More than 15 million Americans (between 5% and 10% of the population)
suffer from asthma and their disease annually includes 1.5 million visits
to the emergency room, 500,000 hospitalizations, and 5500 deaths. Up to
20% of those with asthma treat their asthma daily and 10% of asthmatics
suffer severe symptoms.
§(Andreadis, 2003).The number of Americans who reported suffering an asthma attack in a given year increased from 3.1% in 1980 to 5.6% in 1995 and 7.3% in 2001 (Litonjua, 2008).More than 5% of American children have suffered an asthma attack. In 1999, asthma caused two million visits to the emergency room and almost 4500 deaths (Wolf, 2008).Asthma is a complex, multifactorial disease which is influenced by both
genetic and environmental factors. Individuals who share the same symptoms
of asthma can develop the disorder through different mechanisms. Not all
asthma is the same. For example, sixty percent of adult asthma patients
are diagnosed with atopic asthma in which antigen-specific antibodies
of IgE, eosinophils, mast cells, and T lymphocytes are elevated. Forty
percent of patients are diagnosed with non-atopic asthma which is not
correlated with IgE hypersensitivity but instead is characterized by increased
numbers of neutrophils and mast cells. Non-atopic asthma is thought to
be induced by small allergens known as haptens (Van der Heijden, 2006).
Is asthma a genetic disorder determined during embryonic development?
There is no one gene whose variation causes asthma. That being said, there
are multiple genes which are known to contribute to asthma and evidence
indicates that additional genes which determine asthma risk have yet to
be identified. About half of one's risk of asthma may be controlled by
inheritable factors. Inherited predisposition for asthma seems to occur
more frequently from maternal genes than paternal genes (Caroll, 2005).
As the following information outlines, there are multiple genes whose
proteins determine the normal physiology, immune defenses, and tolerance
of a normal person's airways. Many of these genes are polymorphic in the
human population, meaning that the protein made by one person's gene may vary
slightly from that of another person. Genetic polymorphisms can affect
the function of a protein and a number of genetic polymorphisms are known
to contribute to asthma. For example, polymorphisms in MHC genes have
been linked to asthma (Caroll, 2005). Polymorphisms in the gene cytotoxic
T lymphocyte antigen 4 (CTLA4) have been linked to asthma, allergy, and
increased IgE levels (Bochner, 2005). When cells antibodies are produced, one section (depicted in blue in the following image), can be varied to produce the antibodies known as IgG, IgM, IgD, IgA, or IgE. The production of IgE is a factor in inflammation and allergy.
The genes which determine asthma risk as determined by population studies are sometimes surprising in that the genes which are thought to be central in asthma pathophysiology are not yet known to include high risk polymorphisms while some of the genes which do contribute to risk are not known to participate in any
of the described mechanisms for asthma. For example, the first genetic polymorphisms
linked to asthma were identified in genes (ADAM33, dipeptidyl peptidase 10, and PHD finger protein)
whose role in asthma prevention were not known (Lily, 2005).
Not only can asthma be affected by both genes and the environment separately,
it can also be brought on by an interaction between genes and environment.
For example, air pollution or an allergen alone might not be sufficient
to induce asthma just as a genetic polymorphism might not be sufficient
to induce asthma but those who have a particular genetic polymorphism
and are exposed to a certain allergen or high level of pollution might
frequently develop asthma. Consideration of gene-environment interaction
effects between cigarette smoke and asthma can produce stronger linkages
of certain chromosomal regions to asthma (such as 1p, 5q, and 17p) when
considering only those exposed to cigarette smoke (Colilla, 2003). Thus
it appears that the risk of cigarette smoke on asthma depends on one's
Abnormal lung development during fetal life and early infancy can cause
structural or physiological changes which can influence asthma risk later
in life. The early development of the fetal lung can be impaired by women
who smoke during pregnancy and infant lungs can be impaired by exposure
to cigarette smoke early in life (Kabeschm, 2006; Kuipers, 2005).
In the U.S., between 4 and 8 percent of pregnant women have asthma and this rate can surpass 12 percent in some parts of the world. It is thought that maternal cytokines can cross the placenta and be produced in breast milk where they can alter the Th1/Th2 balance in the fetus/infant. Maternal IgE has been found in amniotic fluid (Barrett, 2008).
EARLY EXPOSURE TO MICROBES AND THE HYGIENE HYPOTHESIS
In many developed regions of the world, children grow up in environments which are fairly clean. Kitchens and bathrooms are relatively clean, children often don't have much contact with soil microbes, and there are typically few animals (with their food, feces, parasites, etc.) in the vicinity.
For most of human history, and in much of the world today, the reverse condition is true. (The first image below depicts a washroom, latrine, and well.)
Does the human body need germs in order to develop properly? Is the current increase in asthma, allergy, and hypersensitivity rates due in part to our modern practice of being too clean? These are the tenets of the Hygiene Hypothesis.
Most systems of the human body develop normally using genetically encoded
developmental pathways. Two systems of the body, the nervous and immune
systems, require input from the environment in order for normal development
to occur. If animals are raised without microbes, their immune systems
do not develop properly--the animals are less likely to mount effective
responses to infectious agents and are more likely to display a hypersensitivity
(or lack of tolerance) to normal stimuli. Thus, a certain level of microbes
of the in the environment may not only be acceptable, it may be required
for normal immune development. Many of those who live in Western, industrialized
nations have reduced exposure to microbes compared to those who grow up
in agricultural environments, surrounded by animals, in areas where the
soil is exposed rather than being covered by asphalt, etc. Some of the
health problems which are increasing in frequency in Western nations,
particularly those involving excessive inflammation, may be by-products
of improved hygiene. Asthma may be caused, in part at least, by abnormal
immune mechanisms which were fostered in childhood environments which
were too hygienic.
There is evidence to suggest that exposure to microbes, especially early
in life, is required for normal human immune responses. Decreased frequency
of allergies and asthma have been associated with infections (such as
hepatitis, measles, and tuberculosis) and exposure to microbes (such as
on farms) (Feleszko, 2006). Many types of infections have been observed
to be associated with decreased risk of asthma including those caused
by bacteria (Salmonella, Heliobactor, mycobacteria, exposure to endotoxin,
and exposure to muramic acid), parasites, fungi, and viruses (hepatitis,
herpes, Epstein Barr). Some viral infections (rhinovirus, RSV) increase
the risk of wheezing and may not offer any protection against asthma (Schaub,
Some reports indicate (consistent with the hygiene hypothesis) that increased
exposure to bacterial lipopolysaccharides (endotoxin_ at low chronic levels
early in life (due to life on a farm, early entrance into daycare, pets
at home, etc) reduce the likelihood of asthma later in life. Other reports
indicate the opposite, that increased levels of endotoxin early in life
can increase asthma risk (Singh, 2005; Schaub, 2006; Grunig, 2005). The
incidence of asthma can be correlated with the prevalence of asphalt in
an area, suggesting that decreased interaction with normal soil microbes
may have a role in decreased tolerance (Von Hertzen, 2006).
A number of noninfectious microbe products are being considered as a type
of vaccine for asthma patients and/or children of the general population
which would reduce the excessive inflammatory responses by the immune
system. These include lipopolysaccharides from Salmonella, microbial DNA
or RNA sequences, noninfectious mycobacteria, bacterial extracts, probiotic
microbes associated with foods (such as Bifidobacterium and Lactobacillus)
(Feleszko, 2006). Animal studies have supported the conclusion that a
number of these agents can reduce hypersensitivity. For example, the exposure
to more probiotic food microbes increases the number of Peyers patches
and IgA secreting cells in young mice (Feleszko, 2006).
The human immune system reacts to parasitic worms using the T helper (Th)
2 inflammatory response, which is also the response which mediates allergies
and asthma. The hygiene hypothesis proposes that exposure to infectious
agents, such as parasitic worms, actually offers protection against allergies
and asthma. There is evidence to support this (such as an increase in
hypersensitivity once worms are removed) and the possibility that deliberate
infection using worms might be used as a therapy is being considered (Falcone,
2005). Might a "vaccine" consisting of parasites (like the worm below) someday protect against asthma and allergy?
Asthma is an inflammatory disorder. The characteristics of asthma include
hypersensitive airways whose excessive inflammation is associated with
increased numbers of eosinophils, degranulation of mast cells, hypersecretion
of mucus, and IgE production. These chronic lung changes can result in
the remodeling of airways including the growth an hypertrophy of epithelial
cells, the hyperplasia of mucus glands, smooth muscle hyperplasia, and
fibrosis (Zimmerman, 2006; Feleszko, 2006).
All immune pathways, including
inflammation, are mediated by local hormones. The levels of pro-inflammatory
signals and genetic polymorphisms of these signals are factors in determining
asthma risk. A basophil (whose granules are full of inflammatory signals) is depicted below.
Bradykinin is a peptide hormone which increases bronchoconstriction
and mucus secretion. Evidence indicates that increased bradykinin production
and activity of its receptors are implicated in the development of asthma
Inflammatory reactions are mediated through the T helper 2 (Th2) pathway
and allergies are caused when IgE is used to respond to an allergen rather
than other antibodies such as IgG. Interleukin-13 is a signal utilized
in Th2 pathways which results in B cell antibody isotype switching from
IgG or IgM to IgE. Polymorphisms in this gene may be linked to asthma
Polymorphisms in the gene for the pro-inflammatory signal TNF alpha
have been linked to asthma (Caroll, 2005).
Dipeptidyl peptidase 10 was one of the first genes to be associated
with asthma. Its function may include the ability to inactivate proinflammatory
cytokines (Lily, 2005).
Interferon is one of the major signals which promotes the activity of
nitric oxide synthase in respiratory epithelia (Andreadis, 2003).
Polymorphisms of the interleukin 4 gene promoter affect asthma risk (Li, 2008).
In addition to forming parts of antibodies, immunoglobulin light chains
can be secreted separately and can induce hypersensitivity in mast cells.
The lymphatic system produces an estimated half kilogram of free light
chains per day. The concentration of these light chains has been found
to increase in inflammatory disorders such as asthma and respiratory allergies
(Van der Heijden, 2006).
IgE receptors activate Syk tyrosine kinase and Syk inhibitors are being
studied for their therapeutic value in treating asthma (Bochner, 2005).
A number of inflammatory states are also associated with increased blood
vessel production (angiogenesis). An increased production of pro-angiogenic
factors may contribute to the remodeling observed in asthma (Puxeddu,
The local hormones known as prostaglandins (and thromboxane) are synthesized
from the fatty acid arachidonic acid in a series of reactions which are
catalyzed by phospholipase (which converts membrane phospholipids to arachidonic
acid), cyclooxygenase (COX) enzymes (also known as prostaglandin H synthase
enzymes), and tissue-specific synthases which create the individual hormones.
Most cells possess COX enzymes and the specific prostaglandins (or prostanoids)
which a cell produces are determined by the tissue specific synthases
which perform the final stems in the pathway in prostaglandin synthesis.
Both COX-1 and COX-2 enzymes are synthesized in the lung (Carey, 2003).
Some prostaglandins protect the lung from asthma (such as PGE2 and PGI2)
and others that cause bronchoconstriction as a result of inflammation
(such as PGD2 and PGF2). Inhalation of PGE2 and PGI2 can alleviate bronchoconstriction
(Carey, 2003). Aspirin inhibits COX-1 enzymes (in addition to COX-2) which can reduce
the production of the bronchoprotective PGE2. About 10% asthma patients
are sensitive to aspirin and can suffer severe attacks following an aspirin
dose. Aspirin-sensitive asthmatics may benefit from drugs which inhibit
COX-2 specifically (Carey, 2003). Corticosteroids reduce inflammation by decreasing the transcription of
the genes that promote inflammation and increasing the transcription of
the anti-inflammatory genes (Baatjes, 2002).
Parental stress and depression are serious stress factors in all children which are capable of raising a child’s production of inflammatory signals. Parental stress is associated with increased risk of asthma symptoms (Wolf, 2008). The comorbidity of asthma, depression, and anxiety is likely due to increased levels of inflammatory factors (Shore, 2008; Katon, 2007). Maternal stress has been reported to increase risk of asthma (Cookson, 2009).
T cells mature in the thymus (as depicted in the following image). Immature (naive) T cells can mature along one of two alternate paths and which of these paths is chosen will affect predisposition to asthma.
Naïve T cells can differentiate into a variety of T helper cells
including Th1 cells which are more involved in responses to infections,
Th2 cells which are associated with inflammatory disorders, and T regulatory
cells. A major factor in the causation of allergy and asthma is a chronic
induction of the Th2 immune responses (Carey, 2003). Th2 cells produce
pro-inflammatory cytokines such as interleukin (IL)-4, IL-5, IL-9, and
IL-13 (Grunig, 2005). Atopic asthma results from a series of events, one
of which is the commitment of a Th2 response to allergens. Asthma can
begin as Th2 responses produce IgE antibodies which react to common substances
such as cow milk, dust mites, pollen and animal dander (Kuipers, 2005).
The Hygiene Hypothesis proposes that if these naïve T cells are not
exposed to the normal levels of microbes, an excess of Th2 cells will
differentiate and cause an increased incidence of allergies, hypersensitivities,
and asthma. Since autoimmune disease are also increasing and are mediated
by Th1 cells, some have modified the Hygiene Hypothesis to propose that
in the absence of microbes, the T regulatory cells do not develop normally
and as a result both the Th1 and Th2 mechanisms react in inappropriate
situations (Feleszko, 2006). Treatments for asthma include attempting
to induce Th1 responses as a way of counterbalancing Th2 responses, directly
inhibit Th2 responses, and induce T regulatory responses (Kuipers, 2005).
Between 5 and 10 percent of the CD4 T cells in healthy adults represent
the naturally occurring T regulatory cells. They are identified by their
expression of the cell surface protein CD25 and the transcription factor
Foxp3. (Mutations in foxp3 cause the human IPEX syndrome whose affects
include allergy and autoimmune disease.) These cells regulate the balance
of Th1 and Th2 responses through signals such as IL-10, TGF beta, CTLA-4,
and GITR. In situations which result in tolerance of an antigen, additional
T cells named inducible T regulatory cells become active. Increasing numbers
of T regulatory cells are associated with increased tolerance. Individuals
with asthma or allergy may possess T regulatory cells with abnormally
low function (Kuipers, 2005).Naturally occurring Treg cells are produced in the thymus and play a major
role in limiting the production of autoantigens (Von Hertzen, 2006). Regulatory T cells can be classified in several groups including the Tr1
cells which secrete interleukin 10 and the type 3 helper cells Th 3 which
secrete TGF beta, both of which are anti-inflammatory. Antigen presenting
cells (such as dendritic cells discussed next) can stimulate the differentiation
of naïve T cells and this occurs primarily on the surface of the
mucosa (Feleszko, 2006). Allergen desensitization therapy increases the
number of inducible T regulatory cells in response to persistent exposure
to an allergen. IL-10 and/or TGF beta are required for the differentiation
of these cells and are produced by these cells in their function (Von
A member of the CD28 protein family known as ICOS (inducible costimulator)
is required for proper interactions between B and T cells and the differentiation
of T cells. Allergy can result from its overexpression and autoimmunity
can result from its absence (Shilling, 2006).
CELLS OF THE INNATE IMMUNE SYSTEM
A) DENDRITIC CELLS
Dendritic cells were first discovered in 1973.Dendritic cells are leukocytes which are produced by the bone marrow and
migrate to the tissues where they become antigen presenting cells (APCs).
Monocytes can differentiate into a class of dendritic cells during inflammation. Some dendritic cells, such as pDCs travel through blood (Buckwalter, 2009). Langerhans cells and dermal (interstitial) dendritic cells are located in the skin. Dendritic cells which have encountered an antigen can migrate to the lymph nodes and spleen where they present it to T cells (Buckwalter, 2009). Dendritic cells are found throughout the lung. Dendritic cells represent
the most important antigen-presenting cells in the body. Monocytes may
differentiate to produce dendritic cells.
They can differentiate into
a variety of subtypes in different tissues and express a variety of cell
membrane proteins (such as CD11c, CD8, CD4, CD11b, CD205, and langerin).
After inflammation (of a lymph node, for example), increased numbers of
dendritic cells migrate there. Lung epithelial cells can determine the
maturation of dendritic cells. DCs also respond to a variety of cytokines
and histamine. As dendritic cells present antigens to naïve T cells,
they can determine the differentiation of T cells into Th1, Th2, or T
regulatory responses (Grunig, 2005).
One of the earliest steps of asthma is the first response of immune cells
to an inhaled allergen. Dendritic cells and other antigen-presenting cells
(APCs) engulf the allergen, break it into shorter segments, and present
the segments on their cell surfaces, bound to MHC II proteins. These cells
then leave the airway and travel to lymphatic tissue near the lung such
as bronchial associated lymphoid tissue or lymph nodes present in the
lung. In this lymphatic tissue, the antigen presenting cells interact
with T cells (Lily, 2005). Dendritic cells respond to a variety of stimuli including pathogenic microbes
and harmless antigens. Their responses can determine the differentiation
of naïve T cells in addition to activating B and T cells (Kuipers,
2005). There are different classes of dendritic cells. Plasmacytoid DCs
(pDCs) are required for tolerant responses from airways and normal functioning
while myeloid dendritic cells (mDCs) are the only cells needed to induce
Th2 responses and the subsequent inflammation (Kuipers, 2005).
Dendritic cells help inhibit hypersensitivity and promote tolerance in
the lung. Distinct environmental signals (such as microbial lipopolysaccharides)
can interact with Toll-like and lectin receptors on dendritic cells and
cause dendritic cells to mature, changing from a tolerance-promoting cell
to an inflammatory cell. Memory T cells can promote the maturation of
dendritic cells which in turn can determine the differentiation of T cells
and their migration (Grunig, 2005). Unlike other tissues of the body, lung leukocytes (T cells, dendritic
cells, macrophages, and neutrophils) can not only migrate to the airspace
from the lung tissue, they can also migrate from the airspace to the lung
tissue and its lymph nodes (Grunig, 2005; Bochner, 2005).
The cells of the acquired immune system, T cells and B cells, are well
known for their receptors (T cell receptors and antibodies, respectively)
which they utilize to recognize foreign substances (antigens) and the
molecules belonging to the human body which are recognized as self. The
cells of the innate immune system also possess a variety of receptors
that they utilize to recognize foreign materials. The toll receptor was first described in fruit flies where it is an immune
protein which protects against fungal infections. There are 11 toll family
members in the human genome which can bind to a variety of ligands including
lipoproteins from bacteria, peptidoglycan, viral proteins, single stranded
viral RNA, double stranded viral RNA, double stranded viral DNA, and other
compounds. Toll receptors are primarily located on cells of innate immune
defenses (such as macrophages, neutrophils, dendritic cells, mucosal epithelial
cells, and dermal endothelial cells). Toll receptors mediate the responses
of cells to a variety of infectious and non-infectious agents (Feleszko,
2006). Plasmacytoid dendritc cells use toll-like receptors to detect viruses. They also use autophagy (self-digestion) to allow the ssRNA from viruses to be detected (Lee, 2007).
Toll receptors can bind to lipopolysaccharide (LPS or endotoxin) which
is the primary component of gram negative bacterial walls, techoic acids
which are major constituents of gram positive bacterial walls, components
of fungal cell walls, and bacterial DNA (which differs from vertebrate
DNA by a high percentage of unmethylated CpG oligonulceotides). Exposure
to bacterial DNA elicits a Th1 response unlike exposure to vertebrate
DNA (or methylated bacterial DNA) (Von Hertzen, 2006). Activation of toll receptors on antigen presenting cells determines their
effects on inducing the differentiation of the naïve T cells with
which they bind (Feleszko, 2006). Polymorphisms in the toll receptors
TLR2 and TLR4 have been linked to asthma (Bochner, 2005; Grunig, 2005). In addition to Toll-like receptors, dendritic cells utilize a variety
of lectin receptors such as DC-SIGN, mannose receptor, and langerin (Grunig,
B) MAST CELLS
Mast cells are produced in the bone marrow and progenitor mast cells then
migrate to different tissues where they mature under the influence of
local environmental conditions (including inflammatory cues) (Bingham,
2000). Mast cells are found in almost all vascularized tissues. Mast cell
function is an early factor in many autoimmune diseases (Van der Heijden,
2006). Mast cells are capable of recognizing bacteria and viruses through toll-like
receptors on their cell surfaces. The cell membrane also possesses receptors
for signals that will inhibit mast cell activation including IgG receptors
and a variety of immunoglobulins (Rivera, 2006). Mast cells possess IgE
receptors and polymorphisms in this receptor are associated with asthma
and allergy. Once activated, the IgE receptors stimulate internal molecules
such as Syk and Fyn enzymes (Rivera, 2006).
When activated, mast cells release their granules of inflammatory molecules
and initiate the production of new cytokine, chemokine, and eicosanoid
signaling molecules (Rivera, 2006).Mast cell levels increase in asthma and their activity can cause bronchoconstriction,
increase mucus production, release cytokine signals which further aggravate
asthma, and promote airway remodeling. Mast cell cytokines can influence fibroblasts, eosinophils, Th2 lymphocytes, B lymphocytes, smooth muscle
in airways, endothelia, and serous cells (Bingham, 2000). Mast cells produce signals which increase eosinophil activity and longevity
and eosinophil signals exert similar influences on mast cells (Puxeddu,
Allergic reactions are associated with an increased production in eosinophils.
In the bone marrow, stem cells known as eosinophil/basophil colony forming
units can be induced to produce eosinophils (rather than basophils) by
pro-inflammatory signals such as interlekin-3, interleukin-5, and granulocyte-macrophage
colony stimulating factor. During inflammation, eosinophils and their
progenitor cells can migrate from the bone marrow to the lung. Once in
the lungs, eosinophils can respond to inflammatory signals and contribute
to inflammation (Baatjes, 2002).
One of the first changes in asthma is an increased migration of eosinophils
to the lungs. The amount of eosinophils is correlated with the severity
of asthma and the degree of inflammation (Andreadis, 2003). In asthma,
eosinophils seem to almost double the amount of intracellular eosinophil
derived toxin (EDN) that they contain (Bochner, 2005).
Preliminary reports suggest that activated eosinophils leave the lung
and differentiate to become more like dendritic cells with new cell surface
proteins and perhaps antigen-presenting capabilities (Bochner, 2005). The effects of corticosteroids and anti-leukotrienes generally decrease
the production of eosinophils although they can increase some aspects
of eosinophil action/production. Antihistamines and therapy which blocks
interleukin-5 reduce the production of eosinophil progenitors (Baatjes,
Neutrophils migrate to the lung in increased numbers during asthma. Neutrophil,
eosinophil, and macrophage enzymes (such as peroxidases) produce reactive
oxygen molecules which cause abnormal levels of oxidation (discussed below;
Decreased alveolar macrophage function can also follow chronic exposure to particulate matter (Fitzpatrick, 2008).
EPITHELIAL CELLS OF THE RESPIRATORY SYSTEM
About 100 square meters of lung surface constitutes the largest area of the body exposed to the outside world. About 100 liters of air pass through the respiratory system per day. The epithelia of the respiratory system are thus important in immune reactions. Abnormalities in the junctions between epithelial cells may result in the dysfunction that increases asthma risk (Holgate, 2007; Wang, 2008).
Epithelial cells possess toll-like receptors and other receptors which recognize microbe sequences. After binding microbes they produce a variety of cytokines, enzymes, collectin,
interleukins (1, 6, and 8), granulocyte-macrophage colony stimulating factor, interferon alpha and beta, eotaxin, TNF alpha.
and other aspects of innate responses. The molecules that epithelial cells express on their membranes and those they secrete can result in reactions from dendritic cells, B cells, and T cells. Epithelial cells produce thymic stromal lymphopoeitin which affects the activity of dendritic cells, T cells, natural killer cells, mast cells, and promotes a Th2 response. When the epithelial lining is compromised, pathogens can interact directly with immune cells and airway remodeling mechanisms are triggered (Wang, 2008; Rochman, 2008).
Oxygen is not only essential for human life, it is potentially toxic due
to the effects of oxidizing oxygen and nitrogen molecules. These oxidants
can be produced through metabolic reactions or present as air pollutants.
The lung has a greater exposure to oxygen and air pollutants than any
other part of the body (Rahman, 2006). Many phenomena induce lung inflammation
including allergens, viruses, exercise and chemical irritants. Inflammation
also results in the production of reactive oxygen species (ROS) and reactive
nitrogen species (RNS). A variety of white blood cells (neutrophils, eosinophils,
and macrophages) produce superoxide ions utilizing the enzyme NADPH oxidase.
This can result in the production of hydrogen peroxide and leukocyte enzymes
may further amplify the oxidative effects of hydrogen peroxide. High levels
of ROS are produced by the eosinophils, alveolar macrophages, and neutrophils
of asthmatics and ROS production is correlated with the severity of asthma
(Andreadis, 2003).Not only are reactive oxygen species produced during inflammation, the
presence of oxidative oxygen and nitrogen radicals can initiate the inflammatory
response (Rahman, 2006).
To balance the effect of the oxidative chemicals present in the lungs,
the respiratory system contains a variety of antioxidants. Some antioxidants
are enzymes such as superoxide dismutases, catalase, and peroxidase while
othes are not enxymes such as glutathione, vitamin C, vitamin E, beta
carotene and uric acid. An imbalance in the ratio of antioxidants to oxidants
can cause asthma and other respiratory disorders. Asthma has been linked
to abnormalities in superoxide dismutase, catalase, and glutathione peroxidase
(Rahman, 2006; Andreadis, 2003). Polymorphisms in the glutathione S-transferase P1 (GSTP1) gene have been
linked to asthma. Glutatione S-transferases function in controlling the
level of oxidative proteins in a cell and GSTP1 is expressed only in the
lung (Caroll, 2005).
NITRIC OXIDE (NO)
In the respiratory tract, nitric oxide is a signal which determines smooth
muscle constriction, the activity of cilia, innate immune defenses, and
electrolyte transport. Cells can control the levels of NO by controlling
the activity of nitric oxide synthase (NOS) and the enzymes which control
subsequent reactions involving NO (Bove, 2006).
Of the three forms of NOS, NOS2 is induced by inflammatory signals such
as TNF alpha, interferon, and interleukin 1beta. Other proteins inhibit
its activity such as NOS-associated protein 110kDa and kalirin (Bove,
Nitric oxide's effects are mediated through three separate pathways. NO
can bind to hemoproteins (such as soluble guanylyl cyclase) through which
it creates second messenger molecules of cGMP. A second effect of NO is
that it modifies the amino acid cysteine in proteins and can disrupt bond
betweein cysteine and zinc ions, allowing it to regulate protein activity
(such as that of zinc finger transcription factors) (Bove, 2006).
Finally, NO can result in the formation of reactive nitrogen species (RNS)
such as nitrous anhydride (N2O3) nitrogen dioxide (NO2), and peroxynitrite
(ONOO-). These RNS can promote inflammation and oxidize molecules (such
as the disruption of cysteine-zinc bonds) (Bove, 2006; Andreadis, 2003).
NO levels in asthmatics increase about threefold (Andreadis, 2003). Genetic
polymorphisms and abnormal expression of nitric oxide synthase genes are
correlated with asthma (Andreadis, 2003).
The amino acid arginine can be metabolized by two enzymes whose actions
are relevant to the development of asthma. When the enzyme nitric oxide
synthase reacts with arginine, it produces nitric oxide. Although low
levels of nitric oxide are beneficial in causing bronchodilation, high
levels of this oxidative molecule can promote inflammation. Asthmatics
typically possess higher levels of nitric oxide synthase activity in their
lungs and increased levels of nitric oxide in their exhaled air (Zimmerman,
Arginine can also be metabolized by the enzyme arginase (in the same pathway
which the liver utilizes to create urea). Arginase is synthesized by macrophages
and its levels can increase after exposure to an allergin. Higher levels
of arginase in asthmatics may result in less arginine on which the enzyme
nitric oxide synthase can act. With less nitric oxide, airways may become
hypersensitive. Increased arginase activity also increases cell division
of endothelial cells and vascular smooth muscle; it is thought that the
arginase released by macrophages promotes tissue repair after damage.
Arginase converts arginine to ornithine which is converted (by the enzyme
ornithine amino transferase) to proline. Proline is required for the synthesis
of collagen which is required for tissue repair (and fibrosis). The cytokine
local hormones released from Th2 cells (such as interleukin 4 and 13)
promote arginase activity and can regulate its levels in the lung (Zimmerman,
Surfactants are proteins present in alveolar fluid that not only decrease
the surface tension of water to keep the alveoli open (like that depicted above), they are lectins
which can bind antigens as part of the innate immune responses. They promote
opsonization as leukocytes are more likely to perform phagocytosis of
the antigens bound to surfactants (Hackzu, 2006). In the induction of phagocytosis by macrophages, neutrophils, and dendritic
cells, surfactant binding to antigens can promote inflammation. However,
surfactant action can also have anti-inflammatory effects in the reduction
of cytokines produced by leukocytes in response to antigens, a reduction
of IgE production, and an inhibition of the Th2 responses. In general,
the effects of surfactant binding of antigen tend to be protective against
inflammation (Hackzu, 2006). Surfactants bind to extracts from pollen granules which reach the distal
portions of airways (unlike the pollen grains themselves which are too
large to penetrate respiratory passageways to that depth). Surfactants
also bind other allergens such as dust mite and fungal products (Hackzu,
Fragments of the lipopolysaccharide molecules (LPS) that cover the cell
wall of gram negative bacteria (the purple bacteria depicted below) are referred to as endotoxin (Singh, 2005).
Endotoxin is present in air and dust but the quantity can vary. Domestic
animals, pets, carpeting, indoor ventilation, cigarette smoke, and air
pollution can increase the amount of endotoxin. Exposure to endotoxin
can cause airways to constrict and become hypersensitive. Asthma risk increases with the presence of indoor allergens (Salo, 2008).
are exposed to endotoxin increases the number of eosinophils in their
airways and overall airway hypersensitivity (Singh, 2005; Wambolt, 2002). About 2% of American suffer from food allergy in which IgE is produced
in response to dietary sources. Food allergy and asthma seem to be correlated
in that frequently individuals suffer from both disorders (Hourihane,
2005).Higher levels of pet allergens in household can be associated with greater severity of asthma symptoms ( Gent, 2009).
Responses to environmental allergens and experience in daycare can vary depending on polymorphisms in diverse genes such as TLR4, CD14, TLR2, NOS3, FCER1B, IL4 receptor, and IL13 (Mutius, 2009). Animal allergens can cause asthma even if these animals are not pets as exemplified by a case in which a magician developed asthma through exposure to rabbits in his act (Miller, 2009).
As many as 15% of the new cases of asthma in adults are thought to be
caused by respiratory irritants encountered in the workplace. Frequently,
symptoms decrease during holidays and sick leave. A large variety of potential allergens are experienced in different professions. Potential animal allergens can be experienced by animal breeders, food processors, research labs, and farmers. Cheese and mushroom production results in exposure to microbial and mushroom compounds. Plant products such as henna dye can affect beauticians, latex affects health care workers, and other plant compounds can affect bakers, pharmaceautical workers, food processors, and book binders. Hairdressers are exposed to persulfates, metal workers and miners to a variety of metal compounds, and woodworkers to wood dusts and other chemicals. Painters and plastic manufacturers can experience a number of potential allergens (Dykewicz , 2009; Malo, 2009). If particles are
larger than 2-4 microns, they will probably be filtered by the mucociliary
mechanism and not contribute to asthma. In other cases, a single exposure
to an irritant (such as fumes from an accident). Another possibility is
that chemicals will aggravate an asthma condition which was already present
(Currie, 2005; Douglas, 2005). Natural rubber latex is a natural allergen.
Health care workers who are exposed to natural rubber latex can develop
allergic reactions and increase their risk of asthma (Bousquet, 2006).
A variety of viruses that can cause respiratory tract infections, including
influenza, respiratory syncitial virus, and rhinovirus, can initially
cause and increase the severity of asthma. More than three quarters of
the children who experience active asthma between ages between 5 and 11
suffered a lower respiratory tract infection prior to age five. Viral
infections result in inflammation and tissue remodeling which may lead
to long term changes in the lung. It is also possible that children whose
lung development has resulted in abnormalities are more susceptible to
both viruses and asthma (Van Rijt, 2005). About three quarters of adult
asthmatics receiving emergency treatment also are infected with a respiratory
virus (Gualano, 2006).
Allergic rhinitis affects between 10 and 25% of humanity. While it affects the upper respiratory tract while asthma affects the lower respiratory tract, the two often coexist and share many of the same mechanisms. They can be induced by the same allergic reactions. Viruses (such as rhinovirus) typically cause allergic rhinitis and, perhaps through the resultant inflammatory cytokines which are produced, can contribute to about half of asthma incidents (Wang, 2008).
One study concluded that asthmatics were no more likely to suffer a respiratory
infection but their responses to infections differed from non-asthmatics
Asthma attacks are often brought on by viral and bacterial infections. Children whose asthma is poorly controlled have decreased alveolar function and increased apoptosis (Fitzpatrick, 2008).
Smooth muscle cells can not only respond to inflammatory signals, apparently
they can produce inflammatory signals as well. Interleukin signaling can
cause airway smooth muscle cells to produce eotaxin (Bochner, 2005).During an asthma attack, the constriction of respiratory passages by the
smooth muscle which lines them limits air flow to the air sacs. Ultimately,
a severe reduction of air flow to alveoli can cause death. The muscle
tone of the smooth muscle around airways is controlled by signals which
bind G protein-coupled receptors. Most asthma medications directly or
indirectly affects the interaction between these receptors and the signals
that bind them (Deshpande, 2006).
The preferred treatment for the immediate effects of asthma is the inhalation
of epinephrine which acts on beta adrenoreceptors. Although all three
types of beta adrenoreceptors are expressed in the lung, the beta 2 receptors
are the most common and are expressed in airway smooth muscle cells, epithelial
cells, surfactant-secreting cells, and mast cells (Broadley, 2006).
Activated beta adrenoreceptors cause bronchodilation which can relieve
an asthma attack. Unfortunately, these open airways can also admit an
increased amount of the allergen which caused the asthma attack and thus
increase subsequent inflammation. Continued activation of these adrenoreceptors
(like all G protein-coupled receptors) can result in desensitization as
the number of receptors are reduced and receptors are separated from the
adenylyl cyclase through which they exert their effects. Regular use of
drugs which activate these receptors can thus actually worsen the disease
Activated beta adrenoreceptors increase the rate of ciliary beating which
increases the clearing of mucus from respiratory passages. It also causes
goblet cells to secrete less fluid and more glycoprotein, effecting the
composition of the respiratory mucus. (Since the goblet cells are only
innervated by parasympathetic neurons, epinephrine can only reach them
through the blood under normal conditions.) (Broadley, 2006).
Polymorphisms exist in the adrenoreceptor genes which can affect the frequency
of wheezing, asthma severity, response of receptors to medication, response
of mast cells to medication, response of airway cells to histamine, and
the likelihood of worsening of asthma during sleep (Broadley, 2006).
A number of respiratory problems from chronic obstructive pulmonary disorder
to infection to inflammation of the lungs are associated with subsequent
airway remodeling. Airway remodeling is a major concern in asthma patients.
Airway remodeling can include increases in the thickness of respiratory
passageways and hyperplasia of goblet cells. Increased inflammatory mechanisms,
increased mucus production, and decreased elasticity also result (Gualano,
2006). Although remodeling can have some adaptive aspects, the overall
effect of narrowing airway diameter is a negative consequence (Tang, 2006).
In asthmatics, airway epithelia are more likely to be shed which contributes
to airway hypersensitivity. This may result from abnormal remodeling mechanisms.
Enlarged glands result from airway remodeling and large glands are a characteristic
of fatal asthma (Tang, 2006).
Signals from mast cells and eosinophils affect fibroblasts and influence
the process of fibrosis (Puxeddu, 2005). Cultured smooth muscle cells
from asthmatic patients produce different extracellular matrix proteins
than those of healthy individuals (increased production of collagen I
and perlecan, decreased production of laminin alpha 1 and collagen IV,
and no production of chondroitin sulfate) (Bochner, 2005). Smooth muscle cells in airways can attract fibrocytes and the muscle of asthmatics contains more fibrocytes than normal (Saunders, 2009).
The human genome includes about 25 metalloproteases whose degradation
of proteins is involved in both inflammation and tissue remodeling. Leukocytes,
epithelial cells, and smooth muscle cells all produce metalloproteases.
In general, higher levels of metalloproteases are found in asthmatics
and those who suffer from COPD. Respiratory viruses may increase the activity
of lung proteases (Gualano, 2006).
Matrix metalloproteinases (MMPs) break down the proteins of the extracellular
matrix such as collagen, fibronectin, laminin, and others. MMPs are involved
in a variety of normal physiological processes such as development, remodeling,
and wound healing in addition to pathophysiological processes such as
arthritis, asthma, cancer, and atherosclerosis (Gueders, 2006).
Asthma patients can express increased levels of MMPs such as MMP-9, MMP-8.
Smooth muscle cells, mast cells, eosinophils, neutrophils, and T cells
can all release MMPs. Neutrophils can produce both MMP-8 and MMP-9. MMP-9
increases after exposure to allergen and its levels are correlated with
the severity of asthma. MMP-2 is an autocrine signal secreted by smooth
muscle cells which signals them to divide. Increased smooth muscle mass
is a primary change in the airway remodeling in asthmatics. Different
MMPs can act on pro-inflammatory cytokines to either activate or inactivate
them (Gueders, 2006).
Cytokine signals of the Th2 response can act on MMPs and their inhibitors.
Therapeutic agents which influence levels of MMPs, their inhibitors, and
the cytokine signals that affect them are being pursued in asthma treatment
Abnormalities in the nervous system may contribute to asthma and trigger
symptoms such as airway hypersensitivity (Nockher, 2006).
Neurotrophins are signaling molecules originally known for their roles
in guiding neuronal function and the development of the nervous system.
Neurotorphins are also produced in the respiratory epithelia and macrophages.
Asthmatic patients and those who have been exposed to allergens increase
the production of these neurotrophins. Neurotrophins in turn affect eosinophils
and mast cell function (Nockher, 2006).
Since around 1950, more than 80,000 new chemicals have been developed.
Almost three thousand of them are produced in volumes of more than one
million pounds per year. Only about half of the large-volume compounds
have been tested for general toxicity and even fewer for the effects on
fetuses and children (Trasande, 2005). Roughly eight hundred thousand
deaths are attributed to air pollution each year throughout the world
(Curtis, 2006). Throughout the world, asthma is estimated to cause one
in every 250 deaths (Singh, 2005). Air pollution is implicated in sixty
thousand deaths per year in the United States. Six percent of Americans
have asthma. In Europe, air pollution causes twice as many premature deaths
as do car accidents (Blatt, 2005).
Asthma rates have increased in industrialized nations and urban centers,
correlated with the increase in exposure to air pollution. Increased air
pollution results in worsening of cough, asthma, bronchitis, and COPD.
Asthma may affect as many as one quarter of children living in urban environments
More than 100 million people in Latin America reside in areas where air
pollution exceeds limits set by the World Health Organization. Air pollution
in Mexico City and Sao Paulo has been linked to deaths in adults and children,
respiratory problems in children (such as asthma), emergency room visits,
and other problems (Bell, 2006). Sixteen of the world's most polluted
cities are in China. One third of the country suffers from acid rain,
the area around Bejing suffers the worst levels of nitrogen dioxide in
the world, and China is second to the U.S. as a producer of greenhouse
gases. More than 100 million people reside in areas in which the air pollution
can reach levels considered to be very dangerous and air pollution is
implicated in more than 400,000 premature deaths per year. There are days
in which a quarter of the particulate pollution of Los Angeles originated
in China (Watts, 2005).
Air pollution is not only known to aggravate diseases such as asthma,
evidence suggests that pollution has a role in causing asthma as well.
Although air quality has improved since the passage of the Clean Air Act
in 1970, about 146 million Americans in the year 2002 lived in counties
that did not meet air pollution level standards (Trasande, 2005). Exposure
to air pollution can alter the development of the lungs and thus have
a permanent effect on its function (Trasande, 2005).
Exposure to carbon monoxide pollution worsens asthma and increases the
number of those admitted to hospitals/emergency rooms for asthma (Curtis,
While atmospheric ozone is required for life on earth, it is potentially
harmful when it is breathed. At low altitudes, it is a pollutant. Even
low concentrations of ozone can decrease lung function in healthy people
and it worsens asthma. Maximum hourly concentrations of .05 ppm may cause
headaches, concentrations of .15 ppm cause eye irritation, and concentrations
of .29 cause coughs and chest discomfort. In L.A. 9/79, there were 10
consecutive days in which ozone concentrations exceded .35 ppm. Hospital
admittance of emphysema and asthma patients increased up to 50%. Ozone
levels in Mexico City are a serious problem for much of the year. Exposure
to ozone pollution worsens asthma and increases the number of those admitted
to hospitals/emergency rooms for asthma (Curtis, 2006). Ozone increases
the frequency of lung infections and the severity of responses to allergens
Sulfur and nitrogen oxides are respiratory irritants that affect breathing,
lower resistance to respiratory infections, and aggravate asthma and emphysema.
Children and the elderly are affected most. In the U.S. and other industrialized countries, asthma incidence is rising.
Between 1979-1991, asthma rates rose 56% for Americans under 18 and children
under 4 were the fastest growing group entering the hospital for asthma
Nitrogen oxides (nitric oxide NO and nitrogen dioxide N2O form in automobile
engines which are not only irritants themselves but react with other molecules
to form the components of photochemical smog. Sulfur is a component of
coal which produces sulfur dioxide when burned. Exposure to nitrogen oxide
pollution worsens asthma and increases the number of those admitted to
hospitals/emergency rooms for asthma (O’Connor, 2008; Curtis, 2006). Children whose mutations in GST enzymes result in decreased function are more likely to experience wheezing after being exposed to air pollution (Grigg, 2008). Particulate matter from petrochemical plants increases asthma risk in children (Wichmann, 2009).
Exposure to particulate matter pollution worsens asthma and increases
the number of those admitted to hospitals/emergency rooms for asthma (Curtis,
Particulate matter is an air pollutant whose sources include diesel fuel
exhaust. Exposure to diesel exhaust particles increase levels of IgE and
secretion of interleukins (Riedl, 2005). Experimental exposure to diesel exhaust particles has increased the production
of pro-inflammatory cytokines, histamine receptors, eosinophil migration
and degranulation, histamine release and cytokine synthesis in basophils,
IgE production in B cells, reactive oxygen species production, and cytokine
production in macrophages. Individuals who are exposed to diesel particles
increase the number of leukocytes in their airways and in circulation,
increase the levels of inflammatory cytokines and histamine, increase
airway resistance, and increase hypersensitivity in asthma patients. In
experimental conditions, subjects exposed to the equivalent of less than
2 days worth of diesel particulates from Los Angeles ambient air increased
IgE levels and IgE isotype switching (Riedl, 2005). When diesel particles are administered with an allergen, the Th2 response
is increased. While dust mite allergen can cause an allergic response,
only one fifth of the normal dose is required if administered with diesel
particulates. Children who live near major highways or play near major
intersections are more likely to suffer from asthma (Riedl, 2005).
Compared to those who live in areas of low traffic incidence, individuals in medium and high traffic areas experience increased incidence of asthma symptoms of 50 and 92%, respectively. Those who live in poverty are much more likely to live in areas of high traffic (in addition to other risk factors more common among low income families such as smoking and weight gain) (Meng, 2008).
Following the bombing of the World Trade Center, particulate matter
pollution (which contained pollutants such as asbestos, reactive organic
compounds, dioxin, and lead) was released into the atmosphere from September
through December. The government changed a safety report after 9/11 and
reported that the area around the Twin Towers was safe for rescue workers.
Actually, the EPA had measured that asbestos levels were 200-300% higher
than accepted levels. More than ¾ of rescue workers suffered lung
ailments as a result of their efforts (Kennedy, 2004).Women who were pregnant
during that time gave birth to children of reduced size, on average (Trasande,
More than a billion people in the world are smokers. Smoking is implicated in rhinitis which is a major risk factor for asthma (Polosa, 2008).Asthma deaths are more common among smokers. Asthma is a risk factor the onset of adult asthma and children who grow up exposed to smoking are more likely to develop asthma (Polosa, 2008).Behavioral problems occur at a greater incidence in asthmatic children and exposure to cigarette smoke has been correlated with behavioral problems in asthmatic children (Fagnano, 2008). A quarter of all children in the U.S. are exposed to second-hand smoke, as are as many as half inner city children who suffer from asthma (Fagnano, 2008). The number of children exposed to second hand smoke varies throughout the world but exceeds 70% in Europe (Tager, 2008). Maternal smoking during pregnancy is a risk factor for asthma (Tager, 2008).
Once asthma develops, exposure to cigarette smoke can worsen symptoms.
Smoking worsens asthma
and can decrease the effectiveness of asthma medication (Singh, 2005;
Wambolt, 2002). Cigarette smoke contains endotoxin (Singh, 2005).
The effects of cigarette smoke on asthma seem to present an example of
gene-environment interaction in that cigarette smoke can induce/worsen
asthma only if you have a genetic predisposition and this genetic predisposition
might not result in asthma were it not for exposure to cigarette smoke.
There are bout 4000 chemicals in cigarette smoke. The body detoxifies
a number of these chemicals (and other air pollutants as well) using glutathione-S-transferases
(GSTs). Not only are polymorphisms of these GSTs common, a large percentage
of a population may possess a deletion for an entire GST gene (e.g. 50%
Caucasians lack a GSTM1 gene and 15-20% lack a GSTT1 gene). Loss of gene
function has been associated with increased asthma risk after exposure
to air pollution in China and in Mexico City. Deleted genes result in
increased lung degeneration in adults and individuals with deleted genes
whose mothers smoked while pregnant have increased risk of asthma and
abnormal lung development (Kabeschm, 2006).
Airways are remodeled in chronic obstructive pulomonary disorder, COPD.
Cigarette smoking is the primary cause of COPD, causing emphysema, chronic
bronchitis, and chronic obstructive bronchiolitis. Viral infections can
aggravate both COPD and asthma (Gualano, 2006). It is not always easy
to distinguish between asthma and chronic obstructive pulmonary disease
(COPD) (Douglas, 2005).
Obesity is a risk factor for asthma. More than ¾ of the asthma
patients who require emergency room treatment are obese or overweight.
Although the physiological connection between obesity and asthma requires
further study, obesity can result in changes in lung development, produce
chronic inflammatory signals which infect the lung, and produce signals
which regulate energy balance which also affect lung cells (Shore, 2005). Studies have linked being overweight and obese with 38% and 92% increases in asthma incidence. Some (but not all) studies have associated increased asthma risk with higher infant and childhood weight (Litonjua, 2008; Shore, 2008)Obese individuals often possess higher levels of the hormone leptin. Leptin
also affects T cells, monocytes, and macrophages in a way which increases
their responses to other signals. Adiponectin levels are lower in obese
individuals and this signal also has the potential to act on smooth muscle
of airways which express receptors for it (Shore, 2005). Obesity is associated with a two-fold increase in asthma risk in women but not in men(Loerbroks, 2008). Central obesity is a better predictor of asthma risk in children than general body mass index measures (Musaad, 2009). Adipose tissue is depicted below.
Western diets may contribute to asthma risk due to a reduced consumption of antioxidants, an increased prevalence of fatty acids, and the promotion of excess fat reserves. Fatty acids can activate toll-like receptor 4 (TLR4) on immune cells and promote inflammation. Fat cells produce pro-inflammatory signals such as interleukin 6, TNF alpha, and CRP in addition to hormones such as leptin which affect cells of the innate immune system (Wood, 2009).
Some have proposed a decrease in vitamin D levels as a cause of asthma, in part a result of decreased time that people spend exposed to sunlight (Litonjua, 2007).Supplements of vitamin D in pregnant women have been shown to decrease asthma risk in children (Litonjua, 2007). Vitamin D deficiency is also linked to other risk factors for asthma, such as obesity (Litonjua, 2007).
Folate has been supplemented to diets due to its demonstrated benefits in preventing neural tube defects. This increased intake may have a negative consequence on asthma incidence. Two studies, one in mice and one in humans, suggest that the increased intake of folate increases asthma. The mechanisms seems to be an epigenetic increase in the methylation of genes such as (Runx3, Nfact1, Jak2, Rcor3, and Ube2j1) (Ownby, 2009).
Thunderstorms provide ideal conditions for the spread of some fungal storms. A number of outbreaks of asthma have immediately followed thunderstorms and have been linked to reactions to fungal spores instead of grass pollen or other sources (Pulimood, 2007).
Hot tub usage can expose individuals to Mycobacterium avium which can
contaminate the water and enter the body through inhaled air. The symptoms
of "hot tub lung" include asthma and bronchitis (Hanak, 2006).
Caesarian section is associated with a slight increase in asthma risk (Tollanes, 2008).
Gender may be a factor in asthma risk since some surveys have shown
asthma prevalence to be higher in males (Singh, 2005).
Although early reports concluded the contrary, the mode of an infant's
delivery is not a factor in determining asthma (Juhn, 2005).