Airway the importance of the airway microenvironment (the epithelial


Airway epithelial cells and tissue remodeling in asthma: role
of the interaction between epithelial cells and allergens


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asthma is one of the most important diseases to be studied worldwide. The chronic
nature of the disease carries huge economic burdens especially in western
countries.  An estimated 300
million people worldwide suffer from asthma, with 250,000 annual deaths attributed to the disease. The main theme
of bronchial asthma was self-limited inflammation that is chronic and leads to airway remodeling in the long-term cases of
asthma. The formerly stated pathology was proved to be not the best
understanding of asthma pathology. With the advancement of modern technology and the inventions of new
diagnostic tools; fiberoptic bronchoscope, helped
a lot in the understanding of the pathology of bronchial
asthma and explaining the importance of the airway microenvironment (the
epithelial mesenchymal trophic unit) in the disease development.

Historical Hint

In 1895, Henry Salter was the
first to describe asthma as a disease of reversible airway obstruction. In
1960, the definition of asthma included bronchial hyper-responsiveness
as an important part of the pathology of asthma.

By 1997, the National Heart,
Lung, and Blood Institute defined asthma as: “a
chronic inflammatory disorder of the airways in which many cells play a role,
in particular mast cells, eosinophils, and T lymphocytes. In susceptible
individuals, this inflammation causes recurrent episodes of wheezing,
breathlessness, chest tightness, and cough particularly at night and/or in the
early morning. These symptoms are usually associated


 with widespread but variable airflow
limitation that is at least partially reversible, either spontaneously or with
treatment. The inflammation also causes an associated increase in airway
responsiveness to a variety of stimuli.”  

In contrast to what had been
stated before that airway remodeling in asthma was a result of chronic
inflammation, recent researches show, through airway biopsy studies in young
children, that restructuring of the airways can start up
to 4 four years
prior to the start of asthma symptoms.

Airways remodeling becomes
the corner stone for asthma development as well as the development of new drugs.
Airways are subjected to interact with different environmental allergens. Those
allergens include a variety of factors as dust, pollens, pet dander and scents
as well as other types of asthma that are due to exertion. All these factors
trigger changes in the body environment through release and control of
different types of cytokines, chemokines, growth factors as well as genetic
modulation of the bronchial airways in asthmatic patients.

Pathophysiology of asthma:

There are different
mechanisms that work synergistically to give the complete picture of asthma. In
the following lines, I am going to touch on those mechanisms rapidly:

Goblet and mucous glands hyperplasia:

In normal subjects, mucous
glands play an important role in the protection of airways against allergens
and foreign bodies. In case of asthma, mucous glands as well as


goblet cells undergo
hyperplasia which is manifested by: increased mucous secretion, which
cannot be cleared via normal physiological body responses e.g. coughing.  Moreover, there is airway narrowing in
addition to increased airway thickness.

Smooth Muscle:

Smooth muscle is one of the
pivot rules of maintaining the homeostatic environment of normal airways. In
asthma, smooth muscles increase in mass as they get stimulated in response to
allergens as well as inflammatory mediators. The end picture of smooth muscles
will be inflammation, fibrosis with severe narrowing of the airways. Hyper- responsiveness
of the airways.


Is one of
the main features that airways of asthmatic patients exhibit. Angiogenesis induces airway edema as well as
the delivery of inflammatory mediators.

Sub-epithelial fibrosis:

Is one of the main indicators
of severe asthma. Sub-epithelial fibrosis is claimed to be a result of
continuous airway hyper responsiveness of airways in asthmatic patients.

Epithelial Alteration:

Is one of the main causes of
decreasing protective barrier. Nowadays, it is the cornerstone of understanding
the development of asthma.

In this review, I am going to
highlight some of the body’s reaction in response to allergens and their effect on the
bronchial airways in asthmatic patients.  


In the following lines, I am
going to talk about the effect of some of the cytokines (IL-1B, TNF Alpha,
GM-CSF (Granulocyte – macrophage colony stimulating factor), IL-11, IL-17,
IL-16 & IL-4), Transforming growth factor – Beta 2 as well as endothelin-1
on the bronchial airway remodeling in asthma.

and airway remodeling:

Cytokines are a broad and loose category of small proteins
(5 – 20kDa) that are important in cell signaling. They affect the surrounding
cells in different ways; autocrine, paracrine and endocrine signaling as
immunomodulating agents. They include;
interferons, interleukines, Tumor necrotizing factors and generally not
hormones or growth factors. Cytokines affect many immune cells especially eosinophils,
macrophages, T lymphocytes and mast cells,
mainly in asthma.

Wasserman et al. were meticulous in studying the effect of
different cytokines on bronchial epithelium in symptomatic vs. asymptomatic
asthmatic patients. They studied different cytokines (TNF, GM-CSF, IL-1B, IL-2
and IL-6) from Bronchio-alveolar lavage (BAL) of symptomatic and asymptomatic patients. They
found that TNF and GM – CSF were able to increase the eosinophil effector
function in vitro. TNF increased the production of superoxide as well as the
cytotoxicity of eosinophils to bronchial endothelium. They also found that TNF
and IL-1B are the main inducers of endothelial – leukocyte adhesion molecule 1
as well as intracellular adhesion molecule 1. They pointed out that the
production of TNF, IL-1B and GM – CSF will increase the adhesion of circulating
leukocytes to the active pulmonary endothelial cells as well as the
inflammatory cells to the antigen stimulated airways.


IL-4 and asthma:

IL-4 is one of the pro-inflammatory cytokines. IL-4 is
secreted via the activation and the differentiation of Th2 cells.

IL- 4 is responsible for the induction of IgE isotype
switch, increased expression of vascular adhesion molecule 1 and stimulates the
eosinophilic transmigration through the endothelium as well as stimulation of
mucous production. That is why IL-4 is critical in the development of asthma.
Knowing that IL-4 is one of the main cytokines claimed in the development of
asthma opened up a spacious venue
for clinical trials to control the development of asthma via opposing the role
of IL-4.

Agosti 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 improves the
FEV1 in asthmatic patients vs. those on placebo.

IL-17 in asthma:

Il-17 is one of the pro-inflammatory cytokines. They are
secreted by Th2 cells. Experiments showed that there is higher expression of
IL-17 in BAL of asthmatic patients than those of healthy subjects. This was
also supported by the higher ratio of Th2 cells in the lavage from asthmatic
patients in contrast to those from healthy patients.

The previously stated effects of different cytokines lead to
modification of the bronchial endothelial cells and keep them in a state of
inflammation as well as cease their ability to go into



complete resolution. Instead, they keep the bronchial
endothelial cells in a continuous state recruiting inflammatory cells as well
as potentiating endothelial overgrowth.

The effect
of IL-11, IL-6 on airway remodeling:

Generally, Interleukin 11 (IL-11) is a protein that in
humans is encoded by IL11 gene. IL-11 is a multifunctional cytokine first
isolated in 1990. It is a key regulator of multiple events in hematopoiesis.
Concerning asthma, IL-11 is a pleiotropic cytokine produced by a variety of
stromal cells. Targeted overexpression of IL11 in mice results in marked
remodeling of both airway hyper responsiveness and obstruction.

Hamid et al. were interested in studying the effect of IL-11
on airway remodeling. They investigated the expression of IL-11 messenger RNA
(mRNA) within the airways of mild to severe asthmatic patients compared to
non-asthmatic healthy controls. They obtained bronchial biopsies from mild,
severe asthmatic patients as well as healthy controls by using fiberoptic
bronchoscopy. They noticed that there was overexpression of IL-11 mRNA and was
significantly higher in the epithelial and sub-epithelial cells in severe
asthmatic patients compared to cells isolated from mild, moderate asthmatic
patients and healthy controls. To confirm this finding, Hamid et al. did
sequential immunostaining for IL-11 in airway tissues and found strong evidence
of positive results within tissues from severe asthmatic patients compared to
other groups. They concluded that IL-11 is involved in chronic airway
remodeling seen in asthmatic patients and that the severity of the disease is
directly correlated to the expression of IL-11.

They also noted that there is a high production of IL-6 from
eosinophils and that IL-6 also has a pivotal role in the development of asthma.
They highlighted that IL-11 was a new venue through


which many treatment modalities could target asthma from the
aspect of controlling airway remodeling. 

airway remodeling and TGF Beta2:

Transforming growth factor beta 2 (TGF-B2) is a very
important key role in the airway remodeling in severe asthmatic cases. TGF-
Beta 2 they are secreted by the fibroblasts and carried via exosomes to
bronchial epithelial cells. They have many important roles: inhibit cell
proliferation as well as stimulate the apoptosis of the bronchial epithelial
cells (BEC).

Salem el al. was interested in investigating the effect of
TG –Beta2 on epithelial remodeling in severe asthmatic patients. Their
hypothesis was that fibroblasts – derived exosomes stimulate the proliferation
of epithelial cells in severe asthmatic patients through carrying lower levels
of TGF–Beta2 in comparison to those of healthy individuals. They used different
techniques to validate their hypothesis. The western blot showed that TGF–Beta2
expression is markedly lower than that excreted from the BECs of the healthy
individuals. They also used different in vitro cultures to emphasize their
objectives. They found out many important things; TGF–Beta2 secretion knock
down will enhance the proliferation of bronchial epithelial cells. They also noted
that the induction of TGF–Beta2 secretion will inhibit bronchial epithelial
cell proliferation even with BECs isolated from severe asthmatic patients.

The previously stated experiments highlighted the importance
of TGF–Beta2 in airway remodeling and as one of the main players in developing
severe asthma. This in turn 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. Consequently, this will help to treat
the cause of asthma rather than merely symptomatic treatment. 

-1 and airway remodeling in asthma:

Endothelin-1 is one of the family of endothelin
iso-peptides, is a potent constrictor of human bronchial smooth muscle and
carries its action via voltage-dependant calcium at low concentrations. Fasoli
et al. demonstrated that human bronchial smooth muscle cells possess a single
class of specific binding sites for endothelin-1. Fasoli et al. ran experiments
on broncho-alveolar lavage (BAL) from asthmatic patients in comparison to
healthy controls. They found that the amount of endothelin-1 in BAL from
asthmatic patients is markedly high than those in BAL of healthy subjects in
the absence of any significant alteration in the level of circulating peptides.
They concluded that, in the case of asthmatic patients the secretion of
endothelin- like material is released in higher amounts compared to those in
healthy controls. They suggested that one of the promising interventions would
be the development of specific antagonists to the endothelin-1 activity at the
receptor level. The previously stated recommendation would support the
importance of endothelin-1 in the pathogenesis of asthma.









Bronchial asthma is one of the most important research topic
worldwide not only being a heavy economic burden but also because of the great
predominance among population. With the grace of modern technology and the
invention of different diagnostic modalities e.g. fiberoptic bronchoscopy,
investigators could obtain various things to help them in examining the
pathology and mechanisms involved in the development of asthma e.g.
Broncho-alveolar Lavage (BAL), Bronchial biopsies. With the advance in imaging
modalities, electron microscopy and different biomarkers, researchers were able
to identify the key roles in the development of asthma. Bronchial asthma turned
to be a very complicated pathological process rather than a simple straight
forward airways hyper-responsiveness and a self-limited, reversible disease.
Airway remodeling is the main key in the pathogenesis of asthma. Airway
remodeling in response to different allergens is initiated by different
factors; cytokines, growth factors as well as voltage gated channels. Having
all that amount of knowledge about asthma is just a small scene of the whole
picture. Understanding the pathology behind asthma opens up various venues for
developing treatments for the cause rather than the currently available
treatments that mainly deal with relieving symptoms.

Some of these treatments, as mentioned above, target IL-4 by
competitively antagonizing IL-4 at the level of the receptors. The previous
treatment has shown a marked improvement in FEV1 is asthmatic patients compared
to those on placebo.



Last but not least, pathophysiology had been studied for 50
years now, yet we still do not know except a small part of this multi-faceted

What is next?

Investigators should dig deeply into the mechanism of
asthma, taking into consideration that pathophysiology of asthma is a sort of
complicated interaction between different cytokines, airway remodeling and
growth factors. Glycogen metabolism should be considered as one of the coming
important factors that affect asthma development.



































Correlational relationships
between percent predicted FEV1 values and numbers of cells expressing
IL-11 mRNA within (A) subepithelium and (B) epithelial
cell layer. There were significant correlations between numbers of IL-11
mRNA-positive cells in both airway epithelium and subepithelial regions and
this index of pulmonary function (P < .05).   IL-11 expression is increased in severe asthma: Association with epithelial cells and eosinophils .Eleanor Minshall, PhD,a Jamila Chakir, PhD,b Michel Laviolette, MD,b Sophie Molet, PhD,a Zhou Zhu, MD,c Ron Olivenstein, MD,d Jack A. Elias, MD,c and Qutayba Hamid, MD, PhDa Montreal and Sainte Foy, Quebec, Canada, and New Haven, Connecticut                                                                                                 References: