Mechanisms of development (pathogenesis) of asthma

Asthma is a chronic inflammatory disease of the respiratory tract, characterized by repeated episodes of wheezing, shortness of breath, heaviness in the chest and cough, especially at night and / or early morning. Symptoms, as a rule, are caused by a widespread, but to varying degrees expressed bronchospasm and restriction of air flow. Symptoms are partially reversible (spontaneously or after treatment). Distinctive features of this disease are hypersensitivity of the respiratory tract to various stimuli, leading to episodically recurring bronchospasm, inflammation of the walls of the bronchi, increased mucus secretion. Some of the stimuli that cause asthma attacks have a minor effect or do not affect patients without airway disease. The inflammatory response involves many cells, in particular lymphocytes, eosinophils, mast cells, macrophages, neutrophils, epithelial cells. Persons with long-term asthma attacks, dyspnea, coughing and wheezing, caused by sudden bronchospasm, can have varying degrees of severity. Rarely develops a state of ongoing bronchospasm, called asthmatic status, which can become fatal. Between episodes of symptoms there can be practically no symptoms. Over the past 40 years, a significant increase in asthma has been recorded in Western countries. Asthma can be atopic (if patients have hypersensitivity to allergens, often with allergic rhinitis, eczema) and non-atopic (without proven hypersensitivity to allergens). For any type of asthma, episodes of bronchospasm can be triggered by various triggers, such as a respiratory infection (especially a viral infection), environmental irritants (such as smoke, odors), cold air, stress, and physical exertion. Recent studies have shown the importance of understanding the different types of airway inflammation – eosinophilic, neutrophilic and mixed. The types of asthma determined in accordance with these options may differ in etiology, immunopathology, and response to therapy. Asthma is also classified according to agents or events that cause bronchospasm. So, seasonal asthma, drug asthma, occupational asthma and smoker’s asthmatic bronchitis are distinguished. a) Atopic asthma. This most common type of asthma is a classic example of an IgE-mediated allergic reaction. The disease usually manifests in childhood after exposure to an exogenous allergen, such as house dust, plant pollen, insect waste products, animal dander, or food. Typically, there is asthma in the family history and a positive skin test for an irritating antigen (immediate hypersensitivity reactions) with reddening of the skin and blistering. Atopic asthma is also diagnosed by the presence of sensitization to an allergen, established using a serum radioallergenic sorbent test, which identifies the presence of specific IgE in the human body. b) Non-atopic asthma. Patients with non-atopic asthma have no hypersensitivity to allergens, and the results of skin tests are usually negative. A family history of asthma is rare. Typically, triggers of non-atopic asthma are respiratory infections caused by viruses (e.g. rhinovirus, parainfluenza virus). In these patients, the disease is based on an increased reactivity of the bronchial tree. It is believed that virus-induced inflammation of the mucous membrane of the respiratory tract reduces the threshold of sensitivity of subepithelial vagal receptors for irritants. Inhaled pollutants, such as sulfur dioxide, ozone and nitrogen dioxide, in some cases can contribute to chronic inflammation of the respiratory tract and increased bronchial reactivity. c) Drug asthma. Some pharmacological agents provoke such asthma. Aspirin-sensitive asthma is a rare type that develops in some patients with recurrent rhinitis and nasal polyps. Theseindividuals are extremely sensitive to small doses of acetylsalicylic acid, as well as other non-steroidal anti-inflammatory drugs. In these patients, not only asthmatic attacks, but also urticaria are observed. Probably, in these patients, acetylsalicylic acid causes asthma by inhibiting the cyclooxygenase pathway of the arachidonic acid metabolism, without affecting the lipoxygenase pathway, shifting the reaction towards increased synthesis of leukotrienes that stimulate bronchoconstriction. d) Occupational asthma. This asthma is caused by fumes (epoxies, plastics), organic and chemical dust (wood, cotton, platinum), gases (toluene) and other chemicals (formaldehyde, penicillin derivatives). An asthma attack can cause a small amount of a chemical, but, as a rule, after its repeated exposure. The main mechanisms are variable, agent-dependent and include a type I hypersensitivity reaction with the release of bronchospasm causing agents and a hypersensitivity reaction of unknown origin. e) Pathogenesis. The main etiological factor in atopic asthma is a genetic predisposition to develop a type I hypersensitivity reaction (atopic reaction) to the effects of environmental factors, which, as a rule, remain unidentified. It has been established that a genetic predisposition to atopic asthma is manifested by an active reaction of Th2 cells to environmental antigens (allergens), to which the body of most people reacts weakly or does not react at all. In the respiratory tract, sensitization to inhaled allergens that stimulate the induction of Th2 cells develops. Th2 cells secrete inflammation-triggering cytokines and stimulate the secretion of IgE and other antibodies by B cells. Such cytokines are: (1) IL-4, stimulating the production of IgE; (2) IL-5 activating local eosinophils; (3) IL-13, enhancing the secretion of mucus by the bronchial glands, and also promoting the production of IgE by B cells. As with other allergic reactions, IgE are fixed on the surface of mast cells located in the submucosal layer, and upon repeated exposure to the allergen, they degranulate mast cells with the release of the contents of their granules and the secretion of cytokines and other mediators. All these agents are involved in the development of the early phase of an allergic reaction (immediate hypersensitivity reaction) and the late phase of an allergic reaction. The early phase of an allergic reaction is characterized by bronchospasm, increased mucus production, vasodilation and increased permeability. Bronchospasm is initiated by direct stimulation of the vagus nerve subepithelial receptors (parasympathetic stimulation) through the mechanism of central and local neural reflexes (including through the mediation of non-myelinated sensitive C-fibers). The late phase of the allergic reaction is characterized by inflammation with leukocyte infiltration, consisting of eosinophils, neutrophils and a large number of T cells. The accumulation of leukocytes in tissues is stimulated by certain cytokines and chemokines secreted by mast and epithelial cells, as well as T cells. Epithelial cells are known to produce a large number of cytokines in response to infectious agents, drugs and gases, as well as inflammatory mediators. This second wave of mediators also stimulates the late phase of an allergic reaction. For example, eotaxin, produced by the epithelial cells of the respiratory tract, is a powerful chemoattractant and activator of eosinophils. In turn, the main main protein of eosinophils damages the epithelium and causes an even greater constriction of the bronchi. A lot of mediators are involved in the asthmatic response, the importance of each of them is difficult to assess. Mediators presumably involved in the pathogenesis of an acute asthma attack can be divided into three groups according to the clinical effect when exposed to inhibitors or antagonists of mediators: – mediators whose role in bronchospasm has been proven by the effectiveness of drug therapy: (1) leukotrienes C4, D4 and E4 (extremely powerful mediators, causing a prolonged spasm of the bronchi, increasing vascular permeability and increasing mucus secretion); (2) acetylcholine (secreted by intrapulmonary motor nerves, which, directly stimulating muscarinic receptors, can cause smooth muscle spasm of the respiratory tract); – mediators present in the lung tissue and with pronounced asthma-like effects: (1) histamine (a powerful bronchoconstrictor); (2) prostaglandin D2 (causes dilatation of blood vessels and bronchi); (3) platelet activation factor (causes platelet aggregation and the release of histamine and serotonin from their granules). The role of these mediators in the pathogenesis of acute allergic asthma seems relatively insignificant due to the lack of effect of their potential antagonists or synthesis inhibitors. These mediators may be involved in the pathogenesis of chronic non-allergic asthma; – mediators for which specific antagonists or inhibitors have not been found or have not yet been studied: numerous cytokines, such as IL-1, TNF and IL-6 (some of these cytokines are contained in mast cell granules), chemokines (eg, eotaxin), neuropeptides , nitric oxide, bradykinin and endothelin. Thus, the development of an acute asthmatic reaction is promoted by a large number of mediators (different in different individuals or with different types of asthma). Understanding the role of cells and inflammatory mediators in the pathogenesis of asthma has led to the use of anti-inflammatory drugs such as corticosteroids in its treatment. Over time, repeated contact with the allergen and immune reactions lead to structural changes in the bronchial wall – remodeling of the airways occurs. These changes (see below for more details) include hypertrophy and hyperplasia of smooth bronchial muscle cells, damage to the epithelium, increased vascularization of the airways, hypertrophy / hyperplasia of the bronchial mucous glands, and subepithelial deposition of collagen. The complex interactions between the immune system, the epithelium of the respiratory tract and the mesenchymal tissues of the respiratory tract are still poorly understood. Respiratory tract infections caused by typical pathogens such as respiratory syncytial virus and influenza virus can exacerbate the changes and seriously worsen the course of the disease. Infections are often the cause of asthma, but some of them, paradoxically, have a protective effect. Epidemiological studies for the first time revealed that the incidence of asthma was higher in populations not significantly affected by microorganisms than in those in an environment with an abundant microbial environment. This explains the ever-increasing frequency of allergic reactions, including asthma in industrialized countries. So the hygienic hypothesis appeared, according to which elimination of the infection can contribute to allergic and other immunopathological reactions of the human body, however, they have not yet been able to explain such a relationship between infection and asthma. Comparison of the structure of the respiratory tract in normal (A) and asthma (B). Pay attention to the accumulation of mucus in the lumen of the bronchus as a result of an increase in its secretion by goblet cells of the mucous membrane and hypertrophic submucosal glands and severe chronic inflammation with infiltration by eosinophils, macrophages and other cells. The epithelial basement membrane is thickened, smooth muscle cells are hypertrophied and hyperplastic. (B) Inhaled allergens (antigen) cause the reaction of Th2 cells, promoting the production of immunoglobulin E (IgE), the migration of eosinophils to the focus of inflammation and their sensitization. (D) Upon repeated exposure to the antigen, an immediate-type hypersensitivity reaction is triggered by IgE associated with mast cell IgE receptors. These cells secrete mediators located in them, which, acting directly or with the help of neural reflexes, induce bronchospasm, increased vascular permeability, mucus production and extravasation of other cells. (E) The migration of leukocytes (neutrophils, eosinophils, basophils, lymphocytes and monocytes) into the focus of inflammation indicates the beginning of the late phase and the release of new mediators from leukocytes, endothelial and epithelial cells. The release of factors, especially from eosinophils (for example, the main major protein, cationic protein), also leads to damage to the epithelium. IL – interleukin. e) Genetics. Asthma is characterized by complex genetic characteristics that relate to a variety of genes that determine a predisposition to asthma and are responsible for interacting with environmental factors, as a result of which a pathological reaction develops. As with other complex processes, each individual has significant variability in the expression of these genes, combinations of polymorphisms, and their significance. Among more than 100 genes, the relationship of which with asthma has been established, only a few of them are widely represented in the population. Many genes affect the immune response or tissue remodeling, some on asthma, and others on the severity of asthma or the patient’s response to treatment: – one of the most reproducible loci associated with asthma susceptibility is located on chromosome 5q near the gene cluster encoding the cytokines IL-3, IL-4, IL-5, IL-9 and IL-13, as well as IL-4 receptors. The LPS receptor gene (CD14) and the gene encoding b2-adrenergic receptors are also located at this location. This region is of great interest because it contains genes that influence the mechanism of IgE regulation, as well as the growth and differentiation of mast cells and eosinophils. IL13 gene polymorphism has the strongest and most consistent association with asthma and other allergic diseases. The relationship of atopic reactions with the polymorphism of the CD14 gene encoding the monocyte endotoxin receptor needs additional comments, since it reveals the essence of the relationship of the genotype with environmental factors. In some studies, the TT CD 14 genotype has been associated with a reduced level of IgE and a reduced risk of asthma and other atopic reactions, but other studies have shown an increased risk of these reactions. Further analysis showed that the TT genotype protects against asthma or allergic sensitization when exposed to a small amount of endotoxin, but is associated with an increased risk of asthma or allergic sensitization when exposed to a large amount of endotoxin. This effect may be due to the different effects of different levels of endotoxin on Tn1 and Tn2 cells. In individuals with a TT genotype and a high level of endotoxin, Th2 cells produce a large amount of IgE, respectively, the predisposition to an allergic reaction in such individuals is higher. Studies have shown that the relationship between genotype and phenotype is context-sensitive, and helped explain some of the conflicting results from different populations; – predisposition to the synthesis of IgE antibodies to certain antigens, such as ragweed pollen, can be directly associated with class II HLA; – ADAM-33 refers to a subfamily of metalloproteinases associated with MMP, for example, collagenases. The exact function remains unclear, however, ADAM-33 is known to be expressed by pulmonary fibroblasts and bronchial smooth muscle cells. Probably, ADAM-33 polymorphism enhances the proliferation of smooth muscle cells and fibroblasts of the bronchial wall, contributing to increased bronchial reactivity and subepithelial fibrosis. ADAM-33 is also involved in suppressing pulmonary function; – The b2-adrenergic receptor gene is located on chromosome 5q. Polymorphism of this gene under in vivo conditions is associated with various hypersensitivity reactions in the respiratory tract, and in vitro, with various responses to stimulation by b-agonists. Thus, knowledge of the genotype allows you to predict the response of the patient to therapy; – many variants of the polymorphism of the IL-4 receptor gene encoding the a-chain of the IL-4 receptor are associated with atopy, elevated levels of total serum IgE and asthma; – in humans, the family of mammalian chitinases (chitinase refers to enzymes that break down chitin – a polysaccharide contained in many human parasites and the cell wall of fungi) includes representatives with and without enzymatic activity. In mammalian acid chitinase, an increase in activity is described in the inflammatory response of Th2 cells. Another member of the family – YKL-40 – does not have enzymatic activity and is associated with the development of asthma. Serum YKL-40 correlates with asthma severity. Fibrosis of the basement membrane, eosinophils as part of inflammatory infiltrate and hyperplasia of smooth muscle cells in asthma (bronchobiopsy). g) Morphology. In patients who have died in a state of asthmatic status, lungs with small portions of atelectasis are dilated as a result of hyperinflation. The most striking macroscopic sign of an asthma attack is occlusion of the bronchi and bronchioles with large, viscous mucous plugs. Histologically, corks are casts of the deflated epithelium of the small bronchi and have a spiral shape (Curshman spirals). These plugs can also form from mucus in the ducts of the bronchial glands, and then move to the bronchioles. Numerous eosinophils and Charcot-Leiden crystals are present in the bronchial contents. The latter are elongated crystals of a protein that binds the lipophospholipase of eosinophils, called galectin-10. Other characteristic histological changes in asthma, denoted by the term “airway remodeling”: • thickening of the walls of the bronchi; • fibrosis of the basement membrane under the bronchial epithelium due to deposition of type I and III collagen under the basement membrane, which normally consists of type IV collagen and laminin; • increased vascularization; • increase in the size of bronchial submucosal glands; • mucous metaplasia of the epithelium of the respiratory tract; • hypertrophy and / or hyperplasia of the smooth muscles of the bronchial wall. This led to the development of a new method of therapy – bronchial thermoplasty, in which the walls of the central respiratory tract are exposed to radio waves through a probe placed in a bronchoscope, which reduces airway hypersensitivity by at least 1 year. Obstruction of air passage in asthma is primarily due to bronchospasm, swelling of the mucous membrane and mucus obstruction, however, airway remodeling can also contribute to obstruction. Airway remodeling is thought to contribute to irreversible chronic airway obstruction. h) Clinical signs. A classic acute asthma attack lasts several hours. In some patients, symptoms such as chest tightness, shortness of breath, wheezing, and coughing with or without sputum are constantly present. With the most severe form of asthma manifestation – asthmatic status – an acute attack lasts several days and even weeks. Under these conditions, obstruction can be so pronounced that it can cause severe stagnation and even death. The clinical diagnosis is made on the basis of progression of obstruction (from the initial level), difficulty in expiration (prolonged expiratory time, wheezing), eosinophilia, as well as the appearance of eosinophils, Kurshman spirals and Charcot-Leiden crystals in the sputum (especially in patients with atopic asthma). Asthma usually occurs with seizures and remissions, i.e. temporary intervals without respiratory symptoms, and exhausts the patient more than carries the risk of death. With therapy that reduces the number and severity of seizures, most people with asthma can lead an active life. Up to 50% of asthma attacks in children soften during adolescence, but quite often return in adulthood. In the absence of therapy, a gradual decrease in lung function occurs.

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