Pathogenesis of bronchial asthma

According to modern conceptions, the morphological basis of bronchial asthma is chronic inflammation of the bronchial wall with an increase in the number of activated eosinophils, mast cells, T-lymphocytes in the bronchial mucosa, a thickening of the basal membrane and the subsequent development of subepithelial fibrosis. As a result of these inflammatory changes, bronchial hyperreactivity and bronchial obstructive syndrome develop.

The development of allergic (atopic, immunological) bronchial asthma is due to type I allergic reaction (immediate allergic reaction) according to Gell and Coombs, in which IgE and IgG participate. This process is promoted by deficiency of T-suppressor function of lymphocytes.

In the pathogenesis of allergic bronchial asthma, four phases are distinguished: immunological, pathochemical, pathophysiological and conditioned reflex.

In the immunological phase, under the influence of the allergen, B-lymphocytes secrete specific antibodies that predominantly belong to the IgE class (reactive antibodies). There is it as follows.

Entered into the respiratory tract, the allergen is captured by the macrophage, processed (split into fragments), binds to class II glycoproteins of the main histocompatibility complex (HLA), and is transported to the cell surface of the macrophage. The described events have received the name of processing. Further, the complex "antigen + molecules of HLA class II" is presented (presented) to T-lymphocytes-helpers (allergic-specific). After this, a subpopulation of T-helpers (Th2) is activated, which produces a number of cytokines involved in the implementation of the type I allergic reaction:

• Interleukins 4, 5, 6 stimulate the proliferation and differentiation of B-lymphocytes, switch the synthesis of immunoglobulins in B-lymphocytes on IgE and IgG4;
• interleukin-5 and GM-SF (granulocyte macrophage stimulating factor) - activates eosinophils.

Activation of the Th2 subpopulation and isolation of these cytokines leads to activation and synthesis of IgE and IgG4 B lymphocytes, activation and differentiation of mast cells and eosinophils.

The formed IgE and IgG4 are fixed on the surface of the allergy target cells I (mast cells and basophils) and II order (eosinophils, neutrophils, macrophages, platelets) with the help of cellular Fc receptors. The majority of mast cells and basophils are in the submucosal layer. When stimulated by an allergen, their number increases by a factor of 10.

Along with activation of Th2, the subpopulation of T-lymphocytes-helpers-Th is inhibited. As is known, the main function of Th is the development of delayed hypersensitivity (type IV allergic reaction according to Gell and Coombs). Thl-lymphocytes secrete gamma-interferon, which inhibits the synthesis of reactants (IgE) in B lymphocytes.

The immunochemical (pathochemical) stage is characterized by the fact that when the allergen re-enters the patient's organism, it interacts with antibody-reactants (primarily IgE) on the surface of allergy target cells. This leads to degranulation of mast cells and basophils, activation of eosinophils with a large number of mediators of allergy and inflammation that cause the development of the pathophysiological stage of pathogenesis.

The pathophysiological stage of bronchial asthma is characterized by the development of bronchospasm, edema of the mucous membrane and infiltration of the bronchial wall by cellular elements, inflammation, hypersecretion of mucus. All these manifestations of the pathophysiological stage are caused by the action of mediators of allergy and inflammation, which are secreted by mast cells, basophils, eosinophils, platelets, neutrophils, and lymphocytes.

During the pathophysiological stage, two phases are distinguished: early and late.

The early phase or early asthmatic reaction is characterized by the development of bronchospasm, expressed by expiratory dyspnea. This phase begins in 1-2 minutes, reaches a maximum in 15-20 minutes and lasts about 2 hours. The main cells involved in the development of an early asthmatic reaction are mast cells and basophils. In the process of degranulation of these cells, a large number of biologically active substances are released - mediators of allergy and inflammation.

From mast cells are allocated histamine, leukotrienes (LTS4, LTD4, LTE4), prostaglandin D various proteolytic enzymes. In addition to these mediators, interleukins 3, 4, 5, 6, 7, 8, neutrophilic and eosinophilic chemotactic factors, thrombocyto-factoring factor, granulocyte-macrophage colony-stimulating factor and tumor necrosis factor are also isolated from mast cells.

Degranulation of basophils is accompanied by the release of histamine, leukotriene, LTE4, eosinophilic and neutrophil chemotactic factors, platelet activating factor, leukotriene B, (causes neutrophil chemotaxis), heparin, kallikrein (cleaves kininogen with the formation of bradykinin).

The leading mechanism of the early asthmatic reaction is bronchospasm, which is caused by the influence of mediators of histamine, a slowly reacting substance of anaphylaxis, consisting of leukotrienes C4, D4, E4 prostaglandin D "bradykinin, platelet activating factor.

Late asthmatic reaction develops after about 4-6 hours, the maximum of its manifestations comes in 6-8 hours, the reaction duration is 8-12 hours. The main pathophysiological manifestations of late asthmatic reaction are inflammation, edema of the bronchial mucosa, hypersecretion of mucus. Mast cells, eosinophils, neutrophils, macrophages, platelets, T-lymphocytes that accumulate in the bronchial tree under the influence of mediators and cytokines secreted by mast cells take part in the development of the late asthmatic reaction . Mediators released by these cells contribute to the development of inflammatory changes in the bronchus, chronic inflammation and the formation of irreversible morphological changes in subsequent exacerbations.

The key cell in the development of a late asthmatic reaction is eosinophil. It produces a large number of biologically active substances:

• the main protein - activates mast cells, damages the epithelium of the bronchi;
• cationic protein - activates mast cells, damages the epithelium of the bronchi;
• eosinophilic protein X - has a neurotoxic effect, inhibits the culture of lymphocytes;
• a factor that activates platelets - causes bronchial and vascular spasm, bronchial mucosal edema, mucus hypersecretion, increases platelet aggregation and induces serotonin release, activates neutrophils and mast cells, promotes microcirculation disturbance;
• leukotriene C4 - causes spasm of bronchi and vessels, increases vascular permeability;
• prostaglandin D2 and F2a - cause bronchospasm, increased vascular permeability and platelet aggregation;
• prostaglandin E2 - causes vasodilation, hypersecretion of mucus, depresses inflammatory cells;
• thromboxane A2 - causes spasm of bronchi and vessels, increases platelet aggregation;
• chemotactic factor - causes chemosensitivity of eosinophils;
• cytokines - granulocyte-macrophage colony-stimulating factor (activates inflammatory cells, promotes granulocyte differentiation); interleukin-3 (activates inflammatory cells and differentiation of granulocytes); interleukin-8 (activates chemotaxis and degranulation of the phanulocytes);
• proteolytic enzymes (arylsulfatase, beta-glucuronidase - cause hydrolysis of glycosaminoglycans and glucuronic acid, collagenase - causes hydrolysis of collagen);
• peroxidase - activates mast cells.

Biologically active substances released by eosinophils contribute to the development of bronchial spasm, pronounced inflammatory process in them, damage to the bronchial epithelium, microcirculation disorders, hypersecretion of mucus, development of bronchial hyperreactivity.

Alveolar and bronchial macrophages play an important role in the development of early and late asthmatic reactions. As a result of contact of allergens and macrophage Fc receptors, they activate, which leads to the production of platelet activating mediators, leukotrienes B4 (in small amounts of C4 and D4), 5-HETE (5-hydroxyecosotetraenoic acid - lipoxygenase oxidation product of arachidonic acid); lysosomal enzymes, neutral proteases, beta-glucuronidase, PgD2.

In recent years, it has been established that the adhesion of cells to the endothelium plays a huge role in the mechanism of attracting eosinophils and other inflammatory cells into the bronchi. The adhesion process is associated with the appearance on the endothelial cells of adhesion molecules (E-selectin and intracellular ICAM-1), and on eosinophils and other inflammation cells - the corresponding receptors for adhesion molecules. The expression of adhesion molecules on the endothelium is enhanced by the action of cytokines - tumor necrosis factor (TFN-alpha) and interleukin-4, which are produced by mast cells.

Now it is known that the epithelium of the bronchi itself plays a big role in the development of inflammation in the bronchus and bronchospasm. The bronchial epithelium secretes inflammatory cytokines that promote the influx of inflammatory cells in the bronchi and activate T-lymphocytes and monocytes involved in the development of immune inflammation. In addition, the bronchial epithelium (as well as the endothelium), produces endothelium, which has a broncho-and vasoconstrictive effect. Along with this, the bronchial epithelium generates nitrogen oxide (NO), which has a bronchodilating effect and functionally counterbalances the effect of numerous bronchospastic factors. Probably, therefore, the amount of NO significantly increases in the air exhaled by the patient with bronchial asthma, which serves as a biological marker of this disease.

In the development of allergic bronchial asthma, the leading role is played by hyperproduction of IgE antibodies class (IgE-dependent bronchial asthma). However, according to the data of VI Pytkiy and AA Goryachkina (1987), in 35% of patients with bronchial asthma there is an increase in production of not only IgE, but also IgG. (IgE-IgG4-dependent bronchial asthma). It is characterized by the onset of the disease at a later age (over 40 years), prolonged seizures, and less effective treatment.

Less often in the pathogenesis of allergic bronchial asthma, the allergic Stip reaction (immunocomplex type) plays a leading role. In this case, antibodies that predominantly belong to class G and M immunoglobulins are formed. Next, an antigen-antibody complex is formed, the pathophysiological effect of which is realized through complement activation, liberation of lysosomal prageolitic enzymes and mediators from macrophages, neutrophils, platelets, activation of kinin and coagulation systems. The consequence of these processes is bronchospasm and the development of edema and bronchial inflammation.

[1], [2], [3], [4], [5], [6], [7]

The role of nitrogen oxide in the development of the pathophysiological stage of bronchial asthma

Nitrogen oxide (NO) is an endothelial relaxing factor and, through activation of guanylate cyclase and synthesis of cGMP, causes relaxation of the smooth muscles of the vessels and, consequently, their expansion. Nitrogen oxide is formed from the amino acid arginine under the influence of the enzyme NO-synthetase (NOS). There are two isoforms of NO synthase - constitutive (cNOS) and inducible (iNOS). Constitutive NOS (cNOS) is in the cytoplasm, is calcium- and calmodulin dependent and promotes the release of a small amount of NO for a short period.

Inducible NOS (iNOS) is calcium- and calmodulin-dependent, contributes to the synthesis of large amounts of NO for a long time. It is formed in inflammatory cells in response to the action of endotoxins and cytokines.

Now it is known that NO-synthetase is present in neurons, endotheliocytes, hepatocytes, Kupffer cells, fibroblasts, smooth myocytes, neutrophils, macrophages.

In the lungs, NO is synthesized under the influence of cNOS in endothelial cells of the pulmonary artery and vein, in the neurons of the non-adrenergic non-cholinergic nervous system.

Under the influence of iNOS, NO is synthesized by macrophages, neutrophils, mast cells, endothelial and smooth muscle cells, bronchial epithelial cells.

NO in the bronchopulmonary system plays the following positive role:

• contributes to vasodilation in a small circle of blood circulation, therefore, an increase in NO production counteracts the development of pulmonary hypertension in chronic obstructive pulmonary disease;
• the increase in NO production promotes bronchodilation and improvement of the function of the ciliated epithelium of the bronchi; NO is considered as a neurotransmitter of bronchodilator nerves, counteracting the effect of bronchoconstrictor nerves;
• participates in the destruction of microorganisms and tumor cells;
• reduces the activity of inflammatory cells, inhibits the aggregation of platelets, improves microcirculation.

Along with this, NO can play a negative role in the bronchopulmonary system.

INOS is expressed in the respiratory tract in response to inflammatory cytokines, endotoxins, oxidants, pulmonary irritants (ozone, cigarette smoke, etc.). The oxide produced under the influence of iNOS nitrogen interacts with the product of partial reduction of oxygen accumulated in the inflammatory focus - superoxide. As a result of this interaction, a peroxynitrite mediator is formed that causes damage to cells, proteins, lipids of cell membranes, damages the vascular epithelium, increases platelet aggregation, stimulates the inflammatory process in the bronchopulmonary system.

With bronchial asthma, iNOS activity rises, the NO content in the bronchial epithelium increases, and the NO concentration in the exhaled air increases. Intensive synthesis of NO under the influence of iNOS can play a role in the formation of bronchial obstruction in patients with moderate and severe forms of bronchial asthma.

The increased content of nitric oxide in the exhaled air is a biological marker of bronchial asthma.

Pathogenesis of infectious-dependent bronchial asthma

In the report "Bronchial asthma. Global strategy. (WHO, National Heart, Lung and Blood Institute, USA), in the Russian Consensus on Bronchial Asthma (1995), in the National Russian Program "Bronchial Asthma in Children" (1997), respiratory infections are considered as factors contributing to the emergence or exacerbation of the course of bronchial asthma. Along with this, the largest specialist in the field of bronchial asthma, prof. GB Fedoseev suggests isolating a separate clinico-pathogenetic variant of the disease - infectious-dependent bronchial asthma. This is justified, first of all, from a practical point of view, since not only the first clinical manifestations or exacerbations of the course of bronchial asthma are often associated with the effect of infection, but significant improvement in the state of patients comes after exposure to an infectious agent.

In the pathogenesis of the infectious-dependent variant of bronchial asthma, the following mechanisms are involved:

1. Hypersensitivity of the delayed type, the main role in the development of which belongs to T-lymphocytes. With repeated contacts with an infectious allergen, they are hapersensitized and lead to the release of mediators of delayed action: neutrophil chemotaxis factors, eosinophils, lymphotoxin, platelet aggregation factor. Mediators of delayed action cause the release of prostaglandins (PgD2, F2a, leukotrienes (LTS4, LTD4, LTC4), etc.) in the target cells (mast cells, basophils, macrophages), and as a result bronchospasm develops. In addition, an inflammatory infiltrate is formed around the bronchus, containing neuropathy, lymphocytes, eosinophils.This infiltrate is a source of mediators of the immediate type (leukotrienes, gastamins) that cause bronchial spasms and inflammation.Obsid from the granules of eosinophils are also proteins that damage the cilantro epithelium of the bronchi, which makes sputum evacuation difficult;
2. an allergic reaction of immediate type with the formation of IgE reagin (similar to atonic asthma). It develops rarely in the early stages of infectious-dependent bronchial asthma, mainly in fungal and neisserial asthma, as well as respiratory syncytial infection, pneumococcal and hemophilic bacterial infection;
3. non-immunological reactions - toxicity damage to the adrenal glands and a decrease in glucocorticoid function, dysfunction of ciliary epithelium and a decrease in beta2-adrenergic receptor activity;
4. activation of complement on the alternative and classical pathway with the release of C3 and C5 components, which determine the isolation of other mediators by mast cells (in case of pneumococcal infection);
5. release of histamine and other mediators of allergy and inflammation from mast cells and basophils under the influence of peptidoglycans and endotoxins of many bacteria, as well as a lectin-mediated mechanism;
6. synthesis of histamine by a hemophilic rod with the help of histidine-decarboxylase;
7. damage to the epithelium of the bronchi with loss of secretion of bronchorelaxing factors and production of proinflammatory mediators: interleukin-8, tumor necrosis factor, etc.

Pathogenesis of the glucocorticoid variant of bronchial asthma

Glucocorticoid insufficiency may be one of the causes of development or exacerbation of bronchial asthma. Glucocorticoid hormones have the following effect on the bronchial state:

• increase the number and sensitivity of beta-adrenergic receptors to adrenaline and, consequently, increase its bronchodilator effect;
• inhibit the degranulation of mast cells and basophils and the release of histamine, leukotrienes and other mediators of allergy and inflammation;
• are physiological antagonists of bronchoconstrictor substances, inhibit the production of endothelin-1, which has a bronchoconstrictor and pro-inflammatory effect, as well as causing subepithelial fibrosis;
• reduce the synthesis of receptors through which the bronchospastic action of substance P is carried out;
• activate the production of neutral endopeptidase, which destroys bradykinin and endothelin-1;
• inhibit the expression of adhesive molecules (ICAM-1, E-selectin);
• reduce the production of pro-inflammatory cytokines (interleukins lb, 2, 3, 4, 5, 6, 8, 12, 13, tumor necrosis factor a) and activate the synthesis of cytokines with anti-inflammatory effect (interleukin 10);
• inhibit the formation of metabolites of arachidonic acid - bronchoconstrictive prostaglandins;
• restore the structure of the damaged epithelium of the bronchi and suppress the secretion of bronchial epithelium of the inflammatory cytokine interleukin-8 and growth factors (platelet, insulin-like, fibroblast-activating, etc.).

In connection with the presence of the above properties, glucocorticoids inhibit the development of inflammation in the bronchi, reduce their hyperreactivity, have anti-allergic and anti-asthmatic effects. On the contrary, glucocorticoid insufficiency can in some cases underlie the development of bronchial asthma.

The following mechanisms are known for the formation of glucocorticoid insufficiency in bronchial asthma:

• violation of cortisol synthesis in the fascicle of the adrenal cortex under the influence of prolonged intoxication, hypoxia;
• violation of the ratio between the main glucocorticoid hormones (reduced cortisol synthesis and an increase in corticosterone, which has less pronounced anti-inflammatory properties than cortisol);
• increased cortisol binding to plasma transcortin and a decrease in its free, biologically active fraction;
• a decrease in the bronchi of the amount or sensitivity of membrane receptors to cortisol, which, naturally, reduces the effect of glucocorticoids on the bronchi (the state of cortisol-resistance);
• sensitization to hormones of the hypothalamic-pituitary-adrenal system with the production of IgE antibodies to ACTH and cortisol;
• an increase in the sensitivity threshold of the cells of the hypothalamus and pituitary gland to the regulating effect (by the feedback principle) of the level of cortisol in the blood, which, in the opinion of VI Trofimov (1996), at the initial stages of the disease leads to stimulation of the synthesis of glucocorticoids by the adrenal cortex, and with the progression of the bronchial asthma - depletion of the reserve capacity of the glucocorticoid function;
• suppression of glucocorticoid function of the adrenal glands due to prolonged treatment of patients with glucocorticoid drugs.

Glucocorticoid insufficiency contributes to the development of inflammation in the bronchi, their hyperreactivity and bronchospasm, leads to the formation of cortico-dependence (cortico-dependent bronchial asthma). Distinguish cortico-sensitive and cortico-resistant cortex-dependent bronchial asthma.

In cortico-sensitive bronchial asthma, small doses of systemic or inhaled glucocorticoids are required to achieve remission and maintain it. With corticore-resistant bronchial asthma, remission is achieved with large doses of systemic glucocorticoids. About corticosteroids should be considered when after a seven-day course of treatment with prednisolone at a dose of 20 mg / day FEV, increases less than 15% compared with the original.

Pathogenesis of the diszovarial form of bronchial asthma

It is now well known that many women experience a sharp deterioration in the course of bronchial asthma (the attacks of suffocation are renewed and worsen) before or during menstruation, sometimes in the last days of menstruation. The effect of progesterone and estrogens on the bronchial tonus and the state of bronchial patency is established:

• progesterone stimulates beta2-adrenergic receptors of the bronchi and the synthesis of prostaglandin E, which determines the bronchodilator effect;
• estrogens inhibit the activity of acetylcholinesterase, respectively, increase the level of acetylcholine, which stimulates the acetylcholine receptors of the bronchi and cause bronchospasm;
• estrogens stimulate the activity of goblet cells, bronchial mucosa and cause their hypertrophy, which leads to hyperproduction of mucus and impairment of bronchial patency;
• estrogens increase the release of histamine and other biological substances from eosinophils and basophils, which causes the appearance of bronchospasm;
• estrogens enhance the synthesis of PgF2a, which has a bronchoconstrictor effect;
• estrogens increase the connection with the transcortin plasma of cortisol and progesterone, which leads to a decrease in the free fraction of these hormones in the blood and, consequently, a decrease in their bronchodilator effect;
• Estrogens reduce the activity of beta-adrenergic receptors in the bronchi.

Thus, estrogens promote bronchoconstriction, progesterone - bronchodilation.

With disovarial pathogenetic variant of bronchial asthma, a decrease in blood level of progesterone in the II phase of the menstrual cycle and an increase in estrogen are observed. These hormonal changes lead to the development of bronchial hyperreactivity and bronchospasm.

Pathogenesis of pronounced adrenergic imbalance

Adrenergic imbalance is a violation of the ratio between the beta and alpha-adrenergic receptors of the bronchi with a predominance of alpha-adrenoreceptor activity, which causes the development of bronchospasm. In the pathogenesis of adrenergic imbalance, the blockade of alpha-adrenergic receptors and the increased sensitivity of alpha-adrenergic receptors are important. The development of adrenergic imbalance can be caused by the inborn inferiority of beta2-adrenoreceptors and the adenylate cyclase-3 ', 5'-cAMP system, their violation under the influence of viral infection, allergic sensitization, hypoxemia, changes in acid-base balance (acidosis), excessive use of sympathomimegics.

Pathogenesis of the neuro-psychic variant of bronchial asthma

About the neuropsychological pathogenetic variant of bronchial asthma can be said in the event that the neuropsychic factors are the cause of the disease, and also reliably contribute to its exacerbation and chronicization. Psychoemotional stresses affect the tone of the bronchi through the autonomic nervous system (the role of the autonomic nervous system in regulating bronchial tone). Under the influence of psychoemotional stress, the sensitivity of the bronchi to histamine and acetylcholine increases. In addition, emotional stress causes hyperventilation, stimulation of the irritative receptors of the bronchi by a sudden deep inhalation, coughing, laughing, crying, which leads to a reflex spasm of the bronchi.

A. Yu. Lototsky (1996) identifies 4 types of the neuropsychological mechanism of the pathogenesis of bronchial asthma: hysterical, neurasthenoid, psihastenopodobny, shunt.

In the hysterical variant, the development of an attack of bronchial asthma is a certain way to attract the attention of others and to get rid of a number of requirements, conditions, circumstances that the patient considers unpleasant and burdensome for himself.

With neurasthenopodobnom option formed internal conflict due to inconsistency of the patient's capabilities as a person and increased requirements for themselves (ie a kind of unattainable ideal). In this case, an attack of bronchial asthma becomes, as it were, an excuse for its failure.

The psychasthenic variant is characterized by the fact that an attack of bronchial asthma appears when necessary to take a serious, responsible decision. Patients are at the same time anxious, incapable of making independent decisions. The development of an asthma attack in this situation, as it were, relieves the patient from an extremely difficult and responsible situation for him.

Shunt version is typical for children and allows them to avoid confrontation with conflicts in the family. In the case of a quarrel between parents, the development of an asthma attack in a child leads the parents away from clarifying the relationship, as it switches their attention to a child's illness, which, at the same time, receives maximum attention and concern for itself.

Pathogenesis of holtergic variant

The cholinergic variant of bronchial asthma is a form of the disease that arises from the increased tone of the vagus nerve against the background of disorders of the cholinergic mediator exchange - acetylcholine. This pathogenetic variant is observed in approximately 10% of patients. At the same time, an increase in the level of acetylcholine and reduction of acetylcholinesterase, an enzyme that inactivates acetylcholine, is observed in the blood of patients; this is accompanied by an imbalance of the autonomic nervous system with a predominance of the tone of the vagus nerve. It should be noted that a high level of acetylcholine in the blood is observed in all patients with bronchial asthma in the period of exacerbation, but in patients with a cholinergic variant of the disease acetylcholinemia is much more pronounced, and the vegetative and biochemical status (including the level of acetylcholine in the blood) does not normalize even in the phase of remission .

In the cholinergic variant, the following important pathogenetic factors are also observed:

• increasing the sensitivity of effector receptors of the vagus nerve and cholinergic receptors to mediators of inflammation and allergies with the development of bronchial hyperreactivity;
• excitation of M1-cholinergic receptors, which improves the spread of the pulse along the reflex arc of the vagus nerve;
• reduction in the rate of inactivation of acetylcholine, its accumulation in blood and tissues, and overexcitation of the parasympathetic part of the autonomic nervous system;
• a decrease in the activity of M2-cholinergic receptors (normally they inhibit the release of acetylcholine from the branches of the vagus nerve), which contributes to bronchoconstriction;
• an increase in the number of cholinergic nerves in the bronchi;
• increased activity of cholinergic receptors in mast cells, mucous and serous cells of bronchial glands, which is accompanied by pronounced hypersensitivity - hypersecretion of bronchial mucus.

The pathogenesis of "aspirin" bronchial asthma

"Aspirin" bronchial asthma is a clinico-pathogenetic variant of bronchial asthma caused by intolerance to acetylsalicylic acid (aspirin) and other non-steroidal anti-inflammatory drugs. The incidence of aspirin asthma among patients with bronchial asthma ranges from 9.7 to 30%.

At the heart of "aspirin" asthma is a violation of the metabolism of arachidonic acid under the influence of aspirin and other non-steroidal anti-inflammatory drugs. After they are taken from arachidonic acid, the cell membranes, due to the activation of the 5-lipoxygenase pathway, form leukotrienes, which cause bronchospasm. Simultaneously, the cyclooxygenase pathway of arachidonic acid metabolism is inhibited, which leads to a decrease in the formation of PgE (dilates the bronchi) and an increase in PgF2 (narrowing the bronchi). "Aspirin" asthma is caused by aspirin, non-steroidal anti-inflammatory drugs (indomethacin, brufen, voltaren, etc.), baralgin, other medicines containing acetylsalicylic acid (theofedrine, citramone, asphene, ascophene), as well as products containing salicylic acid (cucumbers, citrus fruits, tomatoes, various berries) or yellow dyes (tartrazine).

There is also a significant role of platelets in the development of "aspirin asthma." In patients with "aspirin" asthma, there is an increased activity of platelets, which is aggravated in the presence of acetylsalicylic acid.

Activation of platelets is accompanied by increased aggregation, an increase in the secretion of serotonin and thromboxane from them. Both these substances cause the development of bronchospasm. Under the influence of excess serotonin secretion of bronchial glands and edema of the bronchial mucosa increase, which contributes to the development of bronchial obstruction.

Primarily altered bronchial reactivity

Primarily altered bronchial reactivity is a clinico-pathogenetic variant of bronchial asthma that does not belong to the above variants and is characterized by the appearance of asthma attacks during physical exertion, inhalation of cold air, weather change, and sharp odors.

As a rule, the attack of bronchial asthma, which occurs when breathing in cold air, irritating and sharply smelling substances, is caused by the excitation of extremely reactive, irritative receptors. In the development of hyperreactivity of bronchi, the increase in interepithelial spaces is of great importance, which facilitates the passage through them of various chemical stimuli from the air, causing degranulation of mast cells, the release of histamine, leukotrienes and other bronchospastic substances.

Pathogenesis of asthma physical effort

Asthma of physical effort is a clinico-pathogenetic variant of bronchial asthma, characterized by the appearance of asthma attacks under the influence of submaximal exercise; while there are no signs of allergies, infections, or disorders of the endocrine and nervous system. VI Pytsky and co-authors. (1999) indicate that it is more correct to speak not about asthma of physical effort, but about "postnagruzochnom bronchospasm", because this variant of bronchial obstruction is rarely found in isolation and is observed, as a rule, not at the time, but after the end of physical activity.

The main pathogenetic factors of asthma physical effort are:

• hyperventilation during exercise; due to hyperventilation, respiratory loss of heat and fluid occurs, cooling of the bronchial mucosa, hyperosmolarity of the bronchial secretions develops; there is also a mechanical irritation of the bronchi;
• irritation of the receptors of the vagus nerve and increase of its tone, development of bronchoconstriction;
• degranulation of mast cells and basophils with release of mediators (histamine, leukotrienes, chemotactic factors and others) that cause spasm and inflammation of the bronchi.

Along with these bronchoconstrictor mechanisms, the bronchodilating mechanism also functions - the activation of the sympathetic nervous system and adrenaline rush. According to S.Godfrey (1984), physical activity has two opposite actions aimed at the smooth muscles of the bronchi: bronchial dilatation as a result of activation of the sympathetic nervous system and hyperkatecholamineemia and narrowing of the bronchi as a result of ejection of mediators from mast cells and basophils. During exercise, sympathetic bronchodilator effects predominate. However, the bronchodilator effect is short - 1-5 min, and soon after the end of the load the action of mediators acts on the foreground, and bronchospasm develops. Approximately after 15-20 min, the mediators are inactivated.

With the release of mediators, mast cells dramatically reduce their ability to further isolate them - the refractoriness of mast cells begins. The half-life of recovery of mast cells to the synthesis of half the number of mediators in them is about 45 minutes, and the complete disappearance of refractoriness occurs 3-4 hours later.

Pathogenesis of an autoimmune variant of bronchial asthma

Autoimmune bronchial asthma is a form of the disease that develops as a result of sensitization to the antigens of the bronchopulmonary system. As a rule, this variant is a stage of further progression and aggravation of the course of allergic and infectious-dependent bronchial asthma. Pathogenetic mechanisms of these forms are joined by autoimmune reactions. With autoimmune bronchial asthma, antibodies (anti-nuclear, anti-pulmonary, smooth muscles of the bronchi, and beta-adrenergic receptors of the bronchi muscles) are detected. The formation of immune complexes (autoantigen + autoanthinol) with complement activation leads to immunocomplex bronchial damage (type III allergic reaction for Cell and Coombs) and beta-adrenergic blockade.

It is also possible to develop type IV allergic reactions - the interaction of the allergen (autoantigen) and sensitized T-lymphocytes secreting the lymphokines with the development of, ultimately, inflammation and spasm of the bronchi.

Mechanisms of bronchospasm

The musculature of the bronchi is represented by smooth muscle fibers. In myofibrils, the protein bodies actin and myosin are present; when they interact with each other and form an actin + myosin complex, the bronchial myofibrils-bronchospasm-are reduced. The formation of the actin + myosin complex is possible only in the presence of calcium ions. In muscle cells there is a so-called "calcium pump", which allows the movement of Ca ⁺⁺ ions from myofibrils into the sarcoplasmic reticulum, which leads to the expansion (relaxation) of the bronchus. The work of the "calcium pump" is regulated by the concentration of two intracellular nucleotides acting antagonistically:

• cyclic adenosine monophosphate (cAMP), which stimulates the reverse intake of Ca ⁺⁺ ions from myofibrils into the sarcoplasmic reticulum and the connection with it, as a result of inhibition of calmodulin activity, the actin + myosin complex can not form, and bronchial relaxation occurs;
• cyclic guanosine monophosphate (cGMP), which inhibits the work of the "calcium pump" and the return of Ca ⁺⁺ ions from myofibrils to the sarcoplasmic reticulum, while the activity of calmodulin increases, Ca ⁺⁺ enters the actin and myosin, the actin + myosin complex forms, and the bronchus is reduced.

Thus, the tone of the bronchial musculature depends on the state of cAMP and cGMP. This ratio is regulated by neurotransmitters (neurotransmitters) of the autonomic nervous system, the activity of the corresponding receptors on the membrane of smooth muscle cells of the bronchi and the enzymes adenylate cyclase and guanylate cyclase, which stimulate respectively the formation of cAMP and cGMP.

The role of the autonomic nervous system in the regulation of bronchial tonus and the development of bronchospasm

In the regulation of bronchial tonus and the development of bronchospasm, the following parts of the autonomic nervous system play an important role:

• cholinergic (parasympathetic) nervous system;
• adrenergic (sympathetic) nervous system;
• non-adrenergic noncholinergic nervous system (NANH).

The role of the cholinergic (parasympathetic) nervous system

The wandering nerve plays a big role in the development of bronchospasm. At the endings of the vagus nerve, the neurotransmitter acetylcholine is released, which interacts with the corresponding cholinergic (muscarinic) receptors, guanylate cyclase is activated, and smooth muscle contraction occurs, and bronchoconstriction develops (the mechanism described above). The bronchoconstriction caused by the vagus nerve is of the greatest importance for the large bronchi.

The role of the adrenergic (sympathetic) nervous system

It is known that in a person sympathetic nerve fibers are not determined in the smooth muscles of the bronchi, their fibers are detected in the vessels and glands of the bronchi. The neurotransmitter adrenergic (sympathetic) nerves is norepinephrine, formed in adrenergic synapses. Adrenergic nerves do not directly control the smooth musculature of the bronchi. It is generally believed that the catecholamines circulating in the blood - adrenomimetics (norepinephrine and epinephrine formed in the adrenal glands) play an important role in regulating bronchial tone.

They exert their influence on the bronchi through the alpha and beta adrenoreceptors.

Activation of alpha-adrenergic receptors causes the following effects:

• reduction of smooth muscles of the bronchi;
• reduction of hyperemia and edema of the bronchial mucosa;
• reduction of blood vessels.

Activation of beta2-adrenergic receptors leads to:

• relaxation of the smooth muscles of the bronchi (through an increase in the activity of adenylate cyclase and an increase in cAMP production, as indicated above);
• increased mucociliary clearance;
• the expansion of blood vessels.

Along with the important role of adrenergic mediators in bronchial dilatation, the adrenergic nervous system has an important role in inhibiting the presynaptic secretion of acetylcholine and thereby preventing vagal (cholinergic) contraction of the bronchus.

Role of non-adrenergic neuhinergic nervous system

In bronchi, along with the cholinergic (parasympathetic) and adrenergic (sympathetic) nervous system, there is a non-adrenergic non-cholinergic nervous system (NANH) that is part of the autonomic nervous system. Fibers of NANH nerves pass in the vagus nerve and release a number of neurotransmitters, which influence through the activation of the corresponding receptors on the tonus of the bronchial musculature.

Bronchial receptors	Effect on the smooth muscles of the bronchi
Receptors for stretching (excited with a deep breath)	Bronchodilation
Irritation receptors (mainly in large bronchi)	Bronchoconstriction
Cholinergic receptors	Bronchoconstriction
Beta2-adrenergic receptors	Bronchodilation
Alpha-adrenergic receptors	Bronchoconstriction
H1-histamine receptors	Bronchoconstriction
VIP receptors	Bronchodilation
Peptide-histidine-methionine receptors	Bronchodilation
Neuropeptide P receptors	Bronchoconstriction
Neurokinin A receptors	Bronchoconstriction
Neurokinin B receptors	Bronchoconstriction
Receptors for calcitonin-like peptides	Bronchoconstriction
Leukotriene Receptors	Bronchoconstriction
PgD2 and PgF2a receptors	Bronchoconstriction
PgE receptors	Bronchodilation
FAT receptors (receptors for the factor activating platelets)	Bronchoconstriction
Serotonergic receptors	Bronchoconstriction
Adenosine receptors of the first type	Bronchoconstriction
Adenosine receptors of the second type	Bronchodilation

It can be seen from the table that the most important bronchodilator mediator of the NANH system is the vasoacchial intestinal polypeptide (VIP). The bronchodilating effect of VIP is realized by raising the level of cAMP. Murray (1997) and Gross (1993) impair the regulation at the level of the NANH system the most important in the development of bronchial obstruction syndrome.