Pulmonary-intestinal cross-talk in mucosal inflammatory disease

Abstract

Chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (IBDs) are chronic inflammatory diseases of mucosal tissues that affect the respiratory and gastrointestinal tracts, respectively. They share many similarities in epidemiological and clinical characteristics, as well as in inflammatory pathologies. Importantly, both conditions are accompanied by systemic comorbidities that are largely overlooked in both basic and clinical research. Therefore, consideration of these complications may maximize the efficacy of prevention and treatment approaches. Here, we examine both the intestinal involvement in COPD and the pulmonary manifestations of IBD. We also review the evidence for inflammatory organ cross-talk that may drive these associations, and discuss the current frontiers of research into these issues.

Full text

Pulmonary-intestinal cross-talk in mucosal inflammatory
disease
Simon Keely, Ph.D.*,
School of Biomedical Sciences and Pharmacy and Hunter Medical Research Institute, The
University of Newcastle, NSW, Australia
Nicholas J. Talley, M.D., Ph.D., and
Faculty of Health and Hunter Medical Research Institute, The University of Newcastle, NSW,
Australia
Philip M. Hansbro, Ph.D.*
Centre for Asthma and Respiratory Disease, School of Biomedical Sciences and Pharmacy and
Hunter Medical Research Institute, The University of Newcastle, NSW, Australia
Abstract
Chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (IBD) are
chronic inflammatory diseases of mucosal tissues that affect the respiratory and gastrointestinal
tracts, respectively. They share many similarities in epidemiological and clinical characteristics as
well as inflammatory pathologies. Importantly, both conditions are accompanied by systemic co-
morbidities that are largely overlooked in both basic and clinical research. Therefore,
consideration of these complications may maximise the efficacy of prevention and treatment
approaches. Here, we examine both the intestinal involvement in COPD and the pulmonary
manifestations of IBD. We also review the evidence for inflammatory organ cross-talk that may
drive these associations, and discuss the current frontiers of research into these issues.
Keywords
COPD; IBD; Crohn’s disease; ulcerative colitis; inflammation; cross-talk; smoking; microbiome;
lymphocyte; autoimmunity
1. Introduction
Chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (IBD) are
mucosal inflammatory diseases affecting the respiratory system and gastrointestinal tract,
respectively. COPD affects 64 million people worldwide and is the 4th leading cause of
death1. IBD has a prevalence of >300/100,000 globally and there has been a dramatic
increase in the incidence of IBD over the last 50 years2, 3. COPD and IBD are both chronic
diseases, which are driven by recurrent cycles of inflammation that lead to tissue damage
and remodelling which progressively worsen symptoms. There are no cures for either
disease and both require lifelong health maintenance, for which current therapies are
suboptimal4–6. Many of the similarities in the pathological features of COPD and IBD are a
result of the common physiology of the respiratory and gastrointestinal systems.
*Joint corresponding authors. Correspondence and request for reprints should be addressed to: Dr. Simon Keely/Prof. Philip M.
Hansbro, School of Biomedical Sciences and Pharmacy and Hunter Medical Research Institute, David Maddison Clinical Sciences
Building, Newcastle, Australia 2300., Simon.Keely@newcastle.edu.au/ Philip.Hansbro@newcastle.edu.au, Phone: +612 4913
8817/8819 Fax: +612 4913 8814.
NIH Public Access
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Mucosal Immunol
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Published in final edited form as:
Mucosal Immunol
. 2012 January ; 5(1): 7–18. doi:10.1038/mi.2011.55.
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1.1 Common physiology of the respiratory and gastrointestinal tracts
Structurally the respiratory and gastrointestinal tracts have many similarities7, 8 . Both have
an extensive, highly vascularised, luminal surface area9–12 which is protected by a selective
epithelial barrier13–15 and an overlying mucus-gel layer16, 17 from commensal bacteria,
pathogens and foreign antigens. These epithelial surfaces cover a sub-mucosal layer of loose
connective tissue and mucosa-associated lymphoid tissue (MALT), comprised of resident
lymphocytes. This lymphoid tissue regulates antigen sampling, lymphocyte trafficking and
mucosal host defence18, 19. Respiratory and gastrointestinal epithelia share a common
embryonic origin in the primitive foregut20, 21, which may account for their similarities.
However, it is most likely that it is the similar inflammatory and immune components of
these organs that are the cause of the overlap in pathological changes in respiratory and
intestinal mucosal diseases.
1.2 COPD
COPD is an umbrella term describing a group of conditions characterized by prolonged
airflow obstruction and loss of the functional capacity of the lungs. Patients suffer from
chronic bronchitis and emphysema that lead to breathing difficulties (dyspnoea)22.
Symptoms are induced by exaggerated and chronic inflammatory responses to the noxious
insult of smoke exposure, with periodic exacerbations of disease typically caused by
bacterial or viral infection23. Smoking is the major causal risk factor in COPD in
westernized countries, but wood smoke and pollution are important in other areas, and there
are genetic and epigenetic components24. Recent studies show that exposure to respiratory
infections or hyperoxia in early life may also contribute to the development of COPD25, 26.
1.3 IBD
IBD is a term that describes a group of inflammatory diseases of the gastrointestinal tract.
Ulcerative colitis (UC) and Crohn’s disease (CD) are the two most common forms of IBD27.
Physiologically, UC and CD are quite distinct. UC is characterized by continuous,
superficial ulceration of the colon, whereas CD manifests with transmural, sporadic (skip)
lesions and may occur at any point along the digestive tract28, 29. Both conditions are
associated with excessive daily bowel movements, severe abdominal pain, diarrhoea, weight
loss, malnutrition and intestinal bleeding. The causes of IBD are unclear, however several
factors are known to contribute to the onset of disease including genetic risk, environmental
stress, the intestinal microbiome and inflammatory dysfunction30.
1.4 Inflammatory organ cross-talk in COPD and IBD
It is widely accepted that secondary organ disease occurs in both COPD and IBD 31–37.
There is much recent clinical interest in intestinal manifestations of COPD and an increasing
number of studies have highlighted the prevalence of pulmonary inflammation in IBD. At an
epidemiological level there is a strong association between the incidence of COPD and
CD38–40. A population-based cohort study performed by Ekbom
et al
., showed that the risk
of CD in COPD sufferers was 2.72 times higher than in healthy controls and greater than the
risk reported for smoking alone39. There is also a familial risk factor, with an increased risk
of CD among first-degree blood relatives of COPD sufferers, although shared environmental
factors may account for this. Specific intestinal manifestations of COPD include atrophic
gastritis and nutritional absorption deficiency in the small intestine34, 41.
Conversely, COPD has been shown to be a significant mortality factor among CD
sufferers38, 40, with standardised mortality ratios of 2.5–3.5 for COPD in the CD population.
Kuzela
et al
., demonstrated a high incidence of abnormal pulmonary function in both CD
and UC patients, despite a lack of radiological abnormalities42. Similar findings by Tzanakis
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et al.
, led them to propose that patients suffering from IBD should undergo pulmonary
evaluation including physical examination, chest X-ray and pulmonary function testing43–45.
Black
et al.
, performed a literature survey that identified 55 articles citing thoracic disorders
in IBD patients, with large airway involvement accounting for 39% of these associations33.
Three more specific studies of randomly selected IBD patients showed incidence rates of
pulmonary organ involvement at 44%46, 48%47 and 50%48. The symptoms manifested as
interstitial lung disease, increased numbers of alveolar lymphocytes and a reduction in the
diffusion capacity of the lung. Pulmonary involvement was more likely in UC, but was still
significant in CD.
Hence there is a clear but undefined link between inflammatory diseases in the respiratory
and intestinal systems. While the associations have been clearly identified in the clinical
literature, there have been few basic research studies that have investigated the mechanisms
of the inflammatory cross-talk involved.
2. Common risk factors in COPD and IBD
COPD and IBD are multifactorial diseases and share many aspects of the classical “triad” of
risk factors; environmental factors, genetic susceptibility and microbial involvement. In
addition, both conditions exhibit clear signs of immunological dysfunction in their
pathologies. However, while smoke or particulate inhalation is a critical environmental
factor for COPD, the corresponding factors for IBD are ill-defined. Conversely, although
there is a clear link between the intestinal microbiome and IBD, the potential of an intrinsic
lung microbiome as a risk factor in COPD has only recently emerged.
2.1 Smoking as a risk factor for COPD and IBD
Cigarette smoking is the single most important risk factor in COPD. Approximately 80% of
people with COPD are past or present smokers. Toxins and particulate matter in inhaled
smoke induce acute inflammation in the airways. With repeated insult, inflammation
becomes chronic and damages the airway epithelium and lung tissue49–51. Eventually this
leads to remodelling of the respiratory epithelium, emphysema and chronic disease.
However, only between 15–50% of all smokers develop COPD, indicating that smoke
inhalation alone is not sufficient to induce disease52, 53 and that other risk factors are likely
contribute to the development of COPD. Twin and familial studies have suggested the
involvement of genetic factors, with first-degree relatives of COPD sufferers at increased
risk54, 55.
Smoking is also a risk factor for IBD and significantly increases the risk of developing CD
by 3-fold56–60. In contrast, and surprisingly, the prevalence of UC among smokers is low,
with smoking alleviating symptoms of disease60, 61. This is exemplified by familial studies
of siblings who are genetically susceptible to IBD. In these studies smokers were shown to
be more likely to develop CD and non-smokers to develop UC62. Nevertheless, ex-smokers
appear to be at increased risk of UC than those who have never smoked63–65.
The issue is further complicated when incidences of smokers and IBD are correlated as a
whole. Eastern countries tend to have a much higher smoking rate than western countries66,
yet western countries have a higher incidence of CD, but not UC compared to eastern
countries67, 68. The lack of epidemiological correlation between smoking and CD incidence
in the east-west divide suggests that, like COPD, smoking by itself is not sufficient to induce
IBD. Studies in animal models of CD-like colitis have demonstrated that smoke-exposure
exacerbates existing colitis in wildtype animals69–71. This suggests that smoking can
augment existing mucosal inflammation, although no-consensus on mechanism has been
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achieved. Thus, while smoking has an obvious impact on both respiratory and
gastrointestinal health, the nature of these phenomena are poorly understood.
2.2 Genetic risk of COPD and IBD
COPD and IBD have known genetic risk factors. To date, four genetic risk factors have been
formally identified for COPD. Deficiency of α1 anti-trypsin (A1AT), an enzyme and a
serum trypsin inhibitor that protects against protease remodelling in the airway, accounts for
2% of COPD in the population72, 73. Recently, genes for α-nicotinic acetylcholine receptor
(CHRNA3/5)74, hedgehog-interacting protein (HHIP)75, 76 and iron regulatory protein 2
(IREB2)77–79 have been shown to be potential susceptibility loci for COPD. However,
functional endpoints have yet to be determined for how these genes influence the
development of COPD.
Both CD and UC are known to have genetic risk factors, and both ethnic and familial
associations have been shown55, 80, 81. Mutations in genes for nucleotide-binding
oligomerization domain containing 2 (NOD2)82–84, autophagy-related protein 16-1
(ATG16L1)85, 86, interleukin-23 receptor (IL23R)87, 88 and immunity-related guanosine-5’-
triphosphatase family M protein (IRGM89) have been shown to dramatically increase the
risk of CD. A recent study has also identified a NOD2 mutation in COPD populations
offering a possible link between this condition and CD90. These genes code for proteins
which control responses to infection at the intestinal mucosa and regulate autophagy. Thus a
paradigm has developed that a defect in bacterial clearance in CD may be one of the key
triggers for disease onset. Polymorphisms of human leukocyte antigen (HLA) class II genes
also have a strong association with UC, suggesting that lymphocyte regulation is an
important factor in its development91, 92. Recent studies have made substantial progress in
understanding gene associations with UC. Among the new susceptibility loci identified are
laminin subunit beta-1 (LAMB1)93, extracellular matrix protein 1 (ECM1)94, hepatocyte
nuclear factor 4 alpha (HNF4A)93 and Cadherin-1 and -3 (CDH1 and 3)93. These genes are
involved in maintaining epithelial barrier integrity81, suggesting that a dysfunction in the
epithelial barrier may predispose to UC.
It is possible that genetic risk factors may also contribute to the association between COPD
and IBD. HHIP is also important in the development of the intestinal crypt axis95, and
further studies are required to identify whether this gene contributes to disease overlap
between COPD and IBD. The diversity of gene susceptibility loci for both COPD and IBD
suggests that susceptibility to these conditions may involve multiple genes and alleles that
couple with environmental triggers to induce disease in some individuals.
2.3 Disruption of the microbiome
Bacterial colonization of the lower respiratory tract, although once controversial, is now
known to influence the pathogenesis of COPD96, 97. The controversy was due to the
classical view, borne largely from culture-based studies, of healthy lungs as a sterile
environment98, 99. Advances in culture-independent techniques for microbial analysis have
shown that the healthy lung plays host to its own microbiome, which changes significantly
during disease100, 101. Nevertheless, the precise role of the lung microbiome in COPD
pathogenesis and the mechanisms that underpin infection-induced COPD exacerbations are
poorly understood97.
It is also known that changes in the intestinal microbiome are associated with IBD30, 102, 103,
however again the nature of the shift in commensal populations is not well established.
Indeed, it is certain that the microbiome contributes to both the initial inflammation and
chronic nature of IBD, but it is unclear if commensals are the initiating factor104. Regardless
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of the role in the initiation of IBD, chronic inflammation contributes to a loss of diversity in
the microbiome, which appears to perpetuate the disease102, 104, 105. In both COPD and IBD
the microbiome of the lung and intestine have changes in the dominant species and a
reduction in diversity106, without decreases in microbial numbers107. Whether these changes
are a mechanism or consequence of inflammation is not understood, but clearly a healthy
microbiome is important to both respiratory and gastrointestinal health.
2.4 Epithelial barrier dysfunction
Maintenance of epithelial barrier function is critical for maintaining the healthy state of the
respiratory and gastrointestinal mucosa. This is because the epithelial barrier separates the
interstitium and underlying tissues from the milieu of antigenic material in the mucosal
lumen. Consequently, loss of barrier function as a result of mucosal inflammation
contributes to the chronic nature of these conditions, although it is not yet understood if loss
of function is a causative factor or a consequence of disease. COPD patients are particularly
susceptible to bronchitis (inflammation of the bronchial mucosa), which develops as smoke
exposure damages the airway epithelial barrier. Shaykhiev
et al.
, have shown that smoking
leads to down-regulation of genes coding for tight junction and adherence proteins, which
was more pronounced in smokers with COPD108.
In vitro
studies examining the effect of
cigarette smoke extract on primary bronchial epithelial cells have shown that the
endogenous protease calpain, mediates degradation of tight junction complexes109. Thus,
smoking, the major environmental risk factor for COPD, promotes the dysregulation of the
pulmonary epithelial barrier.
Epithelial barrier dysfunction is a common feature of IBD110. However, although this is well
established, like COPD, it is unknown if barrier dysfunction is a causative or consequential
factor111, 112. Certainly, in IBD, increased epithelial permeability promotes the progression
of chronic inflammation. Soderholm
et al.
, demonstrated that the epithelial tight junctions of
non-inflamed intestinal tissue from CD patients were more susceptible to breakdown upon
luminal antigenic stimulation113. Epithelial breakdown allows the establishment of invasive
bacterial infections, which are more characteristic of CD than UC114. However, both UC
and CD patients have high IgG titres against intestinal microbes115, and both diseases show
histopathologic evidence for the loss of tight-junctional integrity 116–118, suggesting that
epithelial dysfunction is important in both conditions.
2.5 Pattern recognition receptors (PRRs)
PRRs are a family of highly conserved proteins that are expressed by cells of the innate
immune system. They recognize components termed pattern associated molecular patterns
(PAMPs) of microorganisms, cellular stress signals and damaged tissue. They may be
membrane-bound or cytoplasmic and, when activated, induce the production and secretion
of inflammatory mediators and signalling molecules. Two PRR families known to be
important in the mucosal inflammatory response are the cytoplasmic NOD family of
receptors and the membrane-bound Toll-like receptor (TLR) family119–121.
COPD patients are known to be at an increased risk of pulmonary infection, leading to
inflammatory exacerbations of their disease, however the mechanisms that underlie this
increased risk are not well understood122. Kinose
et al.
, have recently identified increases in
the prevalence of the NOD2 rs1077861 single nucleotide polymorphism (SNP) in COPD
patients90. NOD2 recognizes muramyl dipeptide (MDP), an element of peptidoglycan,
which is an important component of the cell wall of virtually all bacteria. This SNP causes a
conformational change in NOD2 and leads to a series of downstream interactions that
culminate in NFκB activation and an enhanced inflammatory cytokine response upon
stimulation. Although baseline NOD2 expression was unaltered in COPD patients, the SNP
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was associated with increased COPD disease severity measured by reduced lung function90.
The mechanism for the involvement of the SNP in COPD pathology has yet to be fully
characterized.
NOD2 is also strongly associated with CD, whereby a defect in NOD2 signalling leads to
impaired epithelial barrier function, increased IL-1β and an overcompensating TLR2
response, and promotes increases in serum IL-12120, 123. NOD2 mutations are present in
15% of the CD population and a NOD2 SNP has recently been associated with smoking and
CD124. Although Kinose
et al.
, did not examine TLR2 or IL-12 in the COPD study, IL-12
has been shown to be associated with increased CD8 cytotoxic T cell and natural killer (NK)
cell activation in COPD patients and mouse models125, 126, although whether this is related
to NOD2 polymorphisms, requires further investigation. NOD2 may therefore be a common
link between COPD and CD, with polymorphisms identified in COPD and CD populations,
including an association with smoking and CD.
TLRs that recognize viral and bacterial proteins maintain mucosal homeostasis, and genetic
varients of TLRs have been identified in COPD and IBD121, 127–130. Certainly, infection
plays a prominent role in COPD pathogenesis and TLR2, which recognises a range of
bacterial and yeast proteins, has reduced expression and responsiveness to LPS in alveolar
macrophages from COPD patients and smokers131. This suggests that there is a defect in the
mucosal innate response in COPD. Conversely, TLR2 was shown to be upregulated in
peripheral blood monocytes from COPD patients compared to healthy controls128, perhaps
indicating the presence of systemic inflammation in these patients. While certain TLR2
polymorphisms are linked with increased infection, they do not appear to be associated with
COPD132. Thus the exact nature of and defects of TLR2 responses in COPD remain unclear.
TLR4, which recognizes LPS, promotes COPD pathogenesis, although the pathways
involved appear to be complex130. Investigation of murine models indicates that TLR4 is
involved in the development of smoke-induced inflammatory responses133. This
inflammatory response was driven by IL-1β secretion from macrophages and neutrophil
recruitment to lung tissue. Smoke exposure also drives TLR4-dependent IL-8 production in
monocyte-derived macrophages134. In both of these studies, smoke-induced TLR4
activation was independent of LPS.
Both TLR2 and TLR4 were found to be induced in the colonic mucosa of pediatric IBD
patients135. Furthermore, Canto
et al.
, identified an increase in TLR2 expression on
peripheral blood monocytes, which was associated with elevated circulating TNF-α
concentrations in active UC and CD136. This suggests that, like COPD, systemic
inflammation may be involved is IBD pathogenesis. The D299G and T399I SNPs of TLR4
have been shown to be associated with both UC and CD137–139, while T399I has also been
identified in COPD patients140, suggesting a possible common link. While the functional
consequences of these gene variants are not yet fully appreciated, it is known that
inflammatory cytokine signalling results in increased TLR4 expression on macrophages
from the intestinal epithelium and
lamina propria
in both UC and CD resulting in increased
responsiveness to LPS141, 142. Thus, TLR4 may play a common role in mucosal
inflammatory disease whereby an inflammatory insult coupled with TLR4 gene variations
results in hypersensitivity to LPS and an exaggerated immune response in the lung or
intestine.
3. Potential mechanisms of organ cross-talk
Despite the similarities in the physiology of the respiratory and gastrointestinal mucosal
organs, the common risk factors involved in the development of COPD and IBD and the
incidences of inflammatory cross-talk between the two organs in disease, no mechanism has
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been identified for pulmonary-intestinal organ cross-talk. While the respiratory and
gastrointestinal tracts both share components of the common mucosal immune system, the
pathways involved in cross-talk may be multi-factorial, like COPD and IBD themselves
(Figure 1).
3.1 Protease regulation in COPD and IBD
There is evidence that dysregulation of protease activity may play a role in both COPD and
IBD. Increased levels of the proteases that break down connective tissue components have
been identified in COPD patients and modelled in animals143. Of particular interest are the
matrix metalloproteinase (MMP) family of proteases, which play a role in the digestion of
collagen, elastin, fibronectin and gelatin, key components in mucosal structural integrity144.
Increased levels of epithelial and leukocyte MMP-2, -9 and -12 have been associated with
the pathogenesis of COPD143, 145, 146 and IBD147–150, which may contribute to a “runaway
remodelling” process.
The role of A1AT in COPD is established, however the prevalence of A1AT in IBD is
debatable. A1AT neutralizes proteases involved in tissue remodelling, such as neutrophil
elastase151 and MMP-12152. Deficiencies in A1AT production promotes extensive tissue
damage during mucosal inflammation as the tissue remodelling process progresses
unchecked. Deficiency of A1AT leads to the development of emphysema and COPD153, 154.
Because of its role in the remodelling of inflamed tissue, faecal A1AT levels are commonly
used as a marker for disease severity in CD patients155, 156. This suggests that lack of A1AT
is does not promote the development of CD. While some studies have suggested higher
levels of A1AT in UC patients157, 158, there is a higher prevalence of the allele linked to
A1AT deficiency (PiZ) among the UC population157 and UC patients with this allele
develop more severe forms of colitis158. Further work is required to address this divergence.
3.2 Immune cell homing and systemic factors
Both COPD and IBD are considered to be systemic inflammatory diseases and peripheral
lymphocyte activity may contribute to pathogenesis36, 159–162. During inflammation, the
bronchus associated lymphoid tissue (BALT) regulates lymphocyte trafficking from lung
tissue through the general circulation18. This mirrors the role of the gut associated lymphoid
tissue (GALT) and both lung and intestinal lymphocytes migrate to other mucosal sites as
part of the common mucosal immune system163. It is possible that this trafficking, while
functioning primarily as a common host mucosal defence, may be responsible for extra-
organ inflammation associated with COPD and IBD.
In the healthy state, lymphocytes continuously migrate through the circulatory system,
entering and exiting the tissue in response to antigen exposure. In order to control trafficking
of lymphocytes through tissues, these cells express unique homing receptors, which are
specific for corresponding ligands on their target tissues. Thus, through a combination of
homing molecules and specific receptor-ligand interactions, lymphocytes will return to their
tissue of origin during an immune response164, 165. The subtype and phenotype of
circulating lymphocytes in COPD patients have not been well characterised159. However,
there is evidence of abnormal function in peripheral lymphocytes that may contribute to
extra-pulmonary disease in COPD patients. Sauleda
et al.
, showed increased cytochrome
oxidase (CytOx) activity in the circulating lymphocytes of COPD patients, which correlated
with increased CytOx detected in wasting skeletal muscle that is commonly associated with
COPD166. Interestingly, this increased oxidative response in circulating lymphocytes is also
observed in other chronic inflammatory diseases, such as asthma and rheumatoid arthritis,
but whether these same responses occur in IBD is unknown.
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For IBD patients the selectivity of lymphocyte-endothelial interaction is lost. Salmi
et al.
,
showed that in IBD patients, the expression of homing receptors in intestinal lymphocytes
did not confer tissue specificity167. These altered homing properties may contribute to the
extra-intestinal manifestations of IBD. It is known that gut-derived lymphocytes possess the
capacity to bind to synovial168 and hepatic169 tissue, possibly accounting for the
manifestations of IBD observed in these organs. This mis-homing of lymphocytes is thought
to contribute to ocular and dermatological extra-intestinal manifestations of IBD165.
Whether this same phenomenon contributes to the lung pathologies observed in IBD is
unknown. Increased lymphocyte populations have been observed in the BAL of IBD
patients170, 171 and analysis of the sputum of IBD patients showed that 65% had an
increased CD4/CD8 T cell ratio in lung tissue172. Whether this represents a further example
of lymphocyte mis-homing involved in the pulmonary manifestations of IBD has yet to be
confirmed.
It is possible that the inhalation of smoke affects gut lymphocyte homing and promotes an
inappropriate immune response. Smoke exposure is known to affect T cell trafficking
through altered chemotactic chemokine levels173, 174. Smoke inhalation also appears to
affect the homing properties and maturation of myeloid dendritic cells (mDCs)175–178,
which are key antigen presenting cells in mucosal immune responses. The result is a rapid
accumulation of mDCs in the airways of smokers175, which may be a result of a reduced
capacity of mDCs to migrate to the lymph node175, 176. A recent animal study has similarly
shown that smoke inhalation results in the accumulation of DCs in the intestinal Peyer’s
patches of wildtype mice, although unlike the airways, this does not seem to be dependent
on changes in expression of the DC homing molecule CCR6179. The increase in DCs was
accompanied by a similar accumulation of CD4+ T cells and an apparent increase in
apoptosis of the cells overlying the follicle-associated epithelial (FAE) tissue of the
intestine.
This loss in epithelial barrier, may lead to increased antigen presentation and promote an
intestinal inflammatory response. A caveat to this study was the use of a whole body smoke
exposure model, which may not induce the same physiological consequence as inhaled
smoke. Erosion of the epithelial layer overlying the FAE has been observed in CD patient
biopsies180. While no data on smoking-status of these patients exists, smoke-induced
epithelial apoptosis is one possible mechanism for the development of these erosions. Thus
smoking may induce an overall increase in antigenic presentation in the intestines, which
may contribute to IBD pathogenesis.
Circulating TNF-α has been strongly implicated in co-morbidities associated with COPD52
and plays a central role in the progression of CD181. While, anti-TNF therapies do not
appear to provide therapeutic relief in COPD52, they have been relatively successful for
inducing remission in CD182–184. Whether this is due to the nature of the damage in COPD
or the efficacy of TNF therapy requires further investigation. Studies in transgenic mouse
models that over-express TNF-α, the TNFΔARE mouse model, have shown the
development of spontaneous Crohn’s-like ileitis and proximal colitis185. While ocular and
synovial involvement has been observed, there have been no reports of respiratory disease in
this model. However, as with pulmonary manifestations of IBD, the airway involvement
may be sub-clinical and histopathological and lung function studies may be required.
IL-6 plays a role in the acute phase response to inflammation and has been implicated in the
pathogenesis of both COPD186, 187 and IBD188, 189. IL-6 is systemically elevated in patients
with emphysema and has been shown be associated with apoptosis in pulmonary
tissue186, 187. Importantly, IL-6, in combination with TGF-β, is a major factor in the
development of the Th17 subset of T helper cells121, 190. Th17 cells are a distinct effector T
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cell subset that secrete IL-17A, IL-17F, IL-21, IL-22, IL-26, and TNF-α and promote
neutrophil chemotaxis121, 191–194. Recent work has identified increased peripheral Th17
cells in COPD patients190.
IL-6 and Th17 cells are also associated with both CD and UC189, 195, and high levels of IL-6
and Th17 associated cytokines have been identified in both the blood189 and the inflamed
and non-inflamed mucosa195, 196 of IBD patients. Moreover, blockade of the IL-6 pathway
is therapeutic in animal models. The fact that IL-6 is elevated in the non-inflamed intestinal
mucosa of IBD patients, without causing tissue damage, may suggest that a secondary tissue
insult is required. As TGF-β regulates mucosal tissue remodelling and is strongly associated
with COPD and IBD, it is conceivable, that increased systemic IL-6, coupled with TGF-β
production at the mucosal surface (due to smoke damage in the lungs of an IBD patient or an
intestinal infection in an COPD patients), may lead to the development of a Th17 polarized
inflammatory response at a secondary organ.
IL-13 is likely to contribute to COPD progression197 and mutations in the IL-13 promoter
may promote this pathogenesis 198. T-cell receptor-invariant natural killer cells (iNKCs) or
DCs, activated by bacterial or viral infection in the airways, secrete IL-13, which activates
macrophages 197, 199–201. This in turn causes further IL-13 production, which leads to
STAT6-dependent goblet cell hyperplasia, smooth muscle hyper-responsiveness, and airway
remodelling192, 202.
IL-13 also plays a role in the pathogenesis of UC, but does not appear to be involved in
CD203. In UC it appears to be the aberrant stimulation of the immune response by the
microbiome, that results in direct iNKC cytotoxic action on the epithelium and secretion of
IL-13 driving epithelial barrier dysfunction and apoptosis, and the enhancement of NKC
toxicity203, 204. Like COPD, STAT6 is an important mediator for the action of IL-13 on the
epithelium205, and the STAT6 pathway is a potential therapeutic target in both conditions.
Whether these pathways act systemically in COPD and IBD is unknown, although serum
IL-13 is increased in COPD198, possibly driving aberrant NKT and macrophage responses
across organs.
3.3 Interaction of the respiratory and intestinal microbiomes
COPD sufferers have an altered lung microbiome compared to healthy individuals,
including “healthy” smokers106. This does not exclude the possibility that smoking
influences the lung microbiome. Smoking has been shown to restrict the ability of alveolar
macrophages to phagocytose and kill bacteria206. This suggests that smoking may lead to a
defect in immunoregulation of the lung microbiome. There is evidence that components of
the enteric microflora, specifically Gram negative bacilli, may also make up a component of
the lung microflora207, 208. These bacteria are resistant to cigarette smoke209 and may
contribute to severe exacerbations of COPD208. Furthermore, inappropriate immune
responses against intestinal microflora are widely accepted to be a critical factor in the
ongoing inflammation associated with IBD. Thus there exists the possibility that the immune
response against commensal microflora observed in IBD patients, may not be restricted to
the gastrointestinal tract, but may also be directed towards enteric bacteria present in the
lung microfora.
There have been no definitive studies on the effect of smoking on the respiratory or
intestinal microbiome. This is especially surprising given cigarette smoke is known to
selectively inhibit bacterial growth, favouring a Gram negative bacilli population209. It is
possible that smoke-induced changes to the intestinal microbiome may promote the
increased risk of IBD observed in COPD sufferers. There is growing interest in how diet and
nutrition may influence the human microbiome and interplay with the immune system and
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ultimately human health210, 211. Faecal bacteriotherapy, whereby the microflora of a healthy
patient is transplanted to a colic patient, has shown promise in case studies, as a treatment
for UC105, 212, 213. This suggests that the composition of the microbiome plays an important
role in the intestinal inflammation, and restoration of a “healthy microbiome” can promote
remission of disease. While ultimately conjecture, it is conceivable that smoking may
disrupt the “healthy microbiome” and therefore link, smoking and COPD to IBD. This could
also account for the familial link of COPD and IBD observed by Ekbom
et al
214, since there
is a familial link to the make-up of an individuals microbiome and genetics play a role in
microbiome development215, 216.
3.4 Autoimmunity
There is some evidence to suggest that COPD has an autoimmune element which leads to
disease progression and relapse217. Key to this concept are the observations that only some
smokers develop COPD and that the clinical features of COPD continue to increase in
severity even after the cessation of smoking. This suggests that ongoing immune responses
occur against elements other than cigarette smoke. Smoke-induced emphysema has been
shown to generate an autoimmune response against elastins144, 218. In this proposed model,
exposure to smoke-antigens promotes an immune response that includes secretion of high
levels of elastin proteases (elastases) from neutrophils and macrophages (eg. neutrophil
elastase, MMP-9 and -12)219. The elastases degrade and fragment elastin proteins, to which
the adaptive immune system mounts a response144. As elastin is a ubiquitous protein in
mucosal tissue, an autoimmune response could lead to pathologies outside the lung, and may
be a mechanism for intestinal pathologies associated with smoking.
Tzortzaki & Siafakas proposed that smoke-induced oxidative epithelial damage initiates the
disease process in COPD through the initiation of autoimmune responses220. In their
proposed model, oxidative DNA damage to epithelial cells leads to phenotypic changes and
recognition of these cells as “non-self” by pulmonary DCs. This results in a loss of barrier
function as a T cell response is initiated against the epithelium. Such autoimmune responses
may affect the intestinal epithelium, or may be driven by smoke exposure at the intestinal
mucosa.
It is generally accepted that CD is a disease with an autoimmune component. The prevailing
hypothesis for the development of CD is that an initial infection or insult leads to an
inappropriate immune response against the intestinal mucosa and/or commensal bacterial
population30, 57. This leads to the recurring cycles of chronic inflammation that characterise
CD. UC also has a clear autoimmune element, albeit different to that of CD221, 222. Recent
work has found that isoforms of human tropomyosin (hTM 1–5) are capable of inducing
auto-antibodies and T cell responses in UC223. Autoimmunity would also explain some
elements of organ cross-talk in inflammatory disease. Immune responses against bacteria or
conserved mucosal protein epitopes of the pulmonary and gastrointestinal tracts may explain
cross-organ inflammation in COPD and IBD. Expression of hTM on extra-intestinal organs
may account for cross-organ inflammatory associations in UC, although hTM5, the
trypomyosin with the strongest link to UC, has not been identified in lung tissue223.
4. Summary
COPD and IBD are driven by inflammatory processes, are systemic diseases and are
epidemiologically linked. Given the consistent indications of the limited research to date, it
is clear that comprehensive studies on the prevalence of intestinal involvement in COPD and
pulmonary disease among IBD patients is required. The mechanisms that underpin the
development of extra-organ inflammation in COPD and IBD patients are confounded by the
complicated aetiologies of these conditions. Both conditions share environmental triggers
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and have similar immune and physiological involvement. However, the diversity of the
mechanisms that may be involved in the development of each condition suggests that
crosstalk in these diseases may be a multi-faceted process involving multiple pathways
(Figure 1). Our understanding of this area is largely based on epidemiological and clinical
observations and there is a need for basic research to elucidate the associations and
mechanisms involved. A better understanding of the nature of organ cross-talk in COPD and
IBD will contribute to the elucidation of the aetiologies of these conditions and may identify
therapeutic strategies for mucosal inflammatory disease.
Acknowledgments
SK has been supported by a Crohn’s and Colitis Fellowship of America and is currently supported by funding from
the National Health and Medical Research Council of Australia. NJT is supported by funding from the National
Health and Medical Research Council of Australia and the National Institute of Health of the United States of
America. PMH is supported by funding from the National Health and Medical Research Council of Australia and
the Australian Research Council.
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Figure 1.
Possible mechanisms of respiratory-gastrointestinal cross-talk include: overproduction of
proteases during excessive inflammation, changes in immune cell function, including
increases in cytochrome oxidase (CytOx) expressing lymphocytes and gut originating T cell
mis-homing. Cigarette smoke exposure may play a role in organ cross-talk by affecting
these processes, and/or by causing mis-homing of dendritic cells (DC) and epithelial cell
apoptosis in respiratory or gastrointestinal tissues. Smoke exposure may also lead to changes
in the microbiome, promoting growth of enteric bacteria in the lung or altering the
microbiome in the intestine that induces inflammatory responses. Inflammation may lead to
the production of autoimmune antibodies against the ubiquitous mucosal protein elastin or
autoimmune responses against antigens produced during smoke-induced oxidative DNA
damage. Systemic IL-6, in conjunction with localized TGF-β, may drive cross-organ Th17
polarized inflammation. Systemic IL-13 may drive aberrant NKT and macrophage responses
across organs.
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