ASTHMA

lungs 
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).


GENETIC PREDISPOSITION

Is asthma a genetic disorder determined during embryonic development?

embryo
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 genotype.

DEVELOPMENT
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.
home home

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.)

latrine feeding chickens

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, 2006).
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?

worm

INFLAMMATION


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).

airways

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.

basophil

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 (Abraham, 2006).

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 (Caroll, 2005).

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, 2005).
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

 

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.

thymus T cell
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).

Tcells

Tcells

Tcells
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).

Tcells

Tcells

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 Hertzen, 2006).

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.

monocytemonocyte

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).

Tcells

Tcells
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).


TOLL-LIKE RECEPTORS
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).

APC

dendritic cell
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, 2005).

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).

Mast cell
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, 2005).

C) EOSINOPHILS

eosinophileosinophil
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, 2002).

eosinophil

D) NEUTROPHILS

neutrophilneutrophil
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; Andreadis, 2003).

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).

OXIDATION


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, 2006).
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).

ARGININE BALANCE
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, 2006).
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, 2006).

SURFACTANTS

alveolus
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, 2006).

ALLERGENS
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).

bacteria

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).

catdog

Asthmatics who 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).


VIRUSES
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 (Gualano, 2006).

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).

 

BRONCHOCONSTRICTION
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).

airways
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 (Broadley, 2006).
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).

AIRWAY REMODELING

air sac
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 (Gueders, 2006).

NERVOUS SYSTEM
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).

AIR POLLUTION

Rio
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 (Lily, 2005).
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).

smokestacks

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, 2006).
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 (Trasande, 2005).


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 attacks.

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, 2006).
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).

pollution

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, 2005).

New York

CIGARETTES

cigarettes
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
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.

adipose

DIET

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

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).

OTHER
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).

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