Airway epithelial cells and tissue remodeling in
asthma: role of interaction between epithelial cells and allergens.
asthma is one of the most critical global diseases. The chronic nature of the
disease carries enormous economic burdens especially in western countries.
According to the statistics done by American Academy of Allergy Asthma and
Immunology, only 50 million asthmatic patients can survive annually out of 300
million asthmatic patients all over the world 1. Bronchial
asthma was thought to be a chronic self-limited inflammation that leads to
airway remodeling in long-term patients. The previously stated pathology was
proven not to be the best understanding of asthma pathology. The advancement of
modern technology and the inventions of new diagnostic tools, such as
fibreoptic bronchoscope, enhanced our understanding of the pathology of
bronchial asthma and the importance of epithelial-mesenchymal trophic units in
the disease development 1.
invention of Nanotechnology helped tracing the complicated intracellular
interactions between adjacent cells. Scientists were able to identify the
effect of different cytokines by labelling them using specific conjugated antibodies
and tracking their immunofluorescence by various means, e.g., Flow cytometer.
of reversible airway obstruction in the pathology of asthma was established in
1985 by Henry Salter. In 1960, the Heart and Lung institution added bronchial
hyper responsiveness as an important part of the pathology of asthma 2.
1997, the National Heart, Lung and Blood Institute defined the role of many
immune cells such as mast cells, eosinophils and T lymphocytes in airway inflammation
causes recurrent episodes of wheezing, breathlessness, chest tightness and
cough particularly at night and in the early morning. These symptoms are
usually associated with widespread and variable airflow limitation that is
reversible either spontaneously or with treatment. This inflammation also
causes an increase in the airway responsiveness to a variety of stimuli 4.
show, through airway biopsy studies in young children, that restructuring of
the airway can start up to four years before the start of asthma symptoms 5. In
contrast to what has been stated before that airway remodeling in asthma was a
result of chronic inflammation.
mechanisms synergistically interact to give the whole picture of asthma. In the
following lines, I am going to briefly uncover some of these mechanisms.
remodeling in asthma means the change in the structure of small airways. These
changes include: hyperplasia of goblet cells and mucous glands, smooth muscles
hyperplasia, angiogenesis, sub-epithelial fibrosis and epithelial-mesenchymal trophic
unit dysfunction 6.
Goblet and mucous glands hyperplasia:
healthy subjects, mucous glands play an essential role in the protection of the
airways against allergens and foreign bodies. In case of asthma, hyperplasia of
both goblet cells and mucous glands lead to airway narrowing on top of
increased airway thickness 7.
Increased smooth muscles mass:
healthy individuals, smooth muscles have a pivot role in maintaining the
homeostatic environment of normal airways. However, in asthmatic patients,
smooth muscles increase in mass as they get stimulated in response to allergens
via inflammatory mediators. Stimulated smooth muscles will become inflamed,
fibrosed with severe narrowing of airways 8.
formation is directly related to the development of asthma. Angiogenesis
induces airway edema as well as the delivery of inflammatory mediators which
lead to more airway narrowing and consequently to asthma progression 9, 10.
one of the leading indicators of severe asthma. Sub-epithelial fibrosis is
claimed to be a result of continuous airway hyperresponsivenss in asthmatic
patients 11, 12.
Epithelial-mesenchymal trophic unit dysfunction:
epithelial-mesenchymal unit dysfunction will directly lead to decreasing
airways protective barrier which might be because of the effect of immune
modulators on the tight junctions between airways building units13.
and epithelial-mesenchymal units in asthmatic patients:
the next lines, I am going to highlight some of the airway epithelial reactions
in response to allergens and how they produce a state of imbalance between the
pro-inflammatory and anti-inflammatory cytokines which in turn results in
changes in the epithelium of the bronchial airways.
will state the effect of some of the cytokines (IL-1B, TNF alpha, GM-CSF,
IL-11, IL-17, IL-16 and IL-4) , Transforming growth factor beta as well as
endothelin-1 on the bronchial airway epithelial cells. Also I will show the
link between all of the above mentioned factors to the airway remodeling in
The Role of IL-1B, TNF alpha, GM-CSF, IL-2 and IL-6 in
et al. were meticulous in studying the effect of different cytokines on
bronchial epithelium in symptomatic vs. asymptomatic asthmatic patients 14. They
examined various cytokines (TNF alpha, GM-CSF, IL-1B, IL-2 and IL-6) derived
via bronchio-alveolar lavage (BAL) of symptomatic and asymptomatic patients.
They found that TNF alpha and GM-CSF were able to increase the eosinophil
effector function in vitro 14. Moreover,
TNF alpha increased the production of superoxide as well as the cytotoxicity of
eosinophils to bronchial endothelium. In addition, they also found that TNF
alpha and IL-1B are the primary inducers of endothelial-leukocyte adhesion
molecules as well as intracellular adhesion molecule 1 14-16. The
production of TNF alpha, IL-1B and GM-CSF increased the adhesion of circulating
leukocytes to the active pulmonary endothelial cells as well as the
inflammatory cells to the antigen-stimulated airways 17. Thus,
specific cytokines affect the adhesion molecules of the epithelial cells in the
airway of asthmatic patients in response to allergens.
The role of IL-4 in asthma:
is responsible for the induction of IgE isotype switch increasing the
expression of vascular adhesion molecule 1 and stimulates the eosinophilic
transmigration through the endothelium as well as stimulation of mucous
production 18. That is
why IL-4 is one of the critical player in the development of asthma. Knowing
that IL-4 is one of the primary cytokines claimed in the event of asthma,
opened an important venue for clinical trials to control the growth of asthma
by opposing the role of IL-4 19-21.
et al. designed an experiment through which they tried to block IL-4 receptor
(IL-4R) and investigate this on the FEV1 in asthmatic patients. They found that
administration of anti-IL-4 improved the FEV1 in asthmatic patients versus
those on placebo 22.
The Role of IL-17 in asthma:
is one of the pro-inflammatory cytokines secreted by Th17 cells. Experiments
showed that there was a higher expression of IL-17 in BAL of asthmatic patients
compared to those of healthy subjects. This was supported by the higher ratio
of Th17 cells in the lavage from asthmatic patients in contrast to those from
healthy individuals 23.
previously stated effects of different cytokines lead to not only modifying the
bronchial epithelial cells but also, keeping the state of inflammation. Thus,
bronchial epithelial cells are not restoring the normal state.
The Role of IL-11 and IL-6 in asthma:
is a pleiotropic cytokine produced by many stromal cells 24. Targeted
overexpression of IL-11 in mice results in marked remodeling of both airway
hyperresponsivenss and obstruction 25.
et al. investigated the expression of IL-11 messenger RNN (mRNA) within the
airways of mild to severe asthmatic patients compared to non-asthmatic healthy
controls 24. They
obtained bronchial biopsies from mild and severe asthmatic patients as well as
healthy controls by using fiberoptic bronchoscopy. They noticed that there was
an increase in the production of IL-11 mRNA. The increase in IL-11 mRNA
production was noticeably higher in the epithelial and sub-epithelial cells in
severe asthmatic patients in contrast to the cells isolated from healthy
confirm that finding, Hamid et al. did sequential immunostaining for IL-11 in
airway tissues and found an evidence of positive results within tissues from
severe asthmatic patients compared to other groups.
concluded that IL-11 is involved in chronic airway remodeling seen in asthmatic patients
and that the severity of the disease was linked to the expression of IL-11 24. They also
noted that there is a high production of IL-6 from eosinophils and that IL-6
also has a central role in the development of asthma 24. They
highlighted that IL-11 was an important area of research through which many
treatment modalities could target asthma from the aspect of controlling
epithelial airway remodeling.
The role of TGF beta in airway remodeling:
growth factor beta 2 (TGF-B2) has a significant participation in the airway
remodeling in severe asthmatic cases. TGF-B2 is secreted and carried via
exosomes to bronchial epithelial cells 26. They have
many vital roles: inhibit cell proliferation and stimulate the apoptosis of the
bronchial epithelial cells (BEC) 26.
et al. studied the effect of TGF-B2 on the epithelial cell remodeling in severe
asthmatic patients. They hypothesized that in asthmatic patients
fibroblasts-derived exosomes enhance the proliferation of epithelial cells
through carrying lower levels of TGF-B2 compared to healthy subjects 26. They
showed that TGF-B2 expression is drastically lower than that excluded from BECs
of healthy subjects.
addition to using different in vitro
cultures to emphasize their objectives, they identified that TGF-B2 secretion
knock-down enhanced the proliferation of bronchial epithelial cells. Moreover,
they noted that the induction of TGF-B2 secretion inhibited the proliferation
of bronchial epithelial cells even with BECs isolated from severe asthmatic
patients 26, 27.
the role of TGF-B2 in airway remodeling as one of the leading players in
developing severe asthma opened a new research area as well as clinical trials
to study the possibility of inducing TGF-B2 secretion either extrinsically or
intrinsically to down regulate the epithelial cells proliferation in severe
asthmatic patients. This will help in treating the cause of asthma rather than
mere symptomatic treatment.
Endothelin-1 and airway remodeling in asthma:
et al. demonstrated that human bronchial smooth muscle cells have specific
binding sites for endothelin-1 28, 29. They
found that the amount of endothelin-1 in bronchio-alveolar lavage from
asthmatic patients was markedly higher than those in the bronchio-alveolar
lavage of healthy subjects in the
absence of any significant alteration in the level of circulating peptides 28.
concluded that in case of asthmatic patients the secretion of endothelin-like
material was released in higher amounts in comparison to those in healthy
controls. They suggested that one of the promising interventions would be the
development of specific antagonists to endothelin-1 activity at the receptor
the clinical perspective, bronchial asthma is one of the most critical research
topics worldwide as representing an enormous economic burden as well as its
high predominance among population. With the advent of modern technology and
the invention of different diagnostic modalities, e.g., fiberoptic
bronchoscopy, the researchers could obtain various samples and specimens to
help them examining the pathology and the mechanisms involved in the
development of asthma.
the basic science perspective, the advancement of imaging modalities, electron
microscopy as well as different conjugated cytokines markers. Researchers were
able to identify the critical role of interaction between different cytokines
and micro building units of airways in asthma. Bronchial asthma turned to be a
very complicated pathological process rather than a simple, straight forward
airway hyperresponsivenss and a self-limited, reversible disease.
remodeling is the primary key in the pathogenesis of asthma. It happened in
response to different allergens initiated by various factors: cytokines, growth
factors as well as voltage-gated channels. Understanding the pathology behind
asthma opens various avenues for developing new curative therapies that target
the pathology rather than the symptoms. Some of these treatments, as mentioned
above, targeted IL-4 by competitively antagonizing IL-4 at the level of the
receptors. Those patients whom received anti-IL-4 showed marked improvement in
FEV1 compared to those on placebo.
pathophysiology of bronchial asthma should be investigated more as it is a sort
of interaction between many key players and the structural unit of the airways.
Many of the previously done studies focused on one or two factors affecting the
airway remodeling in asthmatic patients and none of them tried to assess the
balance between different factors at the same time. Moreover, different study
groups did not take into consideration the different cofounders that may be
involved in asthma like: ethnicity of the studied groups, the genetic
predisposition in different patients. I think that investigating those
cofounders in future experiments will open up new aspects for understanding
One of the
most interesting findings in asthma pathogenesis was the role of Nuclear Factor
kappa (NF) in the development of asthma. Researchers investigated the effect of
glycogen synthetase kinase 3 in asthma. They found that GSK3 Beta has a
regulatory role on nuclear factor kappa 30. Going
down the stream of GSK3 Beta, many cytokines can be regulated to restore the
balance between the pro-inflammatory and anti-inflammatory cytokines that might
in turn modulated the effect of hyper responsive airways in response to various allergens and stimuli.
S.T., The airway epithelium is central to
the pathogenesis of asthma. Allergol Int, 2008. 57(1): p. 1-10.
P., Understanding asthma pathophysiology.
Allergy Asthma Proc, 2003. 24(2): p.
D., On hematopoietic stem cell fate.
Immunity, 2007. 26(6): p. 669-73.
W., M.J. Ege, and E. von Mutius, The
asthma epidemic. N Engl J Med, 2006. 355(21):
H.K., et al., The GINA asthma strategy
report: what’s new for primary care? NPJ Prim Care Respir Med, 2015. 25: p. 15050.
C., M.K. Tulic, and Q. Hamid, Airway remodelling
in asthma: from benchside to clinical practice. Can Respir J, 2010. 17(4): p. e85-93.
D.F., Airway goblet cells: responsive and
adaptable front-line defenders. Eur Respir J, 1994. 7(9): p. 1690-706.
L.F. and P. Borger, The Three A’s in
Asthma – Airway Smooth Muscle, Airway Remodeling & Angiogenesis. Open
Respir Med J, 2015. 9: p. 70-80.
E.M., et al., Angiogenesis and airway
reactivity in asthmatic Brown Norway rats. Angiogenesis, 2015. 18(1): p. 1-11.
L.M., et al., Pulmonary vascular changes
in asthma and COPD. Pulm Pharmacol Ther, 2014. 29(2): p. 144-55.
A., et al., Parabromophenacyl bromide
inhibits subepithelial fibrosis by reducing TGF-beta1 in a chronic mouse model
of allergic asthma. Int Arch Allergy Immunol, 2015. 167(2): p. 110-8.
I.S., et al., Effects of montelukast on
subepithelial/peribronchial fibrosis in a murine model of ovalbumin induced
chronic asthma. Int Immunopharmacol, 2013. 17(3): p. 867-73.
M., D.E. Davies, and C. Blume, Epithelial
function and dysfunction in asthma. Clin Exp Allergy, 2014. 44(11): p. 1299-313.
W., et al., Association of TNF-alpha and
IL-13 genes polymorphisms with bronchial asthma. Zhonghua Yi Xue Yi Chuan
Xue Za Zhi, 2015. 32(5): p. 707-10.
E.A., et al., Levels of TNF, TNF
autoantibodies and soluble TNF receptors in patients with bronchial asthma.
J Asthma, 2013. 50(7): p. 705-11.
M., et al., TNF-alpha in asthma. Curr
Opin Pharmacol, 2007. 7(3): p.
D.H., et al., Cytokines in symptomatic
asthma airways. J Allergy Clin Immunol, 1992. 89(5): p. 958-67.
J.W. and L. Borish, Th2 cytokines and
asthma. Interleukin-4: its role in the pathogenesis of asthma, and targeting it
for asthma treatment with interleukin-4 receptor antagonists. Respir Res,
2001. 2(2): p. 66-70.
N.M., et al., Increased IL-4 mRNA
expression and poly-aromatic hydrocarbon concentrations from children with
asthma. BMC Pediatr, 2014. 14:
G.M., Anti-IL-4/-13 based therapy in
asthma. Expert Opin Emerg Drugs, 2015. 20(3):
L., H.G. Lin, and B.F. Chen, Association
of IL-4 promoter polymorphisms with asthma: a meta-analysis. Genet Mol Res,
2014. 13(1): p. 1383-94.
L.C., et al., Interleukin-4 receptor in
moderate atopic asthma. A phase I/II randomized, placebo-controlled trial.
Am J Respir Crit Care Med, 1999. 160(6):
J., et al., IL-17 in severe asthma. Where
do we stand? Am J Respir Crit Care Med, 2014. 190(10): p. 1094-101.
E., et al., IL-11 expression is increased
in severe asthma: association with epithelial cells and eosinophils. J
Allergy Clin Immunol, 2000. 105(2 Pt
1): p. 232-8.
T., et al., IL-11: insights in asthma
from overexpression transgenic modeling. J Allergy Clin Immunol, 2001. 108(4): p. 489-96.
I., et al., Fibroblast-derived exosomes
promote epithelial cell proliferation through TGF-beta2 signalling pathway in
severe asthma. Allergy, 2017.
V., et al., Bronchoalveolar lavage fluid
concentrations of transforming growth factor (TGF)-beta1, TGF-beta2,
interleukin (IL)-4 and IL-13 after segmental allergen challenge and their
effects on alpha-smooth muscle actin and collagen III synthesis by primary
human lung fibroblasts. Clin Exp Allergy, 2004. 34(3): p. 437-44.
S., et al., Levels of endothelin in the
bronchoalveolar lavage fluid of patients with symptomatic asthma and reversible
airflow obstruction. J Allergy Clin Immunol, 1991. 88(3 Pt 1): p. 376-84.
E., et al., Increased expression of
endothelin in bronchial epithelial cells of asthmatic patients and effect of
corticosteroids. Am Rev Respir Dis, 1992. 146(5 Pt 1): p. 1320-5.
Z., et al., Glycogen synthase
kinase-3beta inhibition attenuates asthma in mice. Am J Respir Crit Care
Med, 2007. 176(5): p. 431-8.