Disease progression and the role of inflammation
The pathogenesis of bronchial asthma is based on a chronic inflammatory process. Persistent inflammation causes damage to the airway epithelium. As a result, bronchial hyperreactivity develops—an abnormally high sensitivity to various stimuli.
The pathological cascade in the bronchial wall includes several consecutive stages:
- Vasodilation and increased vascular permeability.
- Development of pronounced mucosal edema.
- Migration of leukocytes (predominantly eosinophils) into the bronchial tissue.
- Release of specific "eosinophilic proteins" by activated eosinophils, which exert a cytotoxic effect and further destroy the epithelial layer.
Immunological phase: how sensitization occurs
The disease develops via an immediate-type hypersensitivity mechanism. Initial contact with the antigen triggers a complex cellular cascade:
- A macrophage captures and presents the foreign antigen.
- With the participation of interleukin-1 (IL-1), T-helper cells are activated and differentiate into Th2 cells.
- T-helper cells and macrophages begin to secrete regulatory cytokines. IL-3 stimulates mast cell proliferation, while IL-5 increases the eosinophil population.
- A key role is played by interleukin-4 (IL-4). It induces B lymphocytes to differentiate into plasma cells and synthesize class E immunoglobulins (IgE).
- Free IgE immunoglobulins circulate in the blood and bind to high-affinity receptors (FcεRI) on the membranes of mast cells. This is how the body becomes sensitized.
Pathochemical phase: degranulation and mediators
When the antigen re-enters the body, it binds to IgE molecules already fixed on mast cells. This leads to cell activation and its degranulation—the massive release of preformed biologically active substances into the extracellular space.
In parallel, arachidonic acid metabolism is initiated inside the mast cell. The enzyme phospholipase A2 cleaves it from cell membrane phospholipids, after which the process proceeds via two pathways:
- Cyclooxygenase (COX-2) pathway: prostaglandins are synthesized.
- 5-lipoxygenase (5-LOX) pathway: cysteinyl leukotrienes are formed.
All released mediators are divided into two groups. Bronchoconstrictor agents (histamine, platelet-activating factor, and leukotrienes forming the "slow-reacting substance of anaphylaxis") cause a sharp spasm. Chemotactic factors (leukotriene B4 and platelet-activating factor) attract new portions of eosinophils, sustaining inflammatory infiltration.
Effector phase and pharmacological correction
Airway tone depends directly on receptors located on bronchial smooth muscle cells. Stimulation of $M_3$ cholinoceptors, adenosine $A_1$ receptors, and leukotriene receptors leads to luminal narrowing (bronchoconstriction). Conversely, stimulation of $\beta_2$-adrenoceptors causes muscle relaxation (bronchodilation).
To relieve attacks, bronchodilating drugs are used that act on these targets:
- $\beta_2$-adrenomimetics: stimulate $\beta_2$-receptors, actively dilating the bronchi.
- M-anticholinergics: block $M_3$ receptors, eliminating the cholinergic component of bronchospasm.
- Methylxanthines (theophylline): act as adenosine antagonists and block $A_1$ receptors.
Myotropic antispasmodics, which directly affect muscle tone, are also used in therapy.
Briefly: answers to topical questions
What are the daily doses and regimens of inhaled glucocorticosteroids in severe bronchial asthma?
In severe bronchial asthma, medium or high doses of inhaled glucocorticosteroids (ICS) are used in combination with long-acting beta-agonists (LABA). This treatment regimen corresponds to step 5 of therapy.
Specific daily dosages for the severe form are not provided in the materials, but the following fixed-combination dosage options are known:
- Budesonide + formoterol — 100/6 mcg (very low doses).
- Budesonide + formoterol — 200/6 mcg (low doses).
The drugs can be used in a single-inhaler regimen (MART therapy), where one inhaler is used for both maintenance therapy and symptom relief.
What international treatment steps according to GINA recommendations are distinguished in the management of bronchial asthma?
According to GINA recommendations, there are five steps of bronchial asthma therapy, which are prescribed depending on the severity of the disease.
- Steps 1 and 2 — used for mild bronchial asthma (e.g., low-dose ICS and formoterol as needed).
- Steps 3 and 4 — prescribed for moderate disease to achieve good control.
- Step 5 — required to control severe bronchial asthma (includes medium or high doses of ICS combined with long-acting beta-agonists).
To easily remember the sites of action of bronchodilators, use the rule «Stimulate the relaxant, block the constrictor»: the drugs stimulate $\beta_2$-adrenoceptors (adrenomimetics) and block $M_3$ cholinoceptors (anticholinergics) along with $A_1$ adenosine receptors (methylxanthines).
Class and exam questions
What is bronchial hyperreactivity and why does it occur?
This is a pathologically increased sensitivity of the airways to irritants (cold, allergens). It develops as a consequence of chronic inflammation and damage to the bronchial epithelium by eosinophilic cytotoxic proteins.
What is the role of interleukin-4 (IL-4) in pathogenesis?
IL-4 is a key mediator of sensitization. It stimulates B lymphocytes to produce immunoglobulin E (IgE) and promotes the expression of IgE receptors on the membranes of mast cells and basophils.
How is the «slow-reacting substance of anaphylaxis» formed?
It consists of cysteinyl leukotrienes synthesized inside the mast cell. The process begins with the cleavage of arachidonic acid by the enzyme phospholipase A2, after which the enzyme 5-lipoxygenase (5-LOX) converts it into leukotrienes.
What else to study on this topic
- Differences between high-affinity ($Fc\epsilon RI$) and low-affinity ($Fc\epsilon RII$) IgE receptors.
- Detailed mechanism of action of myotropic antispasmodics.
- The role of platelet-activating factor (PAF) in bronchoconstriction and chemotaxis.
- Specific functions of prostaglandins ($E_2, I_2, D_2$) in the inflammatory cascade.
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