated
macrophages on fibrogenic activities of human fibroblasts,”
Cellular Immunology, vol. 204, no. 1, pp. 19–28, 2000.
 R. Hanania, H. Song Sun, K. Xu, S. Pustylnik, S. Jeganathan,
and R. E. Harrison, “Classically activated macrophages use
stable microtubules for matrix metalloproteinase-9 (MMP-9)
secretion,” The Journal of Biological Chemistry, vol. 287, no. 11,
pp. 8468–8483, 2012.
 S. Gordon, “Alternative activation of macrophages,” Nature
Reviews Immunology, vol. 3, no. 1, pp. 23–35, 2003.
 M. Stein, S. Keshav, N. Harris, and S. Gordon, “Interleukin
4 potently enhances murine macrophage mannose receptor
activity: a marker of alternative immunologic macrophage
12 Mediators of Inflammation
activation,” Journal of Experimental Medicine, vol. 176, no. 1, pp.
tion: in vivo veritas,” Journal of Clinical Investigation, vol. 122,
no. 3, pp. 787–795, 2012.
 T. Satoh, O. Takeuchi, A. Vandenbon et al., “The Jmjd3-Irf4
axis regulates M2 macrophage polarization and host responses
against helminth infection,” Nature Immunology, vol. 11, no. 10,
pp. 936–944, 2010.
 F. O. Martinez, L. Helming, and S. Gordon, “Alternative activa-
tion of macrophages: an immunologic functional perspective,”
Annual Review of Immunology, vol. 27, pp. 451–483, 2009.
 F. O. Martinez, L. Helming, R. Milde et al., “Genetic programs
expressed in resting and IL-4 alternatively activated mouse and
human macrophages: similarities and differences,” Blood, 2013.
 T. Kreider, R. M. Anthony, J. F. Urban, and W. C. Gause,
“Alternatively activated macrophages in helminth infections,”
Current Opinion in Immunology, vol. 19, no. 4, pp. 448–453,
 M. G. Nair, D. W. Cochrane, and J. E. Allen, “Macrophages in
ized by the abundant expression of Ym1 and Fizz1 that can be
 A. Mantovani, S. Sozzani, M. Locati, P. Allavena, and A. Sica,
“Macrophage polarization: tumor-associated macrophages as a
Immunology, vol. 23, no. 11, pp. 549–555, 2002.
 D. H. Madsen, S. Ingvarsen, H. J. J¨ urgensen et al., “The non-
phagocytic route of collagen uptake: a distinct degradation
pathway,” The Journal of Biological Chemistry, vol. 286, no. 30,
pp. 26996–27010, 2011.
 G. Cairo, S. Recalcati, A. Mantovani, and M. Locati, “Iron
polarized phenotype,” Trends in Immunology, vol. 32, no. 6, pp.
 C. A. M. Almeida, S. G. Roberts, R. Laird et al., “Automation
of the ELISpot assay for high-throughput detection of antigen-
specific T-cell responses,” Journal of Immunological Methods,
vol. 344, no. 1, pp. 1–5, 2009.
 K. R. Karlmark, R. Weiskirchen, H. W. Zimmermann et al.,
“Hepatic recruitment of the inflammatory Gr1+monocyte
subset upon liver injury promotes hepatic fibrosis,” Hepatology,
vol. 50, no. 1, pp. 261–274, 2009.
 A.Schmid-Kotsas,H. J.
“Lipopolysaccharide-activated macrophages stimulate the
synthesis of collagen type I and C-fibronectin in cultured
pancreatic stellate cells,” American Journal of Pathology, vol.
155, no. 5, pp. 1749–1758, 1999.
 Z. Xing, G. M. Tremblay, P. J. Sime, and J. Gauldie, “Overex-
pression of granulocyte-macrophage colony-stimulating factor
Gross, A.Menkeet al.,
induction of transforming growth factor-훽1 and myofibroblast
 T. Lawrence and G. Natoli, “Transcriptional regulation of
macrophage polarization: enabling diversity with identity,”
Nature, vol. 11, no. 11, pp. 750–761, 2011.
Allergy, vol. 38, no. 6, pp. 872–897, 2008.
 S. Wenzel, “Severe asthma in adults,” American Journal of
Respiratory and Critical Care Medicine, vol. 172, no. 2, pp. 149–
 G. P. Anderson, “Endotyping asthma: new insights into key
pathogenic mechanisms in a complex, heterogeneous disease,”
The Lancet, vol. 372, no. 9643, pp. 1107–1119, 2008.
 H. Hammad and B. N. Lambrecht, “Dendritic cells and airway
epithelial cells at the interface between innate and adaptive
immune responses,” Allergy, vol. 66, no. 5, pp. 579–587, 2011.
 M. Peters-Golden, “The alveolar macrophage: the forgotten cell
in asthma,” American Journal of Respiratory Cell and Molecular
Biology, vol. 31, no. 1, pp. 3–7, 2004.
 C. Draijer, P. Robbe, C. E. Boorsma, M. N. Hylkema, and B. N.
Melgert, “Characterization of macrophage phenotypes in three
murine models of house dust mite-induced asthma,” Mediators
of Inflammation, vol. 2013, 2013.
 Y. K. Kim, S. Y. Oh, S. G. Jeon et al., “Airway exposure levels of
asthma,” The Journal of Immunology, vol. 178, no. 8, pp. 5375–
 J. Shannon, P. Ernst, Y. Yamauchi et al., “Differences in air-
way cytokine profile in severe asthma compared to moderate
asthma,” Chest, vol. 133, no. 2, pp. 420–426, 2008.
 N. H. T. ten Hacken, W. Timens, M. Smith, G. Drok, J. Kraan,
and D. S. Postma, “Increased peak expiratory flow variation in
asthma: severe persistent increase but not nocturnal worsening
of airway inflammation,” European Respiratory Journal, vol. 12,
no. 3, pp. 546–550, 1998.
approach to asthma: identification of in-vitro T-cell response
patterns associated with different wheezing phenotypes in
children,” The Lancet, vol. 365, no. 9454, pp. 142–149, 2005.
 N. Hayashi, T. Yoshimoto, K. Izuhara, K. Matsui, T. Tanaka,
and K. Nakanishi, “T helper 1 cells stimulated with ovalbumin
and IL-18 induce airway hyperresponsiveness and lung fibrosis
Journal of Medicine, vol. 354, no. 7, pp. 697–708, 2006.
by IFN-훾 and IL-13 production,” Proceedings of the National
37, pp. 14765–14770, 2007.
 P. S. Thomas and G. Heywood, “Effects of inhaled tumour
57, no. 9, pp. 774–778, 2002.
 N. W. Lukacs, R. M. Strieter, S. W. Chensue, M. Widmer,
182, no. 8, pp. 5107–5115, 2009.
and S. L. Kunkel, “TNF-훼 mediates recruitment of neutrophils
 O. Michel, J. Kips, J. Duchateau et al., “Severity of asthma
is related to endotoxin in house dust,” American Journal of
Respiratory and Critical Care Medicine, vol. 154, no. 6, pp. 1641–
 P. S. Thorne, K. Kulh´ ankov´ a, M. Yin, R. Cohn, S. J. Arbes, and
D. C. Zeldin, “Endotoxin exposure is a risk factor for asthma:
the national survey of endotoxin in United States housing,”
172, no. 11, pp. 1371–1377, 2005.
and eosinophils during airway inflammation,” The Journal of
Immunology, vol. 154, no. 10, pp. 5411–5417, 1995.
Mediators of Inflammation 13
 O. Michel, J. Duchateau, and R. Sergysels, “Effect of inhaled
endotoxin on bronchial reactivity in asthmatic and normal
subjects,” Journal of Applied Physiology, vol. 66, no. 3, pp. 1059–
 R. Rylander, B. Bake, J. J. Fischer, and I. M. Helander, “Pul-
monary function and symptoms after inhalation of endotoxin,”
American Review of Respiratory Disease, vol. 140, no. 4, pp. 981–
 C. Wang, M. J. Rose-Zerilli, G. H. Koppelman et al., “Evidence
of association between interferon regulatory factor 5 gene
the neutrophil the key effector cell in severe asthma?” Thorax,
vol. 60, no. 7, pp. 529–530, 2005.
 E. Goleva, P. J. Hauk, C. F. Hall et al., “Corticosteroid-resistant
asthma is associated with classical antimicrobial activation of
airway macrophages,” Journal of Allergy and Clinical Immunol-
ogy, vol. 122, no. 3, pp. 550–e3, 2008.
 J. E. Korf, G. Pynaert, K. Tournoy et al., “Macrophage repro-
gramming by mycolic acid promotes a tolerogenic response
in experimental asthma,” American Journal of Respiratory and
Critical Care Medicine, vol. 174, no. 2, pp. 152–160, 2006.
 C. Tang, M. D. Inman, N. Van Rooijen et al., “Th type 1-
allergic airway inflammation by an IFN-훾-dependent mecha-
 P. G. Holt, J. Oliver, N. Bilyk et al., “Downregulation of the
antigen presenting cell function(s) of pulmonary dendritic
cells in vivo by resident alveolar macrophages,” Journal of
Experimental Medicine, vol. 177, no. 2, pp. 397–407, 1993.
 I. Meyts, P. W. Hellings, G. Hens et al., “IL-12 contributes
to allergen-induced airway inflammation in experimental
asthma,” The Journal of Immunology, vol. 177, no. 9, pp. 6460–
in the lung and circulation of patients with severe asthma,” The
 Z. Zhu, T. Zheng, R. J. Homer et al., “Acidic mammalian
chitinase in asthmatic Th2 inflammation and IL-13 pathway
activation,” Science, vol. 304, no. 5677, pp. 1678–1682, 2004.
 B. N. Melgert, N. H. Ten Hacken, B. Rutgers, W. Timens, D.
S. Postma, and M. N. Hylkema, “More alternative activation of
macrophages in lungs of asthmatic patients,” Journal of Allergy
and Clinical Immunology, vol. 127, no. 3, pp. 831–833, 2011.
into chronic lung disease,” Nature Medicine, vol. 14, no. 6, pp.
 L. S. Subrata, J. Bizzintino, E. Mamessier et al., “Interactions
between innate antiviral and atopic immunoinflammatory
pathways precipitate and sustain asthma exacerbations in chil-
 B. N. Melgert, T. B. Oriss, Z. Qi et al., “Macrophages: regulators
of sex differences in asthma?” American Journal of Respiratory
Cell and Molecular Biology, vol. 42, no. 5, pp. 595–603, 2010.
 A. Q. Ford, P. Dasgupta, I. Mikhailenko, E. P. Smith, N.
nism,” The Journal of Immunology, vol. 166, no. 3, pp. 1471–1481,
macrophages is sufficient to enhance eosinophilic inflamma-
tion in a mouse model of allergic lung inflammation,” BMC
Immunology, vol. 13, p. 6, 2012.
 A. P. Moreira, K. A. Cavassani, R. Hullinger et al., “Serum
amyloid P attenuates M2 macrophage activation and protects
 D. Y. Kim, B. S. Park, G. U. Hong et al., “Anti-inflammatory
Journal of Pharmacology, vol. 162, no. 1, pp. 210–225, 2011.
 R. I. Zuberi, D. K. Hsu, O. Kalayci et al., “Critical role for
galectin-3 in airway inflammation and bronchial hyperrespon-
siveness in a murine model of asthma,” American Journal of
Pathology, vol. 165, no. 6, pp. 2045–2053, 2004.
 H. Maarsingh, A. B. Zuidhof, I. S. T. Bos et al., “Arginase inhi-
bition protects against allergen-induced airway obstruction,
hyperresponsiveness, and inflammation,” American Journal of
Respiratory and Critical Care Medicine, vol. 178, no. 6, pp. 565–
 N. E. Nieuwenhuizen, F. Kirstein, J. Jayakumar et al., “Aller-
gic airway disease is unaffected by the absence of IL-4R훼-
 K. Maneechotesuwan, S. Supawita, K. Kasetsinsombat, A.
Wongkajornsilp, and P. J. Barnes, “Sputum indoleamine-2,
3-dioxygenase activity is increased in asthmatic airways by
using inhaled corticosteroids,” Journal of Allergy and Clinical
Immunology, vol. 121, no. 1, pp. 43–50, 2008.
 A. M. Fitzpatrick, M. Higgins, F. Holguin, L. A. S. Brown, and
W. G. Teague, “The molecular phenotype of severe asthma in
children,” Journal of Allergy and Clinical Immunology, vol. 125,
no. 4, pp. 851–e18, 2010.
 Y. Ogawa, E. A. Duru, and B. T. Ameredes, “Role of IL-10
in the resolution of airway inflammation,” Current Molecular
Medicine, vol. 8, no. 5, pp. 437–445, 2008.
 J. L. M. Vissers, B. C. A. M. van Esch, P. V. Jeurink, G.
A. Hofman, and A. J. M. van Oosterhout, “Stimulation of
allergen-loaded macrophages by TLR9-ligand potentiates IL-
10-mediated suppression of allergic airway inflammation in
mice,” Respiratory Research, vol. 5, 2004.
 C. D. Mathers and D. Loncar, “Projections of global mortality
and burden of disease from 2002 to 2030,” PLoS Medicine, vol.
3, no. 11, Article ID e442, pp. 2011–2030, 2006.
 K. F. Rabe, S. Hurd, A. Anzueto et al., “Global strategy for the
diagnosis, management, and prevention of chronic obstructive
nal of Respiratory and Critical Care Medicine, vol. 176, no. 6, pp.
 J. E. McDonough, R. Yuan, M. Suzuki et al., “Small-airway
obstruction and emphysema in chronic obstructive pulmonary
disease,” The New England Journal of Medicine, vol. 365, no. 17,
pp. 1567–1575, 2011.
 J. C. Hogg and W. Timens, “The pathology of chronic obstruc-
tive pulmonary disease,” Annual Review of Pathology, vol. 4, pp.
 A. D. Jackson, “Airway goblet-cell mucus secretion,” Trends in
Pharmacological Sciences, vol. 22, no. 1, pp. 39–45, 2001.
 M. Fraig, U. Shreesha, D. Savici, and A. L. A. Katzenstein,
“Respiratory bronchiolitis: a clinicopathologic study in current
dependent alternatively activated macrophages,” Journal of
Allergy and Clinical Immunology, vol. 130, no. 3, pp. 743–750,
14Mediators of Inflammation
smokers, ex-smokers, and never-smokers,” American Journal of
Surgical Pathology, vol. 26, no. 5, pp. 647–653, 2002.
 I. K. Demedts, K. R. Bracke, G. Van Pottelberge et al., “Accu-
mulation of dendritic cells and increased CCL20 levels in
the airways of patients with chronic obstructive pulmonary
disease,” American Journal of Respiratory and Critical Care
Medicine, vol. 175, no. 10, pp. 998–1005, 2007.
 M. Decramer, W. Janssens, and M. Miravitlles, “Chronic
obstructive pulmonary disease,” The Lancet, vol. 379, no. 9823,
pp. 1341–1351, 2012.
 G. G. Brusselle, G. F. Joos, and K. R. Bracke, “New insights into
the immunology of chronic obstructive pulmonary disease,”
The Lancet, vol. 378, no. 9795, pp. 1015–1026, 2011.
 N. M. Siafakas, P. Vermeire, N. B. Pride et al., “Optimal
 M. Saetta, G. Turato, F. M. Facchini et al., “Inflammatory cells
in the bronchial glands of smokers with chronic bronchitis,”
156, no. 5, pp. 1633–1639, 1997.
matory cells in the airways in COPD,” Thorax, vol. 61, no. 5, pp.
 R. Finkelstein, R. S. Fraser, H. Ghezzo, and M. G. Cosio, “Alve-
olar inflammation and its relation to emphysema in smokers,”
152, no. 5, pp. 1666–1672, 1995.
 A. F. Ofulue and M. Ko, “Effects of depletion of neutrophils
or macrophages on development of cigarette smoke-induced
emphysema,” American Journal of Physiology, vol. 277, no. 1, pp.
 R. D. Hautamaki, D. K. Kobayashi, R. M. Senior, and S. D.
Shapiro, “Requirement for macrophage elastase for cigarette
pp. 2002–2004, 1997.
 C. Le Qu´ ement, I. Gu´ enon, J. Y. Gillon et al., “The selective
MMP-12 inhibitor, AS111793 reduces airway inflammation in
mice exposed to cigarette smoke,” British Journal of Pharmacol-
ogy, vol. 154, no. 6, pp. 1206–1215, 2008.
 R. Shaykhiev, A. Krause, J. Salit et al., “Smoking-dependent
reprogramming of alveolar macrophage polarization: implica-
tion for pathogenesis of chronic obstructive pulmonary dis-
ease,” The Journal of Immunology, vol. 183, no. 4, pp. 2867–2883,
 S. Hodge, G. Matthews, V. Mukaro et al., “Cigarette smoke-
induced changes to alveolar macrophage phenotype and func-
tion are improved by treatment with procysteine,” American
Journal of Respiratory Cell and Molecular Biology, vol. 44, no.
5, pp. 673–681, 2011.
 R. L. Stedman, “The chemical composition of tobacco and
tobacco smoke,” Chemical Reviews, vol. 68, no. 2, pp. 153–207,
“Increase in reactive nitrogen species production in chronic
obstructive pulmonary disease airways,” American Journal of
Respiratory and Critical Care Medicine, vol. 162, no. 2, pp. 701–
F. Kauffman, and W. Timens, “Macrophages in lung tissue from
patients with pulmonary emphysema express both inducible
and endothelial nitric oxide synthase,” Modern Pathology, vol.
11, no. 7, pp. 648–655, 1998.
 P. Maestrelli, C. P´ aska, M. Saetta et al., “Decreased haem
lung of severe COPD patients,” European Respiratory Journal,
vol. 21, no. 6, pp. 971–976, 2003.
 K. Ito and P. J. Barnes, “COPD as a disease of accelerated lung
aging,” Chest, vol. 135, no. 1, pp. 173–180, 2009.
 P. Paredi, S. A. Kharitonov, D. Leak, S. Ward, D. Cramer, and
P. J. Barnes, “Exhaled ethane, a marker of lipid peroxidation,
is elevated chronic obstructive pulmonary disease,” American
pp. 369–373, 2000.
 P. Montuschi, J. V. Collins, G. Ciabattoni et al., “Exhaled 8-
isoprostane as an in vivo biomarker of lung oxidative stress in
patients with COPD and healthy smokers,” American Journal of
Respiratory and Critical Care Medicine, vol. 162, no. 3, pp. 1175–
 I. Rahman, A. A. M. Van Schadewijk, A. J. L. Crowther et al.,
“4-Hydroxy-2-nonenal, a specific lipid peroxidation product,
is elevated in lungs of patients with chronic obstructive pul-
monary disease,” American Journal of Respiratory and Critical
Care Medicine, vol. 166, no. 4, pp. 490–495, 2002.
 E. Doz, N. Noulin, E. Boichot et al., “Cigarette smoke-induced
pulmonary inflammation is TLR4/MyD88 and IL-1R1/MyD88
signaling dependent,” The Journal of Immunology, vol. 180, no.
2, pp. 1169–1178, 2008.
 F. Facchinetti, F. Amadei, P. Geppetti et al., “훼,훽-unsaturated
Cell and Molecular Biology, vol. 37, no. 5, pp. 617–623, 2007.
aldehydes in cigarette smoke release inflammatory mediators
from human macrophages,” American Journal of Respiratory
of cigarette smoke on TNF-훼 release by macrophages mediated
 M. J. Walters, M. J. Paul-Clark, S. K. McMaster, K. Ito, I. M.
Adcock, and J. A. Mitchell, “Cigarette smoke activates human
monocytes by an oxidant-AP-1 signaling pathway: implications
for steroid resistance,” Molecular Pharmacology, vol. 68, no. 5,
pp. 1343–1353, 2005.
 S. R. Yang, A. S. Chida, M. R. Bauter et al., “Cigarette smoke
induces proinflammatory cytokine release by activation of NF-
through the erk1/2 pathway,” Biochimica et Biophysica Acta, vol.
1762, no. 6, pp. 592–597, 2006.
휅B and posttranslational modifications of histone deacetylase
 K. Karimi, H. Sarir, E. Mortaz et al., “Toll-like receptor-
4 mediates cigarette smoke-induced cytokine production by
human macrophages,” Respiratory Research, vol. 7, article 66,
 E. Sapey, A. Ahmad, D. Bayley et al., “Imbalances between
interleukin-1 and tumor necrosis factor agonists and antago-
nists in stable COPD,” Journal of Clinical Immunology, vol. 29,
no. 4, pp. 508–516, 2009.
 S. F. P. Man, J. E. Connett, N. R. Anthonisen, R. A. Wise, D.
P. Tashkin, and D. D. Sin, “C-reactive protein and mortality
in mild to moderate chronic obstructive pulmonary disease,”
Thorax, vol. 61, no. 10, pp. 849–853, 2006.
 A. Bhowmik, T. A. R. Seemungal, R. J. Sapsford, and J.
A. Wedzicha, “Relation of sputum inflammatory markers to
symptoms and lung function changes in COPD exacerbations,”
Thorax, vol. 55, no. 2, pp. 114–120, 2000.
in macrophages,”American Journal of Physiology, vol. 291, no. 1,
pp. L46–L57, 2006.
Mediators of Inflammation 15
 E. Bucchioni, S. A. Kharitonov, L. Allegra, and P. J. Barnes,
“High levels of interleukin-6 in the exhaled breath condensate
 C. Yamamoto, T. Yoneda, M. Yoshikawa et al., “Airway inflam-
mation in COPD assessed by sputum levels of interleukin-8,”
Chest, vol. 112, no. 2, pp. 505–510, 1997.
 S. W. Crooks, D. L. Bayley, S. L. Hill, and R. A. Stockley,
“Bronchial inflammation in acute bacterial exacerbations of
chronic bronchitis: the role of leukotriene B4,” European Res-
piratory Journal, vol. 15, no. 2, pp. 274–280, 2000.
 S. Gompertz, C. O’Brien, D. L. Bayley, S. L. Hill, and R. A.
Stockley, “Changes in bronchial inflammation during acute
nal, vol. 17, no. 6, pp. 1112–1119, 2001.
 M. Di Francia, D. Barbier, J. L. Mege, and J. Orehek, “Tumor
necrosis factor-alpha levels and weight loss in chronic obstruc-
tive pulmonary disease,” American Journal of Respiratory and
Critical Care Medicine, vol. 150, no. 5, pp. 1453–1455, 1994.
 V. M. Keatings, P. D. Collins, D. M. Scott, and P. J. Barnes,
“Differences in interleukin-8 and tumor necrosis factor-훼 in
Critical Care Medicine, vol. 153, no. 2, pp. 530–534, 1996.
 R. Mueller, P. Chanez, A. M. Campbell, J. Bousquet, C.
Heusser, and G. R. Bullock, “Different cytokine patterns in
bronchial biopsies in asthma and chronic bronchitis,” Respira-
tory Medicine, vol. 90, no. 2, pp. 79–85, 1996.
induced sputum from patients with chronic obstructive pul-
of CCL11, CXCL8 and TNF-훼 in sputum and plasma of patients
Research, vol. 38, no. 9, pp. 1359–1365, 2005.
 B. R. Vuillemenot, J. F. Rodriguez, and G. W. Hoyle, “Lymphoid
undergoing asthma or chronic obstructive pulmonary dis-
ease exacerbation,” Brazilian Journal of Medical and Biological
expressing tumor necrosis factor-훼,” American Journal of Respi-
 I. Couillin, V. Vasseur, S. Charron et al., “IL-1R1/MyD88
signaling is critical for elastase-induced lung inflammation and
emphysema,” The Journal of Immunology, vol. 183, no. 12, pp.
 U. Lappalainen, J. A. Whitsett, S. E. Wert, J. W. Tichelaar,
ratory Cell and Molecular Biology, vol. 30, no. 4, pp. 438–448,
and K. Bry, “Interleukin-1훽 causes pulmonary inflammation,
32, no. 4, pp. 311–318, 2005.
 T. Fujisawa, S. Velichko, P. Thai, L. Y. Hung, F. Huang, and R.
IL-17A; the NF-휅B paradigm,” The Journal of Immunology, vol.
pulmonary emphysema in the adult murine lung,” The Journal
of Experimental Medicine, vol. 192, no. 11, pp. 1587–1600, 2000.
 A. Churg, R. D. Wang, H. Tai, X. Wang, C. Xie, and J.
emphysema, and airway remodeling in the adult murine lung,”
Wu, “Regulation of airway MUC5AC expression by IL-1훽 and
183, no. 10, pp. 6236–6243, 2009.
 Z. Wang, T. Zheng, Z. Zhu et al., “Interferon 훾 induction of
L. Wright, “Tumor necrosis factor-훼 drives 70% of cigarette
 M. Fujita, J. M. Shannon, C. G. Irvin et al., “Overexpression of
Respiratory and Critical Care Medicine, vol. 170, no. 5, pp. 492–
tumor necrosis factor-훼 produces an increase in lung volumes
and pulmonary hypertension,” American Journal of Physiology,
vol. 280, no. 1, pp. L39–L49, 2001.
 E. M. Thomson, A. Williams, C. L. Yauk, and R. Vincent,
“Overexpression of tumor necrosis factor-훼 in the lungs alters
no. 4, pp. 1413–1430, 2012.
immune response, matrix remodeling, and repair and mainte-
nance pathways,” The American Journal of Pathology, vol. 180,
 M. G. Matera, L. Calzetta, and M. Cazzola, “TNF-훼 inhibitors
no. 2, pp. 121–128, 2010.
in asthma and COPD: we must not throw the baby out with the
 M. Saetta, S. Baraldo, L. Corbino et al., “CD8+ve cells in the
lungs of smokers with chronic obstructive pulmonary disease,”
160, no. 2, pp. 711–717, 1999.
 T. C. O’Shaughnessy, T. W. Ansari, N. C. Barnes, and P. K.
Jeffery, “Inflammation in bronchial biopsies of subjects with
with FEV1,” American Journal of Respiratory and Critical Care
Medicine, vol. 155, no. 3, pp. 852–857, 1997.
 R. E. K. Russell, S. V. Culpitt, C. DeMatos et al., “Release
and activity of matrix metalloproteinase-9 and tissue inhibitor
of metalloproteinase-1 by alveolar macrophages from patients
 R. Foronjy, T. Nkyimbeng, A. Wallace et al., “Transgenic
expression of matrix metalloproteinase-9 causes adult-onset
emphysema in mice associated with the loss of alveolar elastin,”
American Journal of Physiology, vol. 294, no. 6, pp. L1149–L1157,
 J. R. Hurst, J. Vestbo, A. Anzueto et al., “Susceptibility to
exacerbation in chronic obstructive pulmonary disease,” The
New England Journal of Medicine,vol. 363, no. 12, pp. 1128–1138,
macrophage phagocytosis of bacteria in COPD,” European
Respiratory Journal, vol. 35, no. 5, pp. 1039–1047, 2010.
 A. Prieto, E. Reyes, E. D. Bernstein et al., “Defective nat-
ural killer and phagocytic activities in chronic obstruc-
tive pulmonary disease are restored by glycophosphopeptical
(Inmunofer´ on),” American Journal of Respiratory and Critical
Care Medicine, vol. 163, no. 7, pp. 1578–1583, 2001.
 C. S. Berenson, M. A. Garlipp, L. J. Grove, J. Maloney, and
S. Sethi, “Impaired phagocytosis of nontypeable Haemophilus
influenzae by human alveolar macrophages in chronic obstruc-
tive pulmonary disease,” Journal of Infectious Diseases, vol. 194,
no. 10, pp. 1375–1384, 2006.
 S. Hodge, G. Hodge, R. Scicchitano, P. N. Reynolds, and M.
Holmes, “Alveolar macrophages from subjects with chronic
obstructive pulmonary disease are deficient in their ability to
phagocytose apoptotic airway epithelial cells,” Immunology and
Cell Biology, vol. 81, no. 4, pp. 289–296, 2003.
macrophage phagocytic function and expression of mannose
receptor in chronic obstructive pulmonary disease,” American
pp. 139–148, 2008.
the adult lung causes matrix metalloproteinase- and cathepsin-
dependent emphysema,” Journal of Clinical Investigation, vol.
106, no. 9, pp. 1081–1093, 2000.
16Mediators of Inflammation
 G. Raes, P. De Baetselier, W. No¨ el, A. Beschin, F. Brombacher,
and H. G. Gholamreza, “Differential expression of FIZZ1 and
Ym1 in alternatively versus classically activated macrophages,”
Journal of Leukocyte Biology, vol. 71, no. 4, pp. 597–602, 2002.
1 interacting chitinase-like protein (SI-CLP) is up-regulated in
alternatively activated macrophages and secreted via lysosomal
pathway,” Blood, vol. 107, no. 8, pp. 3221–3228, 2006.
 S. L´ etuv´ e, A. Kozhich, A. Humbles et al., “Lung chitinolytic
activity and chitotriosidase are elevated in chronic obstruc-
tive pulmonary disease and contribute to lung inflammation,”
1 stratifies chronic obstructive lung disease,” American Journal
 H. Matsuura, D. Hartl, M. J. Kang et al., “Role of breast
regression protein-39 in the pathogenesis of cigarette smoke-
induced inflammation and emphysema,” American Journal of
Respiratory Cell and Molecular Biology, vol. 44, no. 6, pp. 777–
 Y. Sakazaki, T. Hoshino, S. Takei et al., “Overexpression of
chitinase 3-like 1/YKL-40 in lung-specific IL-18-transgenic
 S. L´ etuv´ e, A. Kozhich, N. Arouche et al., “YKL-40 is elevated
in patients with chronic obstructive pulmonary disease and
activates alveolar macrophages,” The Journal of Immunology,
vol. 181, no. 7, pp. 5167–5173, 2008.
 A. Kahnert, P. Seiler, M. Stein et al., “Alternative activation
deprives macrophages of a coordinated defense program to
vol. 36, no. 3, pp. 631–647, 2006.
lar macrophage activation state induced by cigarette smoking,”
172, no. 11, pp. 1383–1392, 2005.
 A. Churg, R. D. Wang, H. Tai et al., “Macrophage metalloelas-
tase mediates acute cigarette smoke-induced inflammation via
tumor necrosis factor-훼 release,” American Journal of Respira-
 M. Monta˜ no, C. Beccerril, V. Ruiz, C. Ramos, R. H. Sansores,
and G. Gonz´ alez-Avila, “Matrix metalloproteinases activity in
COPD associated with wood smoke,” Chest, vol. 125, no. 2, pp.
 S. S. Valenc ¸a, K. da Hora, P. Castro, V. G. Moraes, L. Carvalho,
lastase expression in mouse lung induced by cigarette smoke,”
Toxicologic Pathology, vol. 32, no. 3, pp. 351–356, 2004.
12 and Cathepsin D expression in pulmonary macrophages and
dendritic cells of cigarette smoke-exposed mice,” International
Archives of Allergy and Immunology, vol. 138, no. 2, pp. 169–179,
 K.daHora,S.S.Valenc ¸a,andL.C.Porto,“Immunohistochemi-
tory and Critical Care Medicine, vol. 167, no. 8, pp. 1083–1089,
cal study of tumor necrosis factor-훼, matrix metalloproteinase-
smoke,” Experimental Lung Research, vol. 31, no. 8, pp. 759–770,
12, and tissue inhibitor of metalloproteinase-2 on alveolar
macrophages of BALB/c mice exposed to short-term cigarette
and J. L. Wright, “훼1-Antitrypsin suppresses TNF-훼 and MMP-
37, no. 2, pp. 144–151, 2007.
 A.Babusyte,K.Stravinskaite,J.Jeroch,J.L¨ otvall,R.Sakalauskas,
and B. Sitkauskiene, “Patterns of airway inflammation and
MMP-12 expression in smokers and ex-smokers with COPD,”
Respiratory Research, vol. 8, article 81, 2007.
 R. A. Dean, J. H. Cox, C. L. Bellac, A. Doucet, A. E. Starr, and
C. M. Overall, “Macrophage-specific metalloelastase (MMP-
12 production by cigarette smoke-stimulated macrophages,”
12) truncates and inactivates ELR+CXC chemokines and
generates CCL2, -7, -8, and -13 antagonists: potential role of
the macrophage in terminating polymorphonuclear leukocyte
influx,” Blood, vol. 112, no. 8, pp. 3455–3464, 2008.
 T. L. Hackett, R. Holloway, S. T. Holgate, and J. A. Warner,
cytokine release during acute inflammation in chronic
obstructive pulmonary disease: an ex vivo study,” Respiratory
Research, vol. 9, article 47, 2008.
 S. Takanashi, Y. Hasegawa, Y. Kanehira et al., “Interleukin-10
level in sputum is reduced in bronchial asthma, COPD and in
smokers,” European Respiratory Journal, vol. 14, no. 2, pp. 309–
 W. A. H. Wallace, P. M. Fitch, A. J. Simpson, and S. E. M.
Howie, “Inflammation-associated remodelling and fibrosis in
the lung: a process and an end point,” International Journal of
Experimental Pathology, vol. 88, no. 2, pp. 103–110, 2007.
 R. M. du Bois, “Strategies for treating idiopathic pulmonary
fibrosis,” Nature Reviews Drug Discovery, vol. 9, no. 2, pp. 129–
 G. Raghu, D. Weycker, J. Edelsberg, W. Z. Bradford, and
G. Oster, “Incidence and prevalence of idiopathic pulmonary
fibrosis,” American Journal of Respiratory and Critical Care
Medicine, vol. 174, no. 7, pp. 810–816, 2006.
 V. Navaratnam, N. Ali, C. J. P. Smith, T. McKeever, A. Fogarty,
and R. B. Hubbard, “Does the presence of connective tissue
disease modify survival in patients with pulmonary fibrosis?”
Respiratory Medicine, vol. 105, no. 12, pp. 1925–1930, 2011.
 M. J. Perrio, D. Ewen, M. A. Trevethick, G. P. Salmon, and J.
K. Shute, “Fibrin formation by wounded bronchial epithelial
cell layers in vitro is essential for normal epithelial repair
and independent of plasma proteins,” Clinical & Experimental
Allergy, vol. 37, no. 11, pp. 1688–1700, 2007.
 Y. P. Bhandary, S. K. Shetty, A. S. Marudamuthu et al., “Regula-
tion of alveolar epithelial cell apoptosis and pulmonary fibrosis
by coordinate expression of components of the fibrinolytic
system,” American Journal of Physiology, vol. 302, no. 5, pp.
 D. T. Eitzman, R. D. McCoy, X. Zheng et al., “Bleomycin-
induced pulmonary fibrosis in transgenic mice that either lack
or overexpress the murine plasminogen activator inhibitor-1
 I. Kotani, A. Sato, H. Hayakawa, T. Urano, Y. Takada, and A.
Takada, “Increased procoagulant and antifibrinolytic actvities
in the lungs with idiopathic pulmonary fibrosis,” Thrombosis
Research, vol. 77, no. 6, pp. 493–504, 1995.
 M. Rossol, H. Heine, U. Meusch et al., “LPS-induced cytokine
production in human monocytes and macrophages,” Critical
Reviews in Immunology, vol. 31, no. 5, pp. 379–446, 2011.
Mediators of Inflammation 17
 R. M. Stricter, “Pathogenesis and natural history of usual
interstitial pneumonia: the whole story or the last chapter of a
long novel,” Chest, vol. 128, no. 5, pp. 526S–532S, 2005.
 M. Selman and A. Pardo, “Role of epithelial cells in idiopathic
pulmonary fibrosis: from innocent targets to serial killers,”
Proceedings of the American Thoracic Society, vol. 3, no. 4, pp.
 T. A. Wynn and T. R. Ramalingam, “Mechanisms of fibrosis:
therapeutic translation for fibrotic disease,” Nature Medicine,
vol. 18, no. 7, pp. 1028–1040, 2012.
 L. Richeldi, H. R. Davies, G. Ferrara, and F. Franco, “Corticos-
teroids for idiopathic pulmonary fibrosis,” Cochrane Database
of Systematic Reviews, no. 3, Article ID CD002880, 2003.
 M. Selman, T. E. King, and A. Pardo, “Idiopathic pulmonary
esis and implications for therapy,” Annals of Internal Medicine,
vol. 134, no. 2, pp. 136–151, 2001.
 H. R. Kang, J. C. Soo, G. L. Chun, R. J. Homer, and J. A. Elias,
“Transforming growth factor (TGF)-훽1 stimulates pulmonary
of Biological Chemistry, vol. 282, no. 10, pp. 7723–7732, 2007.
 P. M. Krein and B. W. Winston, “Roles for insulin-like growth
fibrosis and inflammation via a Bax-dependent, Bid-activated
factor I and transforming growth factor-훽 in fibrotic lung
 U. Bartram and C. P. Speer, “The role of transforming growth
disease,” Chest, vol. 122, no. 6, 2002.
factor 훽 in lung development and disease,” Chest, vol. 125, no. 2,
 R. E. Vandenbroucke, E. Dejonckheere, and C. Libert, “A
therapeutic role for matrix metalloproteinase inhibitors in lung
 M. Selman, V. Ruiz, S. Cabrera et al., “TIMP-1, -2, -3, and -4
in idiopathic pulmonary fibrosis. A prevailing nondegradative
lung microenvironment?” American Journal of Physiology, vol.
279, no. 3, pp. L562–L574, 2000.
 T. Nagai, M. Tanaka, K. Hasui et al., “Effect of an immuno-
toxin to folate receptor on bleomycin-induced experimental
pulmonary fibrosis,” Clinical and Experimental Immunology,
vol. 161, no. 2, pp. 348–356, 2010.
 W. Xia, A. R. Hilgenbrink, E. L. Matteson, M. B. Lockwood, J.
during macrophage activation and can be used to target drugs
to activated macrophages,” Blood, vol. 113, no. 2, pp. 438–446,
 S. Herold, K. Mayer, and J. Lohmeyer, “Acute lung injury: how
macrophages orchestrate resolution of inflammation and tissue
repair,” Frontiers in Immunology, vol. 2, p. 65, 2011.
 N. P. Barlo, C. H. M. van Moorsel, N. M. Korthagen et al.,
“Genetic variability in the IL1RN gene and the balance between
pp. 754–765, 2004.
interleukin (IL)-1 receptor agonist and IL-1훽 in idiopathic
by inhaled lipopolysaccharide, independent of oxidative stress,
exacerbates silica-induced pulmonary fibrosis in mice,” PLoS
ONE, vol. 7, no. 7, Article ID e40789, 2012.
pulmonary fibrosis,” Clinical & Experimental Immunology, vol.
166, no. 3, pp. 346–351, 2011.
and IL-1훽-mediated pulmonary fibrosis is IL-17A dependent,”
Journal of Experimental Medicine, vol. 207, no. 3, pp. 535–552,
 Y. Zhang, T. C. Lee, B. Guillemin, M. C. Yu, and W. N.
Immunology, vol. 150, no. 9, pp. 4188–4196, 1993.
 M. W. Ziegenhagen, S. Schrum, G. Zissel, P. F. Zipfel, M.
Schlaak, and J. M¨ uller-Quernheim, “Increased expression of
proinflammatory chemokines in bronchoalveolar lavage cells
of patients with progressing idiopathic pulmonary fibrosis and
sarcoidosis,” Journal of Investigative Medicine, vol. 46, no. 5, pp.
 J. Strausz, J. Muller-Quernheim, H. Steppling, and R. Ferlinz,
“Oxygen radical production by alveolar inflammatory cells in
idiopathic pulmonary fibrosis,” American Review of Respiratory
Disease, vol. 141, no. 1, pp. 124–128, 1990.
 J. Kiemle-Kallee, H. Kreipe, H. J. Radzun et al., “Alveolar
macrophages in idiopathic pulmonary fibrosis display a more
monocyte-like immunophenotype and an increased release of
free oxygen radicals,” European Respiratory Journal, vol. 4, no.
4, pp. 400–406, 1991.
ber of alveolar macrophages expressing surface molecules of
the CD11/CD18family insarcoidosis andidiopathic pulmonary
fibrosis is related to the production of superoxide anions by
6, pp. 1507–1513, 1993.
 J. N. Kline, D. A. Schwartz, M. M. Monick, C. S. Floerchinger,
messenger RNA expression in macrophages from idiopathic
pulmonary fibrosis or after asbestos exposure,” The Journal of
and G. W. Hunninghake, “Relative release of interleukin-1훽
idiopathic pulmonary fibrosis,” Chest, vol. 104, no. 1, pp. 47–53,
 M. A. Gibbons, A. C. MacKinnon, P. Ramachandran et al.,
“Ly6Chi monocytes direct alternatively activated profibrotic
macrophage regulation of lung fibrosis,” American Journal of
Respiratory and Critical Care Medicine, vol. 184, no. 5, pp. 569–
and interleukin-1 receptor antagonist by alveolar macrophages:
a study in asbestos-induced lung disease, sarcoidosis, and
necrosis factor-훼 induces epithelial expression of granulocyte-
Care Medicine, vol. 180, no. 6, pp. 521–532, 2009.
 J. S. Duffield, S. J. Forbes, C. M. Constandinou et al., “Selective
depletion of macrophages reveals distinct, opposing roles dur-
ing liver injury and repair,” Journal of Clinical Investigation, vol.
115, no. 1, pp. 56–65, 2005.
 M. T. Henry, K. McMahon, A. J. Mackarel et al., “Matrix
metalloproteinases and tissue inhibitor of metalloproteinase-1
in sarcoidosis and IPF,” European Respiratory Journal, vol. 20,
no. 5, pp. 1220–1227, 2002.
 H. Lemjabbar, P. Gosset, E. Lechapt-Zalcman et al., “Over-
expression of alveolar macrophage gelatinase B (MMP-9) in
patients with idiopathic pulmonary fibrosis effects of steroid
and immunosuppressive treatment,” American Journal of Res-
piratory Cell and Molecular Biology, vol. 20, no. 5, pp. 903–913,
metalloproteinase-9, tissue inhibitor of metalloprotinease-1,
and their molar ratio in patients with chronic obstructive
pulmonary disease, idiopathic pulmonary fibrosis and healthy
macrophage colony-stimulating factor: impact on alveolar
epithelial repair,” American Journal of Respiratory and Critical
18Mediators of Inflammation
 C. Jakubzick, S. L. Kunkel, R. K. Puri, and C. M. Hogaboam,
“Therapeutic targeting of IL-4- and IL-13-responsive cells in
pulmonary fibrosis,” Immunologic Research, vol. 30, no. 3, pp.
 M. G. Chiaramonte, L. R. Schopf, T. Y. Neben, A. W. Cheever,
D. D. Donaldson, and T. A. Wynn, “IL-13 is a key regulatory
cytokine for Th2 cell-mediated pulmonary granuloma forma-
tion and IgE responses induced by Schistosoma mansoni eggs,”
The Journal of Immunology, vol. 162, no. 2, pp. 920–930, 1999.
 R. K. Kumar, C. Herbert, M. Yang, A. M. L. Koskinen, A. N. J.
accumulation and airway remodelling in a mouse model of
chronic asthma,” Clinical & Experimental Allergy, vol. 32, no.
7, pp. 1104–1111, 2002.
of the type II interleukin 4 receptor identified in mice lacking
the interleukin 13 receptor 훼1 chain,” Nature Immunology, vol.
 V. N. Lama, H. Harada, L. N. Badri et al., “Obligatory role
for interleukin-13 in obstructive lesion development in airway
 M. P. Keane, B. N. Gomperts, S. Weigt et al., “IL-13 is pivotal
in the fibro-obliterative process of bronchiolitis obliterans
syndrome,” The Journal of Immunology, vol. 178, no. 1, pp. 511–
fluorescein isothiocyanate-induced fibrosis in IL-13-deficient,
but not IL-4-deficient, mice results from impaired collagen
synthesis by fibroblasts,” The Journal of Immunology, vol. 172,
no. 7, pp. 4068–4076, 2004.
 G. Yang, A. Volk, T. Petley et al., “Anti-IL-13 monoclonal
antibody inhibits airway hyperresponsiveness, inflammation
and airway remodeling,” Cytokine, vol. 28, no. 6, pp. 224–232,
of interleukin 13 by alveolar macrophages from normal and
fibrotic lung,” American Journal of Respiratory Cell and Molecu-
lar Biology, vol. 18, no. 1, pp. 60–65, 1998.
 D. V. Pechkovsky, A. Prasse, F. Kollert et al., “Alternatively
production and intracellular signal transduction,” Clinical
Immunology, vol. 137, no. 1, pp. 89–101, 2010.
 S. T. Uh, Y. Inoue, T. E. King, E. D. Chan, L. S. Newman,
and D. W. H. Riches, “Morphometric analysis of insulin-like
growth factor-1 localization in lung tissues of patients with
idiopathicpulmonaryfibrosis,”AmericanJournal of Respiratory
and Critical Care Medicine, vol. 158, no. 5, pp. 1626–1635, 1998.
 J. M. Vignaud, M. Allam, N. Martinet, M. Pech, F. Plenat,
and Y. Martinet, “Presence of platelet-derived growth factor
in normal and fibrotic lung is specifically associated with
interstitial macrophages, while both interstitial macrophages
and alveolar epithelial cells express the c-sis proto-oncogene,”
American journal of respiratory cell and molecular biology, vol.
5, no. 6, pp. 531–538, 1991.
 F. Chen, Z. Liu, W. Wu et al., “An essential role for TH2-type
responses in limiting acute tissue damage during experimental
9, no. 1, pp. 25–33, 2008.
 A. C. MacKinnon, S. L. Farnworth, P. S. Hodkinson et al.,
“Regulation of alternative macrophage activation by galectin-
3,” The Journal of Immunology, vol. 180, no. 4, pp. 2650–2658,
 Y. Nishi, H. Sano, T. Kawashima et al., “Role of galectin-3 in
human pulmonary fibrosis,” Allergology International, vol. 56,
no. 1, pp. 57–65, 2007.
 A. Prasse, D. V. Pechkovsky, G. B. Toews et al., “A vicious circle
Care Medicine, vol. 173, no. 7, pp. 781–792, 2006.
 K. Furuhashi, T. Suda, Y. Nakamura et al., “Increased expres-
sion of YKL-40, a chitinase-like protein, in serum and lung
of patients with idiopathic pulmonary fibrosis,” Respiratory
Medicine, vol. 104, no. 8, pp. 1204–1210, 2010.
 A. L. Mora, E. Torres-Gonz´ alez, M. Rojas et al., “Activa-
tion of alveolar macrophages via the alternative pathway in
herpesvirus-induced lung fibrosis,” American Journal of Respi-
ratory Cell and Molecular Biology, vol. 35, no. 4, pp. 466–473,
 S. K. Mathai, M. Gulati, X. Peng et al., “Circulating monocytes
from systemic sclerosis patients with interstitial lung disease
show an enhanced profibrotic phenotype,” Laboratory Investi-
gation, vol. 90, no. 6, pp. 812–823, 2010.
 G. Matute-Bello, M. M. Wurfel, J. S. Lee et al., “Essential role
of MMP-12 in fas-induced lung fibrosis,” American Journal of
Respiratory Cell and Molecular Biology, vol. 37, no. 2, pp. 210–
 S. K. Madala, J. T. Pesce, T. R. Ramalingam et al., “Matrix
metalloproteinase 12-deficiency augments extracellular matrix
degrading metalloproteinases and attenuates IL-13-dependent
fibrosis,” The Journal of Immunology, vol. 184, no. 7, pp. 3955–
 T. Liu, S. M. Dhanasekaran, H. Jin et al., “FIZZ1 stimulation of
myofibroblast differentiation,” American Journal of Pathology,
vol. 164, no. 4, pp. 1315–1326, 2004.
 J. T. Pesce, T. R. Ramalingam, M. M. Mentink-Kane et al.,
“Arginase-1-expressing macrophages suppress Th2 cytokine-
driven inflammation and fibrosis,” PLoS Pathogens, vol. 5, no.
4, Article ID e1000371, 2009.
 D. R. Herbert, C. H¨ olscher, M. Mohrs et al., “Alternative
macrophage activation is essential for survival during schis-
tosomiasis and downmodulates T helper 1 responses and
uptake by macrophages,” Journal of Clinical Investigation, vol.
119, no. 12, pp. 3713–3722, 2009.
 J. M. Lopez-Guisa, X. Cai, S. J. Collins et al., “Mannose receptor
2 attenuates renal fibrosis,” Journal of the American Society of
Nephrology, vol. 23, no. 2, pp. 236–251, 2012.
 P. G. Tsoutsou, K. I. Gourgoulianis, E. Petinaki et al., “Cytokine
Respiratory Medicine, vol. 100, no. 5, pp. 938–945, 2006.
 R. W. Freeburn, L. Armstrong, and A. B. Millar, “Cultured
fibrosis (IPF) show dysregulation of lipopolysaccharide-
induced tumor necrosis factor-훼 (TNF-훼) and interleukin-10
(IL-10) inductions,” European Cytokine Network, vol. 16, no. 1,
pp. 5–16, 2005.
Mediators of Inflammation 19 Download full-text
H synthase-2-mediated conversion of arachidonic acid in con-
trolling 3T6 fibroblast growth,” American Journal of Physiology,
vol. 273, no. 5, pp. C1466–C1471, 1997.
 L. Armstrong, N. Jordan, and A. Millar, “Interleukin 10 (IL-
10) regulation of tumour necrosis factor 훼 (TNF-훼) from
 R. L. Kradin, H. Sakamoto, F. Jain, L. H. Zhao, G. Hymowitz,
and F. Preffer, “IL-10 inhibits inflammation but does not affect
and Molecular Pathology, vol. 76, no. 3, pp. 205–211, 2004.
 K. Nakagome, M. Dohi, K. Okunishi, R. Tanaka, J. Miyazaki,
and K. Yamamoto, “In vivo IL-10 gene delivery attenuates
bleomycin induced pulmonary fibrosis by inhibiting the pro-
Thorax, vol. 51, no. 2, pp. 143–149, 1996.
duction and activation of TGF-훽 in the lung,” Thorax, vol. 61,
 L. Sun, M. C. Louie, K. M. Vannella et al., “New concepts of
IL-10-induced lung fibrosis: fibrocyte recruitment and M2 acti-
vation in a CCL2/CCR2 axis,” American Journal of Physiology,
vol. 300, no. 3, pp. L341–L353, 2011.
 B. N. Melgert, P. Olinga, V. K. Jack, G. Molema, D. K. F.
Meijer, and K. Poelstra, “Dexamethasone coupled to albumin
is selectively taken up by rat nonparenchymal liver cells and
attenuates LPS-induced activation of hepatic cells,” Journal of
Hepatology, vol. 32, no. 4, pp. 603–611, 2000.
no. 10, pp. 886–894, 2006.