Pathogenesis of bronchial asthma

According to modern concepts, 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, thickening of the basement membrane and subsequent development of subepithelial fibrosis. As a result of these inflammatory changes, bronchial hyperreactivity and broncho-obstructive syndrome develop.

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

In the pathogenesis of allergic bronchial asthma, 4 phases are distinguished: immunological, pathochemical, pathophysiological and conditioned reflex.

In the immunological phase, under the influence of an allergen, B-lymphocytes secrete specific antibodies, mainly belonging to the IgE class (reagin antibodies). This occurs as follows.

An allergen that has entered the respiratory tract is captured by a macrophage, processed (split into fragments), bound to class II glycoproteins of the major histocompatibility complex (HLA) and transported to the cell surface of the macrophage. The described events are called processing. Then the complex "antigen + HLA class II molecules" is presented to T-helper lymphocytes (allergen-specific). After this, a subpopulation of T-helpers (Th2) is activated, which produces a number of cytokines involved in the implementation of a type I allergic reaction:

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

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

The resulting IgE and IgG4 are fixed on the surface of target cells of the I allergy (mast cells and basophils) and II order (eosinophils, neutrophils, macrophages, thrombocytes) using cellular Fc receptors. The majority of mast cells and basophils are located in the submucosal layer. When stimulated by an allergen, their number increases 10-fold.

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

The immunochemical (pathochemical) stage is characterized by the fact that when the allergen enters the patient's body again, it interacts with reagin antibodies (primarily IgE) on the surface of the allergy target cells. This results in degranulation of mast cells and basophils, activation of eosinophils with the release of a large number of allergy and inflammation mediators, which cause the development of the pathophysiological stage of pathogenesis.

The pathophysiological stage of bronchial asthma is characterized by the development of bronchospasm, mucosal edema and infiltration of the bronchial wall by cellular elements, inflammation, and hypersecretion of mucus. All these manifestations of the pathophysiological stage are caused by the impact of allergy and inflammation mediators that are secreted by mast cells, basophils, eosinophils, thrombocytes, 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, pronounced expiratory dyspnea. This phase begins after 1-2 minutes, reaches its maximum after 15-20 minutes and lasts for about 2 hours. The main cells involved in the development of the early asthmatic reaction are mast cells and basophils. During the degranulation of these cells, a large number of biologically active substances are released - mediators of allergy and inflammation.

Mast cells secrete histamine, leukotrienes (LTC4, LTD4, LTE4), prostaglandin D, and various proteolytic enzymes. In addition to these mediators, mast cells also secrete interleukins 3, 4, 5, 6, 7, 8, neutrophil and eosinophil chemotactic factors, platelet-activating factor, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor.

Degranulation of basophils is accompanied by the release of histamine, leukotriene LTD4, eosinophil and neutrophil chemotactic factors, platelet-activating factor, leukotriene B (causes neutrophil chemotaxis), heparin, and kallikrein (breaks down kininogen to form bradykinin).

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

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

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

• basic protein - activates mast cells, damages bronchial epithelium;
• cationic protein - activates mast cells, damages bronchial epithelium;
• eosinophil protein X - has a neurotoxic effect, inhibits lymphocyte culture;
• platelet-activating factor - causes spasm of the bronchi and blood vessels, swelling of the bronchial mucosa, hypersecretion of mucus, increases platelet aggregation and induces the release of serotonin, activates neutrophils and mast cells, and contributes to microcirculation disorders;
• leukotriene C4 - causes spasm of the bronchi and blood vessels, increases vascular permeability;
• prostaglandin D2 and F2a - cause bronchospasm, increased vascular permeability and platelet aggregation;
• prostaglandin E2 - causes vasodilation, hypersecretion of mucus, inhibits inflammatory cells;
• thromboxane A2 - causes spasm of the bronchi and blood vessels, increases platelet aggregation;
• chemotactic factor - causes chemotaxis of eosinophils;
• cytokines - granulocyte-macrophage colony-stimulating factor (activates inflammatory cells, promotes differentiation of granulocytes); interleukin-3 (activates inflammatory cells and differentiation of granulocytes); interleukin-8 (activates chemotaxis and degranulation of fanulocytes);
• proteolytic enzymes (arylsulfatase, beta-glucuronidase - cause hydrolysis of glycosaminoglycans and glucuronic acid, collagenase - causes hydrolysis of collagen);
• peroxidase - activates mast cells.

Biologically active substances secreted by eosinophils contribute to the development of bronchial spasm, severe inflammatory process in them, damage to the bronchial epithelium, disruption of microcirculation, hypersecretion of mucus, and the development of bronchial hyperreactivity.

Alveolar and bronchial macrophages play a major role in the development of early and late asthmatic reactions. As a result of contact between allergens and Fc receptors of macrophages, they are activated, which leads to the production of mediators - platelet-activating factor, leukotrienes B4 (in small quantities C4 and D4), 5-HETE (5-hydroxyeicosotetraenoic acid - a product of lipoxygenase oxidation of arachidonic acid), lysosomal enzymes, neutral proteases, beta-glucuronidase, PgD 2.

In recent years, it has been established that cell adhesion to the endothelium plays a major role in the mechanism of attracting eosinophils and other inflammatory cells to the bronchi. The adhesion process is associated with the appearance of adhesion molecules (E-selectin and intracellular ICAM-1) on endothelial cells, and corresponding receptors for adhesive molecules on eosinophils and other inflammatory cells. 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.

It is now known that the bronchial epithelium itself plays a major role in the development of inflammation in the bronchus and bronchospasm. The bronchial epithelium secretes proinflammatory cytokines that promote the entry of inflammatory cells into the bronchus and activate T-lymphocytes and monocytes involved in the development of immune inflammation. In addition, the bronchial epithelium (like the endothelium) produces endothelium, which has a broncho- and vasoconstrictor effect. Along with this, the bronchial epithelium produces nitrogen oxide (NO), which has a bronchodilator effect and functionally balances the action of numerous bronchoconstrictor factors. This is probably why the amount of NO significantly increases in the air exhaled by a 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 the IgE antibody class (IgE-dependent bronchial asthma). However, according to V. I. Pytskiy and A. A. Goryachkina (1987), 35% of patients with bronchial asthma have increased 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 attacks, and lower effectiveness of the treatment measures.

Less often, the leading role in the pathogenesis of allergic bronchial asthma is played by the allergic reaction of Shtip (immune complex type). In this case, antibodies are formed, belonging mainly to immunoglobulins of class G and M. Then, an antigen-antibody complex is formed, the pathophysiological effect of which is realized through the activation of complement, the release of lysosomal prageolytic enzymes and mediators from macrophages, neutrophils, platelets, activation of the kinin and coagulation systems. The consequence of these processes is bronchospasm and the development of edema and inflammation of the bronchus.

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

Nitric oxide (NO) is an endothelial relaxing factor and by activating guanylate cyclase and synthesizing cGMP causes relaxation of vascular smooth muscles and, consequently, their dilation. Nitric oxide is formed from the amino acid arginine under the influence of the enzyme NO synthetase (NOS). There are two isoforms of NO synthetase - constitutive (cNOS) and inducible (iNOS). Constitutive NOS (cNOS) is located 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, promotes the synthesis of large amounts of NO for a long time. It is formed in inflammatory cells in response to endotoxins and cytokines.

It is now known that NO synthase is present in neurons, endothelial cells, hepatocytes, Kupffer cells, fibroblasts, smooth myocytes, neutrophils, and macrophages.

In the lungs, NO is synthesized under the influence of cNOS in the endothelial cells of the pulmonary artery and vein, in 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, and bronchial epithelial cells.

NO in the bronchopulmonary system plays the following positive role:

• promotes vasodilation in the pulmonary circulation, therefore, increasing NO production counteracts the development of pulmonary hypertension in chronic obstructive pulmonary disease;
• increased NO production promotes bronchodilation and improves the function of the bronchial ciliated epithelium; NO is considered a neurotransmitter of bronchodilator nerves, counteracting the influence of bronchoconstrictor nerves;
• participates in the destruction of microorganisms and tumor cells;
• reduces the activity of inflammatory cells, inhibits platelet aggregation, 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 nitric oxide produced under the influence of iNOS interacts with the product of partial oxygen reduction accumulated in the inflammation site - superoxide. As a result of such interaction, the mediator peroxynitrite is formed, which causes damage to cells, proteins, lipids of cell membranes, damages the vascular epithelium, increases platelet aggregation, stimulates the inflammatory process in the bronchopulmonary system.

In bronchial asthma, iNOS activity increases, NO content in the bronchial epithelium increases, and the concentration of NO in exhaled air increases. Intensive NO synthesis 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.

Elevated levels of nitric oxide in exhaled air are a biological marker of bronchial asthma.

Pathogenesis of infection-dependent bronchial asthma

In the report "Bronchial asthma. Global strategy. Treatment and prevention" (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 occurrence or exacerbation of bronchial asthma. Along with this, the leading specialist in the field of bronchial asthma, Professor G. B. Fedoseyev, suggests distinguishing a separate clinical and pathogenetic variant of the disease - infection-dependent bronchial asthma. This is justified, first of all, from a practical point of view, since quite often not only the first clinical manifestations or exacerbations of bronchial asthma are associated with the influence of infection, but also a significant improvement in the condition of patients occurs after exposure to the infectious agent.

The following mechanisms are involved in the pathogenesis of the infection-dependent variant of bronchial asthma:

1. delayed-type hypersensitivity, the main role in the development of which belongs to T-lymphocytes. With repeated contacts with an infectious allergen, they become hypersensitized and lead to the release of slow-acting mediators: neutrophil chemotactic factors, eosinophils, lymphotoxin, platelet aggregation factor. Delayed-action mediators cause the release of prostaglandins (PgD2, F2a, leukotrienes (LTC4, LTD4, LTK4), etc. in target cells (mast cells, basophils, macrophages), which results in bronchospasm. In addition, an inflammatory infiltrate containing neutrophils, lymphocytes, and eosinophils is formed around the bronchus. This infiltrate is a source of immediate-type mediators (leukotrienes, gastamine), which cause bronchial spasm and inflammation. Proteins that directly damage the ciliated epithelium of the bronchi are also released from eosinophil granules, which complicates the evacuation of sputum;
2. an immediate-type allergic reaction with the formation of IgE reagin (similar to atopic asthma). It develops rarely, in the early stages of infection-dependent bronchial asthma, mainly with fungal and neisserial asthma, as well as with respiratory syncytial infection, pneumococcal and hemophilic bacterial infection;
3. non-immunological reactions - damage to the adrenal glands by toxins and a decrease in glucocorticoid function, disruption of the function of the ciliated epithelium and a decrease in the activity of beta2-adrenergic receptors;
4. activation of complement via the alternative and classical pathways with the release of C3 and C5 components, which cause the release of other mediators by mast cells (in pneumococcal infection);
5. release of histamine and other mediators of allergy and inflammation from mast cells and basophils under the influence of peptide glycans and endotoxins of many bacteria, as well as by a lectin-mediated mechanism;
6. synthesis of histamine by Haemophilus influenzae using histidine decarboxylase;
7. damage to the bronchial epithelium with loss of secretion of bronchodilator factors and production of proinflammatory mediators: interleukin-8, tumor necrosis factor, etc.

Pathogenesis of glucocorticoid variant of bronchial asthma

Glucocorticoid deficiency may be one of the reasons for the development or exacerbation of bronchial asthma. Glucocorticoid hormones have the following effect on the condition of the bronchi:

• increase the number and sensitivity of beta-adrenergic receptors to adrenaline and, consequently, increase its bronchodilating 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 proinflammatory effect, and also causes the development of subepithelial fibrosis;
• reduce the synthesis of receptors through which the bronchoconstrictive effect of substance P is carried out;
• activate the production of neutral endopeptidase, which destroys bradykinin and endothelin-1;
• inhibit the expression of adhesion molecules (ICAM-1, E-selectin);
• reduce the production of proinflammatory cytokines (interleukins 1b, 2, 3, 4, 5, 6, 8, 12, 13, tumor necrosis factor a) and activate the synthesis of cytokines that have an anti-inflammatory effect (interleukin 10);
• inhibit the formation of arachidonic acid metabolites - bronchoconstrictor prostaglandins;
• restore the structure of damaged bronchial epithelium and suppress the secretion of the inflammatory cytokine interleukin-8 and growth factors (platelet, insulin-like, fibroblast-activating, etc.) by the bronchial epithelium.

Due to the above properties, glucocorticoids inhibit the development of inflammation in the bronchi, reduce their hyperreactivity, and have an antiallergic and antiasthmatic effect. On the contrary, glucocorticoid deficiency may in some cases underlie the development of bronchial asthma.

The following mechanisms of formation of glucocorticoid deficiency in bronchial asthma are known:

• disruption of cortisol synthesis in the fascicular zone of the adrenal cortex under the influence of prolonged intoxication and hypoxia;
• disruption of the ratio between the main glucocorticoid hormones (decrease in the synthesis of cortisol and increase in corticosterone, which has less pronounced anti-inflammatory properties compared to cortisol);
• increased binding of cortisol to plasma transcortin and, thus, a decrease in its free, biologically active fraction;
• a decrease in the number or sensitivity of membrane receptors to cortisol in the bronchi, which naturally reduces the effect of glucocorticoids on the bronchi (a 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 hypothalamus and pituitary gland cells to the regulatory effect (according to the feedback principle) of the level of cortisol in the blood, which, according to V. I. 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 bronchial asthma - to the depletion of the reserve capacity of the glucocorticoid function;
• suppression of glucocorticoid function of the adrenal glands due to long-term treatment of patients with glucocorticoid drugs.

Glucocorticoid deficiency promotes the development of inflammation in the bronchi, their hyperreactivity and bronchospasm, leading to the formation of corticosteroid dependence (corticosteroid-dependent bronchial asthma). A distinction is made between corticosteroid-sensitive and corticosteroid-resistant corticosteroid-dependent bronchial asthma.

In corticosensitive bronchial asthma, low doses of systemic or inhaled glucocorticoids are required to achieve and maintain remission. In corticoresistant bronchial asthma, remission is achieved with high doses of systemic glucocorticoids. Corticoresistant asthma should be considered when, after a seven-day course of treatment with prednisolone at a dose of 20 mg/day, FEV increases by less than 15% compared to the initial value.

Pathogenesis of dysovarian form of bronchial asthma

It is now well known that many women experience a sharp worsening of bronchial asthma (asphyxiation attacks recur and worsen) before or during menstruation, sometimes in the last days of menstruation. The influence of progesterone and estrogens on bronchial tone and the state of bronchial patency has been established:

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

Thus, estrogens promote bronchoconstriction, progesterone promotes bronchodilation.

In the dysovarial pathogenetic variant of bronchial asthma, a decrease in the blood level of progesterone in the second phase of the menstrual cycle and an increase in estrogen are observed. The indicated hormonal shifts lead to the development of bronchial hyperreactivity and bronchospasm.

Pathogenesis of severe adrenergic imbalance

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

Pathogenesis of the neuropsychic variant of bronchial asthma

A neuropsychiatric pathogenetic variant of bronchial asthma can be discussed if neuropsychiatric factors are the cause of the disease and also reliably contribute to its exacerbation and chronicity. Psychoemotional stresses affect the tone of the bronchi through the autonomic nervous system (on the role of the autonomic nervous system in the regulation of 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 irritative receptors of the bronchi by a sudden deep breath, coughing, laughing, crying, which leads to a reflex spasm of the bronchi.

A. Yu. Lototsky (1996) identifies 4 types of neuropsychic mechanism of pathogenesis of bronchial asthma: hysterical-like, neurasthenic-like, psychasthenic-like, 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 free oneself from a number of demands, conditions, and circumstances that the patient considers unpleasant and burdensome for himself.

In the neurasthenic variant, an internal conflict is formed due to the discrepancy between the patient's capabilities as an individual and the increased demands on himself (i.e., a kind of unattainable ideal). In this case, an attack of bronchial asthma becomes a kind of justification for one's failure.

The psychasthenic variant is characterized by the fact that an attack of bronchial asthma occurs when it is necessary to make a serious, responsible decision. Patients are anxious and incapable of making independent decisions. The development of an asthma attack in this situation seems to relieve the patient from an extremely difficult and responsible situation for him.

The shunt variant is typical for children and allows them to avoid confrontation with conflicts in the family. When parents quarrel, the development of an asthma attack in a child distracts the parents from clarifying the relationship, as it switches their attention to the child's illness, who at the same time receives maximum attention and care for himself.

Pathogenesis of the holtergic variant

The cholinergic variant of bronchial asthma is a form of the disease that occurs due to increased tone of the vagus nerve against the background of metabolic disorders of the cholinergic mediator - acetylcholine. This pathogenetic variant is observed in approximately 10% of patients. In this case, an increase in the level of acetylcholine and a decrease in 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 during an exacerbation, but in patients with the cholinergic variant of the disease, acetylcholineemia is much more pronounced, and the vegetative and biochemical status (including the level of acetylcholine in the blood) does not normalize even in the remission phase.

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

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

Pathogenesis of "aspirin" bronchial asthma

"Aspirin" bronchial asthma is a clinical and 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%.

The basis of "aspirin" asthma is a disorder of arachidonic acid metabolism under the influence of aspirin and other non-steroidal anti-inflammatory drugs. After their administration, leukotrienes are formed from the arachidonic acid of the cell membrane due to the activation of the 5-lipoxygenase pathway, causing bronchospasm. At the same time, the cyclooxygenase pathway of arachidonic acid metabolism is suppressed, which leads to a decrease in the formation of PgE (expands the bronchi) and an increase in PgF2 (constricts the bronchi). "Aspirin" asthma is caused by aspirin, non-steroidal anti-inflammatory drugs (indomethacin, brufen, voltaren, etc.), baralgin, other medications that contain acetylsalicylic acid (theophedrine, citramon, asfen, askofen), as well as products containing salicylic acid (cucumbers, citrus fruits, tomatoes, various berries) or yellow dyes (tartrazine).

The major role of platelets in the development of "aspirin asthma" has also been established. Patients with "aspirin" asthma have increased platelet activity, which is aggravated by the presence of acetylsalicylic acid.

Activation of platelets is accompanied by their increased aggregation, increased release of serotonin and thromboxane from them. Both of these substances cause the development of bronchial spasm. 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.

Primary altered bronchial reactivity

Primary altered bronchial reactivity is a clinical and pathogenetic variant of bronchial asthma that does not relate to the above-mentioned variants and is characterized by the appearance of asthma attacks during physical exertion, inhalation of cold air, changes in weather, and from strong odors.

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

Pathogenesis of exercise-induced asthma

Exercise-induced asthma is a clinical and pathogenetic variant of bronchial asthma characterized by the occurrence of asthma attacks under the influence of submaximal physical exertion; in this case, there are no signs of allergy, infection, or dysfunction of the endocrine and nervous systems. V. I. Pytsky et al. (1999) indicate that it is more correct to speak not of exercise-induced asthma, but of "post-exertional bronchospasm", because this variant of broncho-obstruction rarely occurs in isolation and is observed, as a rule, not during, but after the end of physical exertion.

The main pathogenetic factors of exercise-induced asthma are:

• hyperventilation during physical exertion; as a result of hyperventilation, respiratory heat and fluid loss occur, the bronchial mucosa cools, hyperosmolarity of bronchial secretions develops; mechanical irritation of the bronchi also occurs;
• irritation of the vagus nerve receptors and an increase in its tone, development of bronchoconstriction;
• degranulation of mast cells and basophils with the release of mediators (histamine, leukotrienes, chemotactic factors and others), causing spasm and inflammation of the bronchi.

Along with the above mentioned bronchoconstrictor mechanisms, a bronchodilating mechanism also functions - activation of the sympathetic nervous system and release of adrenaline. According to S. Godfrey (1984), physical activity has two opposite effects directed at the smooth muscles of the bronchi: dilation of the bronchi as a result of activation of the sympathetic nervous system and hypercatecholaminemia and constriction of the bronchi as a result of release of mediators from mast cells and basophils. During physical activity, sympathetic bronchodilating effects predominate. However, the bronchodilating effect is short-lived - 1-5 minutes, and soon after the end of the load, the action of mediators comes to the fore, and bronchospasm develops. Inactivation of mediators occurs approximately after 15-20 minutes.

When mediators are released, mast cells sharply reduce their ability to further release them - mast cell refractoriness sets in. The half-life of mast cells to synthesize half the amount of mediators in them is about 45 minutes, and the complete disappearance of refractoriness occurs after 3-4 hours.

Pathogenesis of the autoimmune variant of bronchial asthma

Autoimmune bronchial asthma is a form of the disease that develops as a result of sensitization to antigens of the bronchopulmonary system. As a rule, this variant is a stage of further progression and aggravation of the course of allergic and infection-dependent bronchial asthma. Autoimmune reactions are added to the pathogenetic mechanisms of these forms. In autoimmune bronchial asthma, antibodies are detected (antinuclear, antipulmonary, to the smooth muscles of the bronchi, to the beta-adrenergic receptors of the bronchial muscles). The formation of immune complexes (autoantigen + autoantibody) with activation of complement lead to immune complex damage to the bronchi (type III allergic reaction according to Cell and Coombs) and beta-adrenergic blockade.

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

Mechanisms of bronchospasm

The bronchial musculature is represented by smooth muscle fibers. Myofibrils contain protein bodies actin and myosin; when they interact with each other and form an actin+myosin complex, bronchial myofibrils contract - bronchospasm. Formation of the actin+myosin complex is possible only in the presence of calcium ions. Muscle cells contain the so-called "calcium pump", due to which Ca ⁺⁺ ions can move from myofibrils to the sarcoplasmic reticulum, which leads to expansion (relaxation) of the bronchus. The work of the "calcium pump" is regulated by the concentration of two intracellular nucleotides that act antagonistically:

• cyclic adenosine monophosphate (cAMP), which stimulates the reverse flow of Ca ⁺⁺ ions from myofibrils into the sarcoplasmic reticulum and connection with it, as a result of which the activity of calmodulin is inhibited, the actin+myosin complex cannot be formed, and relaxation of the bronchus 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, the flow of Ca ⁺⁺ to actin and myosin increases, the actin+myosin complex is formed, and the bronchus contracts.

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

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

The following parts of the autonomic nervous system play a major role in regulating bronchial tone and the development of bronchospasm:

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

The role of the cholinergic (parasympathetic) nervous system

The vagus nerve plays a major role in the development of bronchospasm. The neurotransmitter acetylcholine is released at the endings of the vagus nerve, which interacts with the corresponding cholinergic (muscarinic) receptors, guanylate cyclase is activated, and smooth muscles contract, and bronchospasm develops (the mechanism is described above). Bronchoconstriction caused by the vagus nerve is of greatest importance for large bronchi.

The role of the adrenergic (sympathetic) nervous system

It is known that in humans, sympathetic nerve fibers are not found in the smooth muscles of the bronchi, their fibers are found in the vessels and glands of the bronchi. The neurotransmitter of adrenergic (sympathetic) nerves is norepinephrine, formed in adrenergic synapses. Adrenergic nerves do not directly control the smooth muscles of the bronchi. It is generally accepted that catecholamines circulating in the blood - adrenomimetics (norepinephrine and adrenaline formed in the adrenal glands) play a significant role in the regulation of bronchial tone.

They exert their influence on the bronchi through alpha- and beta-adrenergic receptors.

Activation of alpha-adrenergic receptors causes the following effects:

• contraction of the smooth muscles of the bronchi;
• reduction of hyperemia and swelling of the bronchial mucosa;
• constriction of blood vessels.

Activation of beta2-adrenergic receptors leads to:

• relaxation of bronchial smooth muscles (through increased adenylate cyclase activity and increased cAMP formation, as indicated above);
• increase in mucociliary clearance;
• dilation of blood vessels.

Along with the important role of adrenergic mediators in bronchial dilation, the property of the adrenergic nervous system to inhibit the presynaptic release of acetylcholine and thereby prevent vagal (cholinergic) contraction of the bronchus is of great importance.

The role of the non-adrenergic non-cholinergic nervous system

In the bronchi, along with the cholinergic (parasympathetic) and adrenergic (sympathetic) nervous systems, there is a non-adrenergic non-cholinergic nervous system (NANC), which is part of the autonomic nervous system. The fibers of the NANC nerves pass through the vagus nerve and release a number of neurotransmitters that affect the tone of the bronchial muscles through the activation of the corresponding receptors.

Receptors of the bronchi	Effect on bronchial smooth muscle
Stretch receptors (activated by deep inhalation)	Bronchodilation
Irritant 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
Calcitonin-like peptide receptors	Bronchoconstriction
Leukotriene receptors	Bronchoconstriction
PgD2- and PgF2a-receptors	Bronchoconstriction
PgE receptors	Bronchodilation
PAF receptors (platelet-activating factor receptors)	Bronchoconstriction
Serotonergic receptors	Bronchoconstriction
Adenosine receptors type I	Bronchoconstriction
Adenosine receptors type II	Bronchodilation

The table shows that the most important bronchodilating mediator of the NANH system is vasoactive intestinal polypeptide (VIP). The bronchodilating effect of VIP is achieved by increasing the level of cAMP. Murray (1997) and Gross (1993) attribute the most important significance to the disruption of regulation at the level of the NANH system in the development of bronchial obstruction syndrome.