Pathogenesis of chronic bronchitis

The main pathogenetic factors of chronic bronchitis are:

1. Dysfunction of the local bronchopulmonary defense system and the immune system.
2. Structural reorganization of the bronchial mucosa.
3. Development of the classical pathogenetic triad (hypercrinia, dyscrinia, mucostasis) and the release of inflammatory mediators and cytokines.

Dysfunction of the local bronchopulmonary defense system

The following layers are distinguished in the bronchial mucosa: the epithelial layer, the basement membrane, the lamina propria, the muscularis and the submucosal (subepithelial) layer. The epithelial layer consists of ciliated, goblet, intermediate and basal cells; serous cells, Clara cells and Kulchitsky cells are also found.

Ciliated cells predominate in the epithelial layer; they have an irregular prismatic shape and ciliated cilia on their surface, performing coordinated movements 16-17 times per second - in a straightened rigid state in the oral direction and in a relaxed state - in the opposite direction. Cilia move the mucous film covering the epithelium at a speed of about 6 mm/min, removing dust particles, microorganisms, cellular elements from the bronchial tree (cleansing, drainage function of the bronchi).

Goblet cells are present in the epithelial layer in smaller quantities than ciliated cells (1 goblet cell per 5 ciliated cells). They secrete mucous secretion. In small bronchi and bronchioles, goblet cells are not normally present, but they appear in pathological conditions.

Basal and intermediate cells are located deep in the epithelial layer and do not reach its surface. Intermediate cells have an elongated, basal cells have an irregular cubic shape, they are less differentiated compared to other cells of the epithelial layer. Physiological regeneration of the bronchial epithelial layer is carried out due to intermediate and basal cells.

Serous cells are few in number, reach the free surface of the epithelium, and produce serous secretion.

Clara's secretory cells are located mainly in the small bronchi and bronchioles. They produce secretion, participate in the formation of phospholipids and, possibly, surfactant. When the bronchial mucosa is irritated, they turn into goblet cells.

Kulchitsky cells (K-cells) are located throughout the bronchial tree and belong to the neurosecretory cells of the APUD system (“amine precursor uptake and decarboxylation”).

The basement membrane is 60-80 microns thick, is located under the epithelium and serves as its base; cells of the epithelial layer are attached to it. The submucosal layer is formed by loose connective tissue containing collagen, elastic fibers, as well as submucosal glands containing serous and mucous cells that secrete mucous and serous secretions. The channels of these glands are collected into an epithelial collecting duct that opens into the lumen of the bronchus. The volume of secretion of the submucosal glands is 40 times greater than the secretion of goblet cells.

The production of bronchial secretions is regulated by the parasympathetic (cholinergic), sympathetic (adrenergic), and "non-adrenergic, non-cholinergic" nervous systems. The mediator of the parasympathetic nervous system is acetylcholine, of the sympathetic - norepinephrine, adrenaline; of the non-adrenergic, non-cholinergic (NANC) - neuropeptides (vasoactive intestinal polypeptide, substance P, neurokinin A). Neurotransmitters (mediators) of the NANC system coexist in the nerve endings of parasympathetic and sympathetic fibers with the classical mediators acetylcholine and norepinephrine.

Neurohumoral regulation of submucosal glands and, consequently, the production of bronchial secretions is carried out through the interaction of receptors of mucous and serous cells with neurotransmitters - mediators of the parasympathetic, sympathetic and non-adrenergic-non-cholinergic nervous system.

The volume of bronchial secretion increases mainly with cholinergic stimulation, as well as under the influence of substance P, a mediator of NANH. Substance P stimulates secretion by goblet cells and submucous glands. Mucociliary clearance (i.e., the function of the ciliated epithelium) of the bronchi is stimulated by excitation of beta2-adrenoreceptors.

The local bronchopulmonary defense system is of great importance in protecting the bronchial tree from infection and aggressive environmental factors. The local bronchopulmonary defense system includes the mucociliary apparatus; surfactant system; the presence of immunoglobulins, complement factors, lysozyme, lactoferrin, fibronectin, interferons in the bronchial contents; alveolar macrophages, protease inhibitors, bronchus-associated lymphoid tissue.

Dysfunction of the mucociliary apparatus

The basic structural unit of the mucociliary apparatus is the ciliated epithelium cell. The ciliated epithelium covers the mucous membranes of the upper respiratory tract, paranasal sinuses, middle ear, trachea and bronchi. There are about 200 cilia on the surface of each ciliated epithelium cell.

The main function of the mucociliary apparatus is to remove foreign particles that have entered the respiratory tract along with secretions.

Due to the coordinated movement of the cilia, the thin film of secretion covering the bronchial mucosa moves in the proximal direction (towards the pharynx). The effective activity of the mucociliary apparatus depends not only on the functional state and mobility of the cilia, but also on the rheological properties of the bronchial secretion. Normally, bronchial secretion contains 95% water, the remaining 5% are mucous glycoproteins (mucins), proteins, lipids, and electrolytes. Mucociliary clearance is optimal with sufficiently fluid and elastic bronchial secretion. With thick and viscous secretion, the movement of the cilia and the cleansing of the tracheobronchial tree are sharply hampered. However, with excessively liquid secretion, mucociliary transport is also impaired, since there is insufficient contact and adhesion of the secretion to the ciliated epithelium.

Congenital and acquired defects of the mucociliary apparatus are possible. Congenital disorder is observed in Kartagener-Siewert syndrome (situs viscerum inversus + congenital bronchiectasis + rhinosinusopathy + infertility in men due to insufficient sperm motility + defect in the function of the ciliated epithelium).

In chronic bronchitis, under the influence of the above-mentioned etiological factors, there is a disruption of the function of the ciliated epithelium (mucociliary transport), its dystrophy and death, which in turn contributes to the colonization of microorganisms in the bronchial tree and the persistence of the inflammatory process.

The disruption of mucociliary transport is also facilitated by insufficient production of testosterone by the testicles in men (testosterone stimulates the function of the ciliated epithelium), which is often observed in chronic bronchitis under the influence of long-term smoking and alcohol abuse.

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Dysfunction of the pulmonary surfactant system

Surfactant is a lipid-protein complex that coats the alveoli as a film and has the property of reducing their surface tension.

The surfactant system of the lungs includes the following components:

• surfactant itself is a surface-active film in the form of a single-layer monomolecular membrane; it is located in the alveoli, alveolar ducts and respiratory bronchioles of the 1st-3rd order;
• hypophase (underlying hydrophilic layer) - a liquid medium located under the mature surfactant; it fills the unevenness of the surfactant itself and contains reserve mature surfactant, osmiophilic bodies and their fragments (secretory products of type II alveolocytes), and macrophages.

Surfactant is 90% lipid; 85% of these are phospholipids. The main component of surfactant is thus phospholipids, of which lecithin has the greatest surface activity.

Along with phospholipids, the surfactant contains apoproteins, which play an important role in stabilizing the phospholipid film, as well as glycoproteins.

Synthesis of pulmonary surfactant is performed by type II alveocytes, which are located in the interalveolar septa. Type II alveocytes make up 60% of all alveolar epithelial cells. There is also evidence of the participation of Clara cells in surfactant synthesis.

The half-life of surfactant does not exceed 2 days, surfactant renewal occurs quickly. The following pathways of surfactant excretion are known:

• phagocytosis and digestion of surfactant by alveolar macrophages;
• removal from the alveoli through the airways;
• endocytosis of surfactant by type I alveolar cells;
• reduction of surfactant content under the influence of locally produced enzymes.

The main functions of surfactant are:

• reducing the surface tension of the alveoli during exhalation, which prevents the alveolar walls from sticking together and expiratory collapse of the lung. Thanks to the surfactant, the honeycomb system of the alveoli remains open during deep exhalation.
• preventing the collapse of small bronchi during exhalation, reducing the formation of mucus agglomerates;
• creation of optimal conditions for mucus transport by ensuring adequate adhesion of secretions to the bronchial wall;
• antioxidant action, protection of the alveolar wall from the damaging effects of peroxide compounds;
• participation in the movement and removal of bacterial and non-bacterial particles that have passed the mucociliary barrier, which complements the function of the mucociliary apparatus; the movement of surfactant from an area with low to an area with high surface tension helps remove particles in areas of the bronchial tree that lack the ciliary apparatus;
• activation of the bactericidal function of alveolar macrophages;
• participation in the absorption of oxygen and regulation of its entry into the blood.

Surfactant production is regulated by a number of factors:

• excitation of the sympathetic nervous system and, accordingly, beta-adrenergic receptors (they are found on type II alveocytes), which leads to an increase in surfactant synthesis;
• increased activity of the parasympathetic nervous system (its neurotransmitter, acetylcholine, stimulates the synthesis of surfactant);
• glucocorticoids, estrogens, thyroid hormones (accelerate the synthesis of surfactant).

In chronic bronchitis, surfactant production is disrupted under the influence of etiological factors. Tobacco smoke and harmful impurities (quartz, asbestos dust, etc.) in the inhaled air play a particularly pronounced negative role in this regard.

Decreased surfactant synthesis in chronic bronchitis leads to:

• increased viscosity of sputum and disruption of the transport of bronchial contents;
• disruption of non-ciliary transport;
• collapse of the alveoli and obstruction of the small bronchi and bronchioles;
• colonization of microbes in the bronchial tree and aggravation of the infectious and inflammatory process in the bronchi.

Violation of the content of humoral protective factors in the bronchial contents

Immunoglobulin A deficiency

The bronchial contents contain immunoglobulins IgG, IgM, IgA in varying amounts. The main role in protecting the tracheobronchial tree from infection belongs to IgA, the content of which in the bronchial secretion is higher than in the blood serum. IgA in the bronchi is secreted by cells of the bronchi-associated lymphoid tissue, in particular, by plasma cells of the submucosal layer of the bronchi (secretory IgA). IgA production in the respiratory tract is 25 mg/kg/day. In addition, bronchial secretion contains a small amount of IgA, which comes here from the blood by transudation.

IgA performs the following functions in the bronchopulmonary system:

• has an antiviral and antimicrobial effect, prevents the proliferation of viruses, reduces the ability of microbes to adhere to the bronchial mucosa;
• participates in the activation of complement via the alternative pathway, which promotes the lysis of microorganisms;
• enhances the antibacterial effect of lysozyme and lactoferrin;
• inhibits IR-cellular and antibody-dependent cellular cytotoxicity;
• has the property of combining with tissue and foreign protein antigens, eliminating them from circulation and thus preventing the formation of autoantibodies.

IgA exhibits its protective properties mainly in the proximal parts of the respiratory tract. In the distal parts of the bronchi, the most significant role in antimicrobial protection is played by IgG, which enters the bronchial secretion by transudation from the blood serum.

Bronchial secretions also contain a small amount of IgM, which is synthesized locally.

In chronic bronchitis, the content of immunoglobulins, primarily IgA, in bronchial secretions is significantly reduced, which disrupts anti-infective protection, promotes the development of cytotoxic reactions with damage to the bronchi and the progression of chronic bronchitis.

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Complement component deficiency

The complement system is a system of blood serum proteins that includes 9 components (14 proteins) that, when activated, are capable of destroying foreign substances, primarily infectious agents.

There are 2 pathways of complement activation: classical and alternative (properdin).

Immune complexes, which most often include IgM, IgG, and C-reactive protein, participate in complement activation via the classical pathway. Immune complexes involving immunoglobulins A, D, and E do not activate the complement system.

In the classical complement activation pathway, the components C1q, C1r, C1g are initially sequentially activated with the participation of Ca ions, resulting in the formation of the active form of C1. The component (active form) has proteolytic activity. Under its influence, the active C3 complex (envelope) is formed from components C2 and C4, and subsequently, with its participation, the so-called "membrane attack block" (active components C5-C6-C7-C8-C9) is formed. This protein is a transmembrane channel permeable to electrolytes and water. Due to the higher colloid osmotic pressure in the microbial cell, Na ⁺ and water begin to enter it, as a result of which the cell swells and lyses.

The alternative pathway of complement activation does not require the participation of early complement components C1, C2, C4. Bacterial polysaccharides, endotoxins and other factors can be activators of the alternative pathway. Component C3 is split into C3a and C3b. The latter, in combination with properdin, promotes the formation of the "membrane attack block" C5-C9, and then cytolysis of the foreign agent occurs (as with activation by the classical pathway).

In bronchial contents, most complement factors are found in small quantities, but their bronchoprotective role is very important.

The complement system of bronchial secretions has the following meaning:

• participates in inflammatory and immune reactions in lung tissue;
• protects the bronchi and lung tissue from infection and other foreign agents by activating complement via the alternative pathway;
• participates in the process of microbial phagocytosis (chemotaxis, phagocytosis);
• activates mucociliary clearance;
• affects the secretion of mucus glycoproteins in the bronchi (via component C3a).

Most of the biological effects of the complement system are realized due to the presence of receptors for the components. Receptors for the C3a component are present on the surface of neutrophils, monocytes, eosinophils, thrombocytes, and alveolar macrophages.

In chronic bronchitis, the synthesis of complement components is disrupted, which is of great importance in the progression of the infectious and inflammatory process in the bronchi.

Decreased lysozyme content in bronchial secretions

Lysozyme (muramidase) is a bactericidal substance contained in bronchial secretions, produced by monocytes, neutrophils, alveolar macrophages and serous cells of the bronchial glands. The lungs are the richest in lysozyme. Lysozyme plays the following role in bronchial secretions:

• provides protection of the bronchopulmonary system from infection;
• affects the rheological properties of sputum (lysozyme in vitro interacts with acidic glycoproteins of mucus, precipitates mucin, which worsens the rheology of sputum and mucociliary transport).

In chronic bronchitis, the production of lysozyme and its content in bronchial secretions and lung tissue is significantly reduced, which contributes to the progression of the infectious and inflammatory process in the bronchi.

Decreased lactoferrin content in bronchial secretions

Lactoferrin is an iron-containing glycoprotein, produced by glandular cells and present in almost all body secretions that wash the mucous membranes. In the bronchi, lactoferrin is produced by serous cells of the bronchial glands.

Lactoferrin has bactericidal and bacteriostatic effects. In chronic bronchitis, lactoferrin production and its content in bronchial secretions are significantly reduced, which helps maintain the infectious and inflammatory process in the bronchopulmonary system.

[ 5 ], [ 6 ], [ 7 ], [ 8 ], [ 9 ]

Reduction of fibronectin content in bronchial secretions

Fibronectin is a high-molecular glycoprotein (molecular weight 440,000 daltons), present in an insoluble form in connective tissue and on the surface of membranes of some cells, and in a soluble form - in various extracellular fluids. Fibronectin is produced by fibroblasts, alveolar macrophages, monocytes and endothelial cells, is found in the blood, cerebrospinal fluid, urine, bronchial secretions, on the membranes of monocytes, macrophages, fibroblasts, platelets, hepatocytes. Fibronectin binds to collagen, fibrinogen, fibroblasts. The main role of fibronectin is participation in intercellular interactions:

• enhances the attachment of monocytes to cell surfaces, attracts monocytes to the site of inflammation;
• participates in the elimination of bacteria, destroyed cells, fibrin;
• prepares bacterial and non-bacterial particles for phagocytosis.

In chronic bronchitis, the content of fibronectin in bronchial contents decreases, which can contribute to the progression of the chronic inflammatory process in the bronchi.

Violation of interferon content in bronchial contents

Interferons are a group of low-molecular peptides with antiviral, antitumor and immunoregulatory activity.

There are alpha, beta, and gamma interferon. Alpha interferon has a predominantly antiviral and antiproliferative effect and is produced by B lymphocytes, O lymphocytes, and macrophages.

Beta-interferon is characterized by antiviral activity and is produced by fibroblasts and macrophages.

Gamma interferon is a universal endogenous immunomodulator. It is produced by T-lymphocytes and NK-lymphocytes. Under the influence of gamma interferon, antigen binding by cells, expression of HLA antigens are enhanced, lysis of target cells, production of immunoglobulins, phagocytic activity of macrophages are increased, tumor cell growth is inhibited, and intracellular reproduction of bacteria is suppressed.

The content of interferons in bronchial secretions during chronic bronchitis is significantly reduced, which contributes to the development and maintenance of the infectious and inflammatory process in the bronchi.

Violation of the ratio of proteases and their inhibitors

Protease inhibitors include alpha1-antitrypsin and alpha2-macroglobulin. They are produced by neutrophils, alveolar macrophages, and the liver. Normally, there is a certain balance between bronchial secretion proteases and antiprotease protection.

In rare cases, chronic non-obstructive bronchitis may involve a genetically determined decrease in antiprotease activity, which contributes to damage to the bronchopulmonary system by proteases. This mechanism is of much greater importance in the development of pulmonary emphysema.

Dysfunction of alveolar macrophages

Alveolar macrophages perform the following functions:

• phagocytize microbial and foreign non-microbial particles;
• participate in inflammatory and immune reactions;
• secrete complement components;
• secrete interferon;
• activate the antiproteolytic activity of alpha2-macroglobulin;
• produce lysozyme;
• produce fibronectin and chemotactic factors.

A significant decrease in the function of alveolar macrophages has been established in chronic bronchitis, which plays a significant role in the development of the infectious and inflammatory process in the bronchi.

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Dysfunction of the local (bronchopulmonary) and general immune system

In various parts of the bronchopulmonary system there are clusters of lymphoid tissue - bronchus-associated lymphoid tissue. This is the source of formation of B- and T-lymphocytes. In bronchus-associated lymphoid tissue there are T-lymphocytes (73%), B-lymphocytes (7%), O-lymphocytes (20%), and many natural killers.

In chronic bronchitis, the function of T-suppressors and natural killers both in the local bronchopulmonary system and in general can be significantly reduced, which contributes to the development of autoimmune reactions, disruption of the function of the antimicrobial and antitumor defense system. In some cases, the function of T-helper lymphocytes is reduced and the formation of protective IgA is disrupted. The above-mentioned disorders in the bronchopulmonary immune system are of great pathogenetic importance in chronic bronchitis.

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Structural reorganization of the bronchial mucosa

Structural reorganization of the bronchial mucosa is the most important factor in the pathogenesis of chronic bronchitis. Mucus is produced by the bronchial glands in the submucosal layer of the trachea and bronchi to the bronchioles (i.e. in the respiratory tract that has a layer of cartilaginous tissue), as well as by goblet cells of the respiratory tract epithelium, the number of which decreases as the caliber of the respiratory tract decreases. Structural reorganization of the bronchial mucosa in chronic bronchitis consists of a significant increase in the number and activity of goblet cells and hypertrophy of the bronchial glands. This leads to an excessive amount of mucus and deterioration of the rheological properties of sputum and contributes to the development of mucostasis.

Development of the classical pathogenetic triad and release of inflammatory mediators and cytokines

An obligatory factor in the pathogenesis of chronic bronchitis is the development of the classical pathogenetic triad, which consists of an increase in mucus production (hypercrinia), a qualitative change in bronchial mucus (it becomes viscous, thick - dyscrinia), and mucus stasis (mucostasis).

Hypercrinia (hypersecretion of mucus) is associated with the activation of secretory cells, which may result in an increase in the size (hypertrophy) and number of these cells (hyperplasia). Activation of secretory cells is caused by:

• increased activity of the parasympathetic (cholinergic), sympathetic (alpha- or beta-adrenergic), or non-adrenergic non-cholinergic nervous system;
• release of inflammatory mediators - histamine, arachidonic acid derivatives, cytokines.

Histamine is released primarily from mast cells, which are found in large quantities in the submucosa near the secretory glands and in the basal membrane near the goblet cells. Under the influence of histamine, the H1 and H2 receptors of the secretory cells are excited. Stimulation of the H1 receptors increases the secretion of mucus glycoproteins. Stimulation of the H2 receptors leads to an increase in the influx of sodium and chlorine into the lumen of the respiratory tract, which is accompanied by an increase in the influx of water and, consequently, an increase in the volume of secretion.

Derivatives of arachidonic acid - prostaglandins (PgA2, PgD2, PgF2a), leukotrienes (LTC4, LTD4) stimulate mucus secretion and increase the content of glycoproteins in it. Among the derivatives of arachidonic acid, leukotrienes are the most powerful secreto-stimulating agents.

It has been established that among cytokines, tumor necrosis factor has a stimulating effect on the secretion of bronchial glands.

The release of these inflammatory mediators is due to the following reasons:

• the inflammatory reaction promotes the influx of inflammatory effector cells (mast cells, monocytes, macrophages, neutrophils, eosinophils) into the subepithelial tissues, which, when active, release inflammatory mediators - histamine, arachidonic acid derivatives, platelet activating factor, tumor necrosis factor, etc.);
• epithelial cells themselves are capable of releasing inflammatory mediators in response to external influences;
• Plasma exudation increases the influx of inflammatory effector cells.

Of great importance in the development of chronic bronchitis is the hyperproduction of proteolytic enzymes by neutrophils - neutrophil elastase, etc.

Excessive amount of mucus, violation of its rheological properties (excessive viscosity) under conditions of decreased function of the ciliated epithelium (ciliary insufficiency) leads to a sharp slowdown in mucus evacuation and even blockage of the bronchioles. The drainage function of the bronchial tree is thus sharply impaired, while against the background of suppression of the local bronchopulmonary defense system, conditions are created for the development of bronchogenic infection, the rate of reproduction of microorganisms begins to exceed the rate of their elimination. Subsequently, with the existence of a pathogenetic triad (hypercrinia, dyscrinia, mucostasis) and further suppression of the local defense system, the infection in the bronchial tree is constantly present and causes damage to the bronchial structures. It penetrates into the deep layers of the bronchial wall and leads to the development of panbronchitis, peribronchitis with the subsequent formation of deforming bronchitis and bronchiectasis.

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Pathomorphology

In chronic bronchitis, there is hypertrophy and hyperplasia of the tracheobronchial glands and an increase in the number of goblet cells. A decrease in the number of ciliated cells and squamous cell metaplasia of the epithelium are noted. The thickness of the bronchial wall increases by 1.5-2 times due to hyperplasia of the bronchial glands, vasodilation, edema of the mucous membrane and submucous layer, cellular infiltration and areas of sclerosis. In the case of exacerbation of chronic bronchitis, infiltration by neutrophilic leukocytes, lymphoid and plasma cells is noted.

In chronic obstructive bronchitis, the most pronounced signs of obstruction are found in the small bronchi and bronchioles: obliteration and stenosis due to pronounced inflammatory edema, cellular proliferation and fibrosis, cicatricial changes; the formation of bronchioloectasis with distal obliteration is possible.