Asthma

Asthma is a chronic inflammatory disorder of the airways that causes recurrent episodes of wheezing, breathlessness,
chest tightness, and cough, particularly at night and/or early in the morning. This clinical picture is caused by repeated
immediate hypersensitivity and late-phase reactions in the lung that give rise to the Ê

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Ê It is thought that inflammation causes an increase in airway responsiveness (bronchospasm) to a variety
of stimuli, which would cause no ill effects in the normal airways of nonasthmatic individuals. The underlying genetic
basis for hyper-responsive airways is not entirely clear, although significant advances have been made in understanding
the pathogenesis and environmental triggers of asthma "attack." In some cases, the attacks are triggered by exposure to an
allergen to which the person has been previously sensitized, but often no trigger can be identified. Of note, there has been
a significant increase in the incidence of asthma in the Western world over the past 3 decades.
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Because asthma is a heterogeneous disease triggered by a variety of inciting agents, there is no universally accepted
classification scheme. About 70% of cases are said to be "extrinsic" or "atopic" and are due to IgE and TH2-mediated
immune responses to environmental antigens. In the remaining 30% of patients, asthma is said to be "intrinsic" or "non-
atopic" and is triggered by non-immune stimuli such as aspirin; pulmonary infections, especially those caused by viruses;
cold; psychological stress; exercise; and inhaled irritants. While this distinction is useful from the point of
pathophysiology, in clinical practice it is not always possible to classify asthma.

Pathogenesis

The major etiologic factors of asthma are genetic predisposition to type I hypersensitivity ("atopy"), acute and chronic
airway inflammation, and bronchial hyper-responsiveness to a variety of stimuli. i
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Ê  The classic "atopic" form of asthma is associated with an excessive TH2 reaction against
environmental antigens. Cytokines produced by TH2 cells account for most of the features of asthma-IL-4 stimulates IgE
production, IL-5 activates eosinophils, and IL-13 stimulates mucus production. All three of these cytokines are produced
by TH2 cells. In addition, epithelial cells are activated to produce chemokines that promote recruitment of more TH2 cells
and eosinophils, as well as other leukocytes, thus amplifying the inflammatory reaction. In addition to the inflammatory
responses mediated by TH2 type cells, asthma is characterized by structural changes in the bronchial wall, referred to as

  
 These changes include hypertrophy of bronchial smooth muscle and deposition of subepithelial
collagen. Until recently, airway remodeling was considered a late, secondary change of asthma; the current view suggests
that it may occur over several years before initiation of symptoms. The etiologic basis for remodeling is not clear,
although there may be an

Ê 

Ê
 associated with polymorphisms in genes that result in accelerated
proliferation of bronchial smooth muscle cells and fibroblasts. One candidate gene that has emerged in recent years is
 which is expressed by the cell types implicated in airway remodeling (smooth muscle cells and fibroblasts),
although there are undoubtedly other genetic factors involved in this process. Ê  part of the inflammatory
infiltrate in asthma, are also thought to contribute to airway remodeling by secreting growth factors that stimulate smooth
muscle proliferation.

Atopic asthma
This most common type of asthma usually begins in childhood. A positive family history of atopy is common, and
asthmatic attacks are often preceded by allergic rhinitis, urticaria, or eczema. The disease is triggered by environmental
antigens, such as dusts, pollen, animal dander, and foods, but potentially any antigen is implicated. A skin test with the
offending antigen results in an immediate wheal-and-flare reaction, a classic example of the Ê ! 
Ê
 
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Ê Ê
 (Chapter 5). In the airways there is an initial 
Ê
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 to the inhaled inciting antigens, which
stimulates induction of TH2-type cells and release of interleukins IL-4 and IL-5 (Fig. 13-11A). This leads to synthesis of
IgE that binds to mucosal mast cells. Subsequent IgE-mediated reaction to inhaled allergens elicits an

Ê 
and a Ê! Ê
 (Fig. 13-11B). Exposure of  !Ê Ê  to the same antigen causes cross-linking of
IgE and the release of chemical mediators. Mast cells on the respiratory mucosal surface are initially activated; the
resultant mediator release opens mucosal intercellular junctions, allowing penetration of the antigen to more numerous
mucosal mast cells. In addition, direct stimulation of 
Ê
 
   ÊÊ
 Ê  provokes reflex
bronchoconstriction through both central and local reflexes. This occurs within minutes after stimulation and is therefore
called the Ê or

Ê  which consists of bronchoconstriction, edema (due to increased vascular
permeability), and mucus secretion. A variety of inflammatory mediators have been implicated in the acute-phase
response, although their relative importance in an actual asthma attack varies widely. Nevertheless, a partial list includes:
#$Ê
%&& &: extremely potent mediators that cause prolonged bronchoconstriction, increase vascular
permeability, and increase mucin secretion.Ê 
' released from intrapulmonary motor nerves, resulting in airway
smooth muscle constriction by direct stimulation of muscarinic receptors.
Ê
' causes bronchospasm and increases
vascular permeability, but is not considered an important mediator since antihistamine drugs do not provide
benefit.( Ê 
2: elicits bronchoconstriction and vasodilatation.( Ê Ê!Ê

Ê
Ê ' causes aggregation of
platelets and release of histamine from their granules.
Mast cells also release additional cytokines that cause the influx of other leukocytes, including neutrophils and
mononuclear cells, and particularly 

 These inflammatory cells set the stage for the Ê! Ê
 which
starts 4 to 8 hours later and may persist for 12 to 24 hours, or more (Fig. 13-11C). 

 are particularly important
in the late phase. As mentioned, their accumulation at sites of allergic inflammation is favored by several mast cell-
derived chemotactic factors, as well as chemokines (e.g., Ê)
) produced by activated bronchial epithelial cells
themselves. The accumulated eosinophils exert a variety of effects. Their armamentarium of mediators is as extensive as
that of mast cells and includes * 
 Ê
 and 

Ê

 Ê
 which are directly toxic to airway
epithelial cells. 

 )
 causes tissue damage through oxidative stress. Activated eosinophils are also a rich
source of leukotrienes, especially leukotriene C4, which contribute to bronchoconstriction. Thus, 

 

Ê
Ê
  Ê   without additional exposure to the triggering antigen. The appreciation of the
importance of inflammatory cells and mediators in asthma has led to greater emphasis on anti-inflammatory therapeutics
in clinical practice.

Non-Atopic Asthma
Figure 13-11 A model for allergic asthma. ‘ Sensitization to allergen. Inhaled allergens (antigens) elicit a TH2-
dominated response favoring IgE production and eosinophil recruitment (priming or sensitization).
Allergen-triggered
asthma. On re-exposure to antigen (Ag) the immediate reaction is triggered by Ag-induced cross-linking of IgE bound to
IgE receptors on mast cells in the airways. These cells release preformed mediators that open tight junctions between
epithelial cells. Antigen can then enter the mucosa to activate mucosal mast cells and eosinophils, which in turn release
additional mediators. Collectively, either directly or through neuronal reflexes, the mediators induce bronchospasm,
increased vascular permeability, and mucus production, besides recruiting additional mediator-releasing cells from the
blood.  Late phase (hours). The arrival of recruited leukocytes (neutrophils, eosinophils, basophils, and TH2 cells)
signals the initiation of the late phase of asthma and a fresh round of mediator release from leukocytes, endothelium, and
epithelial cells. Factors, particularly from eosinophils (e.g., major basic protein, eosinophil cationic protein), also cause
damage to the epithelium.
The mechanism of bronchial inflammation and hyper-responsiveness is much less clear in individuals with non-atopic
asthma. Incriminated in such cases are

 
Ê
Ê 
Ê Ê Ê (most common) and
 
 ÊÊ
such as sulfur dioxide, ozone, and nitrogen dioxide. These agents increase airway hyper-reactivity in both normal and
asthmatic subjects. In the latter, however, the bronchial response, manifested as spasm, is much more severe and
sustained. A positive family history is uncommon, serum IgE levels are normal, and there are no associated allergies. Ê

ÊÊÊÊ

!

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ÊÊ Although the connections are not well understood, the ultimate humoral and cellular mediators of
airway obstruction (e.g., eosinophils) are common to both atopic and non-atopic variants of asthma, and hence they are
treated in a similar way.

Drug-Induced Asthma
Several pharmacologic agents provoke asthma, 

 being the most striking example. Individuals with aspirin
sensitivity present with recurrent rhinitis and nasal polyps, urticaria, and bronchospasm. The precise mechanism remains
unknown, but it is presumed that aspirin inhibits the cyclooxygenase pathway of arachidonic acid metabolism without
affecting the lipoxygenase route, thereby shifting the balance toward bronchoconstrictor leukotrienes.

Occupational Asthma
This form of asthma is stimulated by fumes (epoxy resins, plastics), organic and chemical dusts (wood, cotton, platinum),
gases (toluene), and other chemicals. Asthma attacks usually develop after repeated exposure to the inciting antigen(s).

Morphology
The morphologic changes in asthma have been described in persons who die of prolonged severe
attacks (status asthmaticus) and in mucosal biopsy specimens of persons challenged with
allergens. In fatal cases, grossly, the lungs are overdistended because of overinflation, and there
may be small areas of atelectasis. The most striking macroscopic finding is occlusion of bronchi
and bronchioles by thick, tenacious |
  Histologically, the mucus plugs contain whorls
of shed epithelium  

|  Numerous eosinophils and 



(collections of crystalloids made up of eosinophil proteins) are also present. The other
characteristic findings of asthma, collectively called "airway remodeling" include (Fig. 13-12):
Thickening of the basement membrane of the bronchial epithelium.Edema and an inflammatory
infiltrate in the bronchial walls, with a prominence of eosinophils and mast cells.An increase in
the size of the submucosal glands.Hypertrophy of the bronchial muscle walls.

Clinical Course
An attack of asthma is characterized by severe dyspnea with wheezing; the chief difficulty lies in expiration. The victim
labors to get air into the lungs and then cannot get it out, so that there is progressive hyperinflation of the lungs with air
trapped distal to the bronchi, which are constricted and filled with mucus and debris. In the usual case, attacks last from 1
to several hours and subside either spontaneously or with therapy, usually bronchodilators and corticosteroids. Intervals
between attacks are characteristically free from respiratory difficulty, but persistent, subtle respiratory deficits can be
detected by spirometric methods. Occasionally a severe paroxysm occurs that does not respond to therapy and persists for
days and even weeks ÊÊÊ Ê
 The associated hypercapnia, acidosis, and severe hypoxia may be fatal,
although in most cases the disease is more disabling than lethal.
Figure 13-12 Comparison of a normal bronchiole with that in a person with asthma. Note the accumulation of mucus in
the bronchial lumen resulting from an increase in the number of mucus-secreting goblet cells in the mucosa and
hypertrophy of submucosal mucous glands. In addition, there is intense chronic inflammation caused by recruitment of
eosinophils, macrophages, TH2 cells and other inflammatory cells. Basement membrane underlying the mucosal
epithelium is thickened, and there is hypertrophy and hyperplasia of smooth muscle cells.
SUMMARY
‘
|Asthma is characterized by reversible bronchoconstriction caused by airway hyper-
responsiveness to a variety of stimuli.Atopic asthma is caused by a TH2 and IgE-mediated
immunologic reaction to environmental allergens and is characterized by acute (immediate) and
late-phase reactions. The TH2 cytokines IL-4, IL-5, and IL-13 are important mediators.Triggers
for non-atopic asthma are less clear but include viral infections and inhaled air
pollutants. 

 are key inflammatory cells found in all subtypes of asthma; eosinophil
products such as major basic protein are responsible for airway damage.Airway remodeling
(basement membrane thickening and hypertrophy of bronchial smooth muscle) adds to the
element of obstructive disease.

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|

Emerging research reveals that there are many factors that contribute to asthmatic symptoms in response to
allergenic exposure. The mast cell, eosinophil, and Th2 cell are well-known major contributors to asthmatic
symptoms, yet they are by no means the only cells involved. New research continues to reveal the complexity
of allergic asthma and the components involved. A range of cells and cytokines have shown to be involved in
the development of asthma and its symptoms.
Figure 1. The cells involved in inducing symptoms of allergic asthma and the cytokines they secrete to activate
other cells. APC, antigen presenting cell; PGD2, prostaglandin D2. (Permission pending. Renauld 2001)

Cells involved:

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Th2 cells are a subset of CD4+ T cells that induce the effector mechanisms carried out by eosinophils and mast
cells, and isotype-switching of B cells to produce IgE antibody. This subset of CD4+ T cells has a distinct
cytokine secretion pattern that leads to further priming and activation of other Th2 cells and aids in the
induction of effector mechanisms carried out by other cells (Janeway et al, 2005). Th2 cells are required for the
development of airway eosinophilia (Renauld 2001) and secrete the cytokines interleukin-4 (IL-4), IL-13, IL-5,
and IL-9. Th2 cell priming primarily relies on IL-4. The function of Th2 cells as well as the other cell players in
allergic asthma can be best illustrated by outlining the functions of the cytokines that the important cell players
secrete.

Cytokines involved:

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IL-4 carries out many functions such as the regulation isotype switching in B cells to IgE, induction of MHC II
and CD23 expression on cell surfaces of antigen-presenting cells (APCs), induction of adhesion molecule
expression on endothelial cells, chemokine production, and activation of mast cells and eosinophils (Karp
2000). The main role of IL-4 is carried out during the initial priming of Th2 cells and thus are necessary for the
initial differentiation of Th2 cells (Herrick and Bottomly 2003). Once Th2 priming has occurred, IL-4 no longer
plays a primary function in asthma induction. The overexpression of IL-4 leads to lymphocytic and eosinophilic
inflammation, but without airway hyperreactivity (Renauld 2001).

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IL-4 was thought to be the key cytokine involved in allergic asthma until a redundancy of function was found in
the cytokine IL-13. Asthmatics show increased mRNA expression in their sputum, indicating that IL-13 is
involved in allergic asthma (Truyen et al, 2006). IL-13 binds to the Į chain of the IL-4 receptor, shares many
functions with IL-4, and its gene is located 25 kilobases upstream of the IL-4 gene. Yet, IL-13 is less involved
in initial Th2 priming and more active in inducing the asthmatic symptoms that follow. IL-13 can induce
allergic responses even in the absence of functional T cells (Karp 2000). IL-13 overexpression induces
inflammation, mucus hypersecretion, subepithelial fibrosis, and eotaxin production. Eosinophil and IgE
infiltration, and IL-5 production are only eliminated in the combined absence of both IL-4 and IL-13 (Renauld
2001).

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The increased expression of IL-5 mRNA in the sputum of asthma patients is a reflection of eosinophil
infiltration in the lungs (Truyen et al, 2006). IL -5 induces an increase in eosinophil production in the bone
marrow as well as the release of eosinophils from the bone marrow into circulation (Janeway et al, 2005).

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In contrast to the other discussed cytokines, IL-10 has inhibitory effects on the effector mechanisms that
dominate in asthmatic and other allergic responses . IL-10 inhibits the production of pro-inflammatory
cytokines and chemokines by macrophages, neutrophils, and eosinophils, expression of HLA-DR, and some co-
stimulatory expression. IL-10 also has direct inhibitory effects on APCs and T cells and modulates eosinophil
accumulation in airways by possibly inhibiting eosinophil production in bone marrow. Those with asthma have
a decreased expression of IL-10 illustrating IL-10¶s important role in regulating allergic responses (Yssel et al,
2001).

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Eosinophils play a prominent role in initiating asthmatic symptoms by causing tissue damage in the airways of
the lungs. Unlike mast cells, they do not constitutiveley express FcİRI on their surface. Once activated by their
appropriate cytokines and chemokines such as CCL5 and eotaxins, they express FcİRI on their surfaces and
bind to IgE (Janeway et al, 2005). When cross-linked by antigen, eosinophils release major basic protein,
eosinophil cationic protein, and free radicals. These secreted products can initiate mast cell and basophil
degranulation as well as cause significant tissue damage in the airways. Other inflammatory cells respond to the
tissue damage by remodeling the airways. This leads to hyperplasia and hypertrophy of the smooth muscle
layer and mucous glands, and thus narrowed airways (Renauld 2001). Eosinophils become part of a positive
feedback loop by synthesizing prostaglandins, leukotrienes, and cytokines that can activate other eosinophils
(Janeway et al, 2005). While the eosinophil contributes to asthmatic symptoms via tissue damage and airway
remodeling, it is not required for allergen-induced airway hyperresponsiveness (Renauld 2001).




As stated previously, mast cells contribute to the triggering of asthma via their FcİRI receptors that
constitutively bind free IgE. When allergen cross-links surface IgE, the mast cell releases histamine, tryptases,
chymase, heparin, and synthesizes lipid mediators such as leukotriene C4 and prostaglandin D2. All of these
play roles in bronchoconstriction and the recruitment of inflammatory cells to the airways. Along with
recruiting inflammatory cells, histamine also plays a role in the activation of inflammatory cells, dendritic cells,
and T cells (Robinson 2004).

The mast cell¶s involvement in recruiting inflammatory cells is not limited to asthma, but to other allergic
responses as well. It has been demonstrated that mast cells also have an involvement that is specific to an
asthmatic response by interacting with airway smooth muscle (ASM). ASM produce a variety of pro-
inflammatory cytokines and chemokines that recruit and retain mast cells in the airways. One such cytokine that
ASM produces is stem cell factor (SCF). SCF aids in the recruitment and survival of mast cells as well as in the
differentiation of mast cell precursors to mature mast cells. Evidence of the role of mast cells in asthma is
demonstrated by the presence of histamine, prostaglandin D2, and tryptase in the bronchoalveolar lavage fluid
of asthmatics. The presence of these components suggest mast cell degranulation (Robinson 2004).

   i


Until recently, Th2 cells were thought to be the major inducers of effector mechanisms that lead to the
development of asthma. The cytokine that Th2 cells depend on for priming is IL-4. Th2 cells synthesize and
release IL-4 on activation, yet the piece of the puzzle missing was the source of IL-4 before Th2 priming
occurs. Research in the past few years has demonstrated the role of natural killer (NK) T cells in initiating the
effector mechanisms carried out by Th2 cells and other leukocytes. NKT cells are T-cell receptor (TCR)+
CD1d-restricted cells that express CD4. They are given the name NKT cells because of the characteristics they
share with NK cells and CD4 T cells (Meyer et al, 2005).

NKT cells express an invariant TCR that consists of Va24-Ja18 in humans. Unlike the classic CD4+ T cell,
NKT cells do not have highly specific receptors that only recognize a specific MHC and peptide. NKT cells
recognize bacterial endogenous glycolipid antigens presented by CD1d, an MHC class I-like protein. They
recognize endogenous glycolipids, glycolipids found in pollens, bacterial glycospingolipids found in the
‰
  and +
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, a self-glycolipid isoglobotrihexosyl ceramide (iGb3), and a synthetic
glycolipid Į-galactosyl ceramide (Meyer et al, 2005). When NKT cells encounter one of these glycolipids
presented by CD1d, they respond with a similar cytokine profile to that of Th2 cells, and produce IL-4 and IL-
13. There are two pathways by which NKT cells can produce IL-4 and IL-13. In one pathway, NKT cells can
be activated by CD1d presenting glycolipids presented by an APC. In the other pathway, NKT cells activate
Th2 cells to secrete IL-4 and IL-13. In this second pathway, dendritic cells produce CDL25, a ligand that binds
to CCR9 on NKT cells, and this leads to phosphorylation on CD226 on NKT cells. This signaling pathway
allows for NKT cells to activate Th2 cells via cell-to-cell contact (Kay 2006). Thus, NKT cells provide a link
between innate and adaptive immunity by activating the Th2 cells of adaptive immunity. IL-4 boosts the
priming of allergen-specific CD4+ Th2 cells and IL-13 aids in the development of asthmatic symptoms.

Akbari et. al demonstrated the ability of NKT cells to rapidly induce AHR, airway inflammation, and non-
specific IgE production upon direct activation by glycolipid antigens. While NKT cells aid in adaptive
immunity with the ability to activate Th2 cells, they can illicit asthmatic symptoms independent of eosinophils,
B cells, and MHC-II restricted CD4+ Th2 cells, and thus of adaptive immunity. Yet, adaptive immunity may
contribute to the activation of NKT cells. Inflammation and tissue damage induced by Th2 cells may uncover
self-glycolipid antigens, such as IGb3, that can activate NKT cells. NKT cells constitute less than 1% of CD4+
T cells in the blood and constitute 63% of CD4+ T cells in patients with moderate-to-severe asthma, illustrating
their prominent involvement in allergic asthma (Akbari et al, 2006).

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Regulatory T cells are a subset of T cells that aid in the regulation of immune responses by inhibiting the
activity of Th1 and Th2 cells. There are naturally occurring regulatory T cells, known as T-regs and three
subsets of inducible regulatory T cells: Th3, TR-1, and NKT cells (Tournoy et al, 2006). TR1 cells are the
subset of regulatory T cells most involved in allergic asthma (Akbari et al, 2003). TR1 cells exert immune
regulation activity via cell-cell interactions and by secreting the immune suppressing cytokines IL-10 and TGF-
ȕ. The induction of antigen-specific tolerance involves the activation of TR1 by an APC and the subsequent
suppression of Th1 or Th2 cells by TR1 cells. Not only can TR1 cells inhibit Th2 cell activation, they have
been found to also reverse a Th2-dominated immune response. The role of regulatory T cells in suppressing the
effector mechanisms that induce asthmatic symptoms indicate that asthmatics may lack functional regulatory T
cells that can inhibit an asthmatic response (Tournoy et al, 1006).

Figure 2. Allergen challenge on non-allergenic individuals vs. allergic asthmatic individuals results in different
T-cell pathways. Non-allergenic individuals respond to allergen with IL-10 cytokines and T regulatory cells.
Asthmatic individuals respond to allergen with Th2 cells and NKT cells and the prominent cytokines they that
these cells secrete, IL-4 and IL-13. (Permission pending. Akbari et al, 2003)

 



Dendritic cells are APCs that have a two-fold role in asthma due to the presence of two subsets of dendritic
cells in the lungs. One subset of DCs, respiratory tract myeloid DCs (mDCs) aid in the development of asthma
symptoms, while the other subset, plasmacytoid DCs (pDCs) aid in respiratory tolerance to allergens. mDCs are
the prominent APC that activates CD4+ cells to produce and secrete cytokines. In conditions that lead to
sensitization to inhaled antigens, mDCs outnumber pDCs, the regulatory subset of DCs (Lambrecht 2006).
pDCs exhibit a regulatory role by either inhibiting mDC-driven T-cell activation or by inducing T regulatory
cells. Either mechanism of function provides a form of protective immunity and respiratory tolerance (Tournoy
et al, 2006). In conditions of respiratory tolerance, pDCs outnumber mDCs in the airways (Lambrecht 2006).

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Since asthma and other allergic responses are the result of a Th2-dominated response, it was initially thought
that resetting the cytokine balance to induce Th1 would counterbalance Th2 activity. A Th1-dominated
response can be induced by administering the cytokines IFN-Ȗ and IL-12 or infectious agents (Tournoy et al,
2006). While this method is efficient in suppressing eosinophilic airway inflammation, a Th1-dominated
response does not have the desired effect on reducing allergic responses. A Th1-dominated response results in
the recruitment of Th1 cells and enhancement rather than a reduction of airway inflammation (Akbari et al,
2003). Now, it is becoming realized that resetting the cytokine balance to regulatory T cells rather than to Th1
cells may result in a decrease in asthmatic symptoms.

i |

| |

Omalizumab is a humanized monoclonal antibody that blocks FcİRI, the Fc receptor that binds the Fc portion
of IgE antibodies. By blocking this receptor, IgE is not able to bind to these receptors and thus cross-linking
cannot be induced on the cells that express the FcİRI receptor. This treatment has shown to be very effective in
inducing a decrease in IL-13 (Holgate et al, 2005), IL-4, eosinophils in epithelial and submucosal
compartments, T cells, B cells, and other cells that stain as IL-4+ (Scheinfeld 2005).



 
  

 
 

The use of inhaled and oral corticosteroids is a prominent treatment in reducing asthmatic symptoms.
Corticosteroids reduce airway inflammation, airway hyperresponsiveness, allergen-induced peribronchial
fibrosis (Miller et al, 2006), and Th2 cytokine synthesis (Xystrakis et al, 2006). Corticosteroids are able to
induce their inhibitory effects by inducing regulatory gene expression and suppressing inflammatory gene
expression. The mechanism in which corticosteroids exert their effects is by reversing histone acetylation of
activated inflammatory genes through the binding of glucocorticoid receptors to coactivators. This prevents the
transcription of inflammatory genes and activates glucocorticoid receptors. Activated glucocorticoid receptors
bind to promoter regions of anti-inflammatory genes, such as IL-10, and activate their transcription (Barnes
2006).

While corticosteroids are generally successful in reducing asthmatic symptoms, there are some who do not
respond to corticosteroids and thus are known as steroid resistant. Steroid resistant asthmatics have CD4+ T
cells that fail to induce IL-10 synthesis following stimulation of corticosteroids (Xystrakis et al, 2006). Steroid
resistance may be the result of abnormalities in the glucocorticoid receptor signaling pathways (Barnes 2006).
One method of combatting steroid resistance is oral administration of vitamin D3 to steroid-resistant patients.
Vitamin D3 enhances these patients' response to glucocorticoids (Xystrakis et al, 2006).