Pathophysiology of asthma

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Pathophysiology of Asthma,
Asthma attack-illustration NIH.jpg
Figure A shows the location of the lungs and airways in the body. Figure B shows a cross-section of a normal airway. Figure C shows a cross-section of an airway during asthma symptoms.
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Asthma is a common pulmonary condition defined by chronic inflammation of respiratory tubes, tightening of respiratory smooth muscle, and episodes of bronchoconstriction. [1] The Centers for Disease Control and Prevention estimate that 1 in 11 children and 1 in 12 adults have asthma in the United States of America. [1] According to the World Health Organization, asthma affects 235 million people worldwide. [2] There are two major categories of asthma: allergic and non-allergic. The focus of this article will be allergic asthma. In both cases, bronchoconstriction is prominent. [1]

Contents

Bronchoconstriction

Inflamed airways and bronchoconstriction in asthma results in airways narrowing and thus wheezing. Asthma before-after-en.svg
Inflamed airways and bronchoconstriction in asthma results in airways narrowing and thus wheezing.
Obstruction of the lumen of the bronchiole by mucoid exudate, goblet cell metaplasia, epithelial basement membrane thickening and severe inflammation of bronchiole. Asthma .jpg
Obstruction of the lumen of the bronchiole by mucoid exudate, goblet cell metaplasia, epithelial basement membrane thickening and severe inflammation of bronchiole.

During an asthma episode, inflamed airways react to environmental triggers such as smoke, dust, or pollen. The airways narrow and produce excess mucus, making it difficult to breathe. In essence, asthma is the result of an immune response in the bronchial airways. [3]

The airways of asthma patients are "hypersensitive" to certain triggers, also known as stimuli (see below). (It is usually classified as type I hypersensitivity.) [4] [5] In response to exposure to these triggers, the bronchi (large airways) contract into spasm (an "asthma attack"). Inflammation soon follows, leading to a further narrowing of the airways and excessive mucus production, which leads to coughing and other breathing difficulties. Bronchospasm may resolve spontaneously in 1–2 hours, or in about 50% of subjects, may become part of a 'late' response, where this initial insult is followed 3–12 hours later with further bronchoconstriction and inflammation. [6]

The normal caliber of the bronchus is maintained by a balanced functioning of the autonomic nervous system, which both operate reflexively. The parasympathetic reflex loop consists of afferent nerve endings which originate under the inner lining of the bronchus. Whenever these afferent nerve endings are stimulated (for example, by dust, cold air or fumes) impulses travel to the brain-stem vagal center, then down the vagal efferent pathway to again reach the bronchial small airways. Acetylcholine is released from the efferent nerve endings. This acetylcholine results in the excessive formation of inositol 1,4,5-trisphosphate (IP3) in bronchial smooth muscle cells which leads to muscle shortening and this initiates bronchoconstriction.

Bronchial inflammation

Normal and Bronchial Asthma Tissues (a) Normal lung tissue does not have the characteristics of lung tissue during (b) an asthma attack, which include thickened mucosa, increased mucus-producing goblet cells, and eosinophil infiltrates. 2311 Lung Tissue.jpg
Normal and Bronchial Asthma Tissues (a) Normal lung tissue does not have the characteristics of lung tissue during (b) an asthma attack, which include thickened mucosa, increased mucus-producing goblet cells, and eosinophil infiltrates.

The mechanisms behind allergic asthma—i.e., asthma resulting from an immune response to inhaled allergens—are the best understood of the causal factors. In both people with asthma and people who are free of the disease, inhaled allergens that find their way to the inner airways are ingested by a type of cell known as antigen-presenting cells, or APCs. APCs then "present" pieces of the allergen to other immune system cells. In most people, these other immune cells (TH0 cells) "check" and usually ignore the allergen molecules. In asthma patients, however, these cells transform into a different type of cell (TH2), for reasons that are not well understood. A possible reason could be the release of Interleukin-4 by Mast cells that induce differentiation of naive helper T cells (Th0 cells) to Th2 cells.

The resultant TH2 cells activate an important arm of the immune system, known as the humoral immune system. The humoral immune system produces antibodies against the inhaled allergen. Later, when a patient inhales the same allergen, these antibodies "recognize" it and activate a humoral response. Inflammation results: chemicals are produced that cause the wall of the airway to thicken, cells which produce scarring to proliferate and contribute to further 'airway remodeling', causes mucus producing cells to grow larger and produce more and thicker mucus, and the cell-mediated arm of the immune system is activated. Inflamed airways are more hyper-reactive, and will be more prone to bronchospasm.

The "hygiene hypothesis" postulates that in early life, an imbalance in the regulation of these TH cell types leads to a long-term domination of the cells involved in allergic responses over those involved in fighting infection. [8] [9] The suggestion is that for a child being exposed to microbes early in life, taking fewer antibiotics, living in a large family, and growing up in the country stimulate the TH1 response and reduce the odds of developing asthma. [10]

Asthma is associated with a procoagulant state in the bronchoalveolar space. [11]

Stimuli

Pathogenesis

The fundamental problem in asthma appears to be immunological: young children in the early stages of asthma show signs of excessive inflammation in their airways. Epidemiological findings give clues as to the pathogenesis: the incidence of asthma seems to be increasing worldwide, and asthma is now very much more common in affluent countries.

In 1968 Andor Szentivanyi first described The Beta Adrenergic Theory of Asthma; in which blockage of the Beta-2 receptors of pulmonary smooth muscle cells causes asthma. [27] Szentivanyi's Beta Adrenergic Theory is a citation classic [28] using the Science Citation Index and has been cited more times than any other article in the history of the Journal of Allergy and Clinical Immunology.

In 1995 Szentivanyi and colleagues demonstrated that IgE blocks beta-2 receptors. [29] Since overproduction of IgE is central to all atopic diseases, this was a watershed moment in the world of allergies. [30]

Asthma and sleep apnea

It is recognized with increasing frequency that patients who have both obstructive sleep apnea and asthma often improve tremendously when the sleep apnea is diagnosed and treated. [31] CPAP is not effective in patients with nocturnal asthma only. [32]

Asthma and gastro-esophageal reflux disease

If gastro-esophageal reflux disease (GERD) is present, the patient may have repetitive episodes of acid aspiration. GERD may be common in difficult-to-control asthma, but according to one study, treating it does not seem to affect the asthma. [33] When there is a clinical suspicion for GERD as the cause of the asthma, an Esophageal pH Monitoring is required to confirm the diagnosis and establish the relationship between GERD and asthma.

Asthma and exposure to air pollution during pregnancy

Asthma affects four to eight out of a hundred pregnant women. [34] This is due to the fact that during pregnancy, there is an immunological shift due to hormonal fluctuations. [35] In some cases, there is an increase in Estrogen levels which in turn reduce the activity of natural killer cells, Th1 cell production of inflammatory cytokines, and production of anti-inflammatory cytokines. [35] As we have seen, these play an important role in the pathophysiology of asthma.

Researchers found a link between the preterm birth and exposure to air pollution in asthmatic pregnant women. [36] Results suggested that women with asthma have a higher risk of preterm birth. [36] Researchers suggested that asthmatic episodes in pregnant women were associated with ongoing exposure to nitrogen dioxide and carbon monoxide - types of air pollutants. [36]

Researchers also studied when women were most susceptible to develop asthma. Data indicated that women were at a higher risk of developing asthma when exposed to pollutants before conception and during pregnancy. [36] In particular, "an increase of 30 parts per billion (ppb) in nitrogen oxide exposure in the three months prior to pregnancy increased preterm birth risk by nearly 30 percent for women with asthma, compared to 8 percent for women without asthma." [36]

In other studies, Scientists have found a link between asthma in children and prenatal exposure to air pollution. Results from a study that consisted of 65, 000 Canadian children suggested that children of mothers who lived near highways during pregnancy had a 25% increased risk of developing asthma before the age of five when compared with children of mothers who did not live near highways. [37] Highways are a major source of traffic-related air pollution such that there is an accumulation of air pollutants such as nitrogen dioxide and carbon monoxide (emitted from vehicles) in the vicinity of highways. [37]

In another study, researchers collected data from 6,000 children attending public schools in California. The results suggested that a high exposure to prenatal air pollution was strongly correlated with increased susceptibility to asthma during childhood. [38]

Related Research Articles

<span class="mw-page-title-main">Asthma</span> Long-term inflammatory disease of the airways of the lungs

Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, coughing, chest tightness, and shortness of breath. These may occur a few times a day or a few times per week. Depending on the person, asthma symptoms may become worse at night or with exercise.

<span class="mw-page-title-main">Allergy</span> Immune system response to a substance that most people tolerate well

Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, allergic asthma, and anaphylaxis. Symptoms may include red eyes, an itchy rash, sneezing, coughing, a runny nose, shortness of breath, or swelling. Note that food intolerances and food poisoning are separate conditions.

An allergen is a type of antigen that produces an abnormally vigorous immune response in which the immune system fights off a perceived threat that would otherwise be harmless to the body. Such reactions are called allergies.

<span class="mw-page-title-main">Allergic rhinitis</span> Nasal inflammation due to allergens in the air

Allergic rhinitis, of which the seasonal type is called hay fever, is a type of inflammation in the nose that occurs when the immune system overreacts to allergens in the air. Signs and symptoms include a runny or stuffy nose, sneezing, red, itchy, and watery eyes, and swelling around the eyes. The fluid from the nose is usually clear. Symptom onset is often within minutes following allergen exposure, and can affect sleep and the ability to work or study. Some people may develop symptoms only during specific times of the year, often as a result of pollen exposure. Many people with allergic rhinitis also have asthma, allergic conjunctivitis, or atopic dermatitis.

<span class="mw-page-title-main">Rhinitis</span> Irritation and inflammation of the mucous membrane inside the nose

Rhinitis, also known as coryza, is irritation and inflammation of the mucous membrane inside the nose. Common symptoms are a stuffy nose, runny nose, sneezing, and post-nasal drip.

<span class="mw-page-title-main">Food allergy</span> Hypersensitivity reaction to a food

A food allergy is an abnormal immune response to food. The symptoms of the allergic reaction may range from mild to severe. They may include itchiness, swelling of the tongue, vomiting, diarrhea, hives, trouble breathing, or low blood pressure. This typically occurs within minutes to several hours of exposure. When the symptoms are severe, it is known as anaphylaxis. A food intolerance and food poisoning are separate conditions, not due to an immune response.

<span class="mw-page-title-main">Bronchoconstriction</span> Constriction of the terminal airways in the lungs

Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath.

Acute severe asthma, also known as status asthmaticus, is an acute exacerbation of asthma that does not respond to standard treatments of bronchodilators (inhalers) and corticosteroids. Asthma is caused by multiple genes, some having protective effect, with each gene having its own tendency to be influenced by the environment although a genetic link leading to acute severe asthma is still unknown. Symptoms include chest tightness, rapidly progressive dyspnea, dry cough, use of accessory respiratory muscles, fast and/or labored breathing, and extreme wheezing. It is a life-threatening episode of airway obstruction and is considered a medical emergency. Complications include cardiac and/or respiratory arrest. The increasing prevalence of atopy and asthma remains unexplained but may be due to infection with respiratory viruses.

Exercise-induced bronchoconstriction (EIB) occurs when the airways narrow as a result of exercise. This condition has been referred to as exercise-induced asthma (EIA), however this term is no longer preferred. While exercise does not cause asthma, it is frequently an asthma trigger.

<span class="mw-page-title-main">Interleukin 13</span> Protein and coding gene in humans

Interleukin 13 (IL-13) is a protein that in humans is encoded by the IL13 gene. IL-13 was first cloned in 1993 and is located on chromosome 5q31.1 with a length of 1.4kb. It has a mass of 13 kDa and folds into 4 alpha helical bundles. The secondary structural features of IL-13 are similar to that of Interleukin 4 (IL-4); however it only has 25% sequence identity to IL-4 and is capable of IL-4 independent signaling. IL-13 is a cytokine secreted by T helper type 2 (Th2) cells, CD4 cells, natural killer T cell, mast cells, basophils, eosinophils and nuocytes. Interleukin-13 is a central regulator in IgE synthesis, goblet cell hyperplasia, mucus hypersecretion, airway hyperresponsiveness, fibrosis and chitinase up-regulation. It is a mediator of allergic inflammation and different diseases including asthma.

<span class="mw-page-title-main">Allergic bronchopulmonary aspergillosis</span> Medical condition

Allergic bronchopulmonary aspergillosis (ABPA) is a condition characterised by an exaggerated response of the immune system to the fungus Aspergillus. It occurs most often in people with asthma or cystic fibrosis. Aspergillus spores are ubiquitous in soil and are commonly found in the sputum of healthy individuals. A. fumigatus is responsible for a spectrum of lung diseases known as aspergilloses.

Pitrakinra is a 15-kDa human recombinant protein of wild-type human interleukin-4 (IL-4). It is an IL-4 and IL-13 antagonist that has been studied in a phase IIb clinical trial for the treatment of asthma. Two point mutations on pitrakinra confer its ability to block signaling of IL-4 and interleukin-13 (IL-13) by preventing assembly of IL-4 receptor alpha (IL-4Rα) with either IL-2Rγ or IL-13Rα. Upregulation of Th2 cytokines, including IL-4 and IL-13, is thought to be critical for the allergic inflammation associated with atopic diseases such as asthma and eczema. The targets of pitrakinra action are inflammatory cells and structural cells that express IL-4Rα. The drug has been applied both as a subcutaneous injection and as an inhalation, but the latter formulation proved to be more effective.

<span class="mw-page-title-main">Thymic stromal lymphopoietin</span> Cytokine, alarmin, and growth factor.

Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-2-like cytokine, alarmin, and growth factor involved in numerous physiological and pathological processes, primarily those of the immune system. It shares a common ancestor with IL-7.

Vocal cord dysfunction (VCD) is a pathology affecting the vocal folds characterized by full or partial vocal fold closure causing difficulty and distress during respiration, especially during inhalation.

Alcohol-induced respiratory reactions, also termed alcohol-induced asthma and alcohol-induced respiratory symptoms, are increasingly recognized as a pathological bronchoconstriction response to the consumption of alcohol that afflicts many people with a "classical" form of asthma, the airway constriction disease evoked by the inhalation of allergens. Alcohol-induced respiratory reactions reflect the operation of different and often racially related mechanisms that differ from those of classical, allergen-induced asthma.

<span class="mw-page-title-main">ILC2</span>

ILC2 cells, or type 2 innate lymphoid cells are a type of innate lymphoid cell. Not to be confused with the ILC. They are derived from common lymphoid progenitor and belong to the lymphoid lineage. These cells lack antigen specific B or T cell receptor because of the lack of recombination activating gene. ILC2s produce type 2 cytokines and are involved in responses to helminths, allergens, some viruses, such as influenza virus and cancer.

Clare Margaret Lloyd is a Professor of Medicine and Vice Dean for Institutional Affairs at Imperial College London. She investigates allergic immunity in early life.

Donna Elizabeth Davies is a British biochemist and professor of respiratory cell and molecular biology at the University of Southampton. In 2003, Davies was the co-founder of Synairgen, an interferon-beta drug designed to treat patients with asthma and chronic obstructive pulmonary disease.

<span class="mw-page-title-main">Asthma trigger</span> Factor that provokes symptoms of asthma

Asthma triggers are factors or stimuli that provoke the exacerbation of asthma symptoms or increase the degree of airflow disruption, which can lead to an asthma attack. An asthma attack is characterized by an obstruction of the airway, hypersecretion of mucus and bronchoconstriction due to the contraction of smooth muscles around the respiratory tract. Its symptoms include a wide range of manifestations such as breathlessness, coughing, a tight chest and wheezing.

Asthma phenotyping and endotyping is a novel approach to asthma classification inspired by precision medicine. It seeks to separate the clinical presentations or clusters of signs and symptoms of asthma, known as asthma phenotypes, from their underlying etiologies or causes, known as asthma endotypes.

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