Pathogenesis of chronic bronchitis

The main pathogenetic factors of chronic bronchitis are:

1. Violation of the function of the system of local bronchopulmonary protection and immunity system.
2. Structural reorganization of the bronchial mucosa.
3. Development of the classical pathogenetic triad (hypercrinia, discrinia, mucostasis) and the release of mediators of inflammation and cytokines.

Violation of the function of the local bronchopulmonary protection system

The following layers are distinguished in the bronchial mucosa: epithelial layer, basal membrane, own plate, muscular and submucosal (subepithelial) layer. The epithelial layer consists of ciliated, goblet, intermediate and basal cells; there are also serous cells, Clara cells and Kulchitsky cells.

The ciliated cells predominate in the epithelial layer; they have an irregular prismatic shape and ciliated cilia on their surface, performing coordinated movements 1b-17 times per second - in the rectified rigid state in the oral direction and in the relaxed state - in the opposite direction. Cilia move the mucous membrane covering the epithelium at a speed of about 6 mm / min, removing from the bronchial tree dust particles, microorganisms, cellular elements (purifying, drainage function of the bronchi).

The goblet cells in the epithelial layer are represented in less quantity than the ciliate cells (1 goblet cell with 5 ciliated cells). They give off a slimy secret. In small bronchi and bronchioles of goblet cells are normal, but they appear in pathological conditions.

Basal and intermediate cells are located in the depth of the epithelial layer and do not reach its surface. Intermediate cells have an elongated, basal - an irregularly cubic form, they are less differentiated compared to other cells of the epithelial layer. Due to the intermediate and basal cells, the physiological regeneration of the epithelial layer of the bronchi is carried out.

Serous cells are few, reach the free surface of the epithelium, produce a serous secret.

Secretory Clara cells are located mainly in the small bronchi and bronchioles. They produce secret, participate in the formation of phospholipids and, possibly, surfactant. When the bronchial mucosa irritates, they become goblet cells.

Kulchytsky's 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 basal membrane has a thickness of 60-80 microns, located under the epithelium and serves as its base; cells of the epithelial layer are attached to it. The submucosa is formed by a loose connective tissue containing collagen, elastic fibers, as well as submucous glands containing serous and mucous cells that secrete mucous and serous secretions. The canals of these glands gather into the epithelial duct, which opens into the lumen of the bronchus. The volume of secretion of submucosal glands is 40 times higher than the secret of goblet cells.

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

Neurohumoral regulation of the submucosal gland and, consequently, the production of the bronchial secretion is realized by 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 - neurotransmitter NANH. Substance P stimulates secretion of goblet cells and submucosal glands. Mucociliary clearance (ie the function of the ciliated epithelium) of the bronchi is stimulated by the excitation of beta2-adrenergic receptors.

The system of local bronchopulmonary protection 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; presence in the bronchial content of immunoglobulins, complement factors, lysozyme, lactoferrin, fibronectin, interferons; alveolar macrophages, protease inhibitors, bronchus-associated lymphoid tissue.

Dysfunction of mucociliary apparatus

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

The main function of the mucociliary apparatus is to remove, together with the secret of foreign particles trapped in the respiratory tract.

Due to the coordinated movement of the cilia, a thin secret film covering the mucous membrane of the bronchi moves in the proximal direction (to 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, the bronchial secretion contains 95% water, the remaining 5% are mucosal glycoproteins (mucins), proteins, lipids, electrolytes. Mucociliary clearance is optimal for a fairly fluid and elastic bronchial secretion. With a thick and viscous secretion, the movement of the cilia and the cleansing of the tracheobronchial tree are severely hampered. However, with an excessively liquid secret, mucociliary transport is also disrupted, since there is insufficient contact and secretion with the ciliated epithelium.

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

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

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

[1], [2]

Violation of the function of the surfactant system of the lungs

Surfactant is a lipid-protein complex covering in the form of an alveolus film and possessing the property of reducing their surface tension.

The surfaktangna lung system includes the following components:

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

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

Along with phospholipids, the surfactant includes apoproteins, which play an important role in the stabilization of the phospholipid film, as well as glycoproteins.

Synthesis of pulmonary surfactant is performed by type II alveocytes, which are located in interalveolar septa. Type II alveocytes account for 60% of all cells of the alveolar epithelium. There is also evidence of the involvement of Clara cells in the synthesis of the surfactant.

The half-life of the surfactant does not exceed 2 days, the surfactant is updated quickly. The following ways of removing the surfactant are known:

• phagocytosis and digestion of surfactant by alveolar macrophages;
• removal from the alveoli along the airways;
• endocytosis of the surfactant type I alveolocytes;
• decrease in the content of surfactant under the influence of locally formed enzymes.

The main functions of the surfactant are:

• a decrease in the surface tension of the alveoli at the time of exhalation, which prevents the alveolar walls from sticking together and the expiratory collapse of the lung. Due to the surfactant, the honeycomb system of the alveoli remains open even during a deep exhalation.
• prevention of the collapse of small bronchi on exhalation, reduction in the formation of agglomerations of mucus;
• creation of optimal conditions for transport of mucus due to ensuring adequate adhesion of the secret to the bronchial wall;
• antioxidant effect, protection of alveolar walls from damaging effects of peroxide compounds;
• participation in the movement and removal of bacterial and non-bacterial particles that passed the mucociliary barrier, which supplements the function of the mucociliary apparatus; moving the surfactant from the low region to the area with a high surface tension facilitates the removal of particles in the areas of the bronchial tree deprived of the ciliary apparatus;
• activation of bactericidal function of alveolar macrophages;
• participation in the absorption of oxygen and regulation of its entry into the blood.

Surfactant products are regulated by a number of factors:

• stimulation of the sympathetic nervous system and, accordingly, beta-adrenergic receptors (they are found on type-2 alveocytes), which leads to an increase in the synthesis of the surfactant;
• 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 under the influence of etiological factors the production of surfactant is disrupted. Especially pronounced negative role in this respect is played by tobacco smoke and harmful impurities (quartz, asbestos dust, etc.) in the inspired air.

Reducing the synthesis of surfactant in chronic bronchitis leads to:

• increasing the viscosity of sputum and disrupting the transport of bronchial contents;
• violation of noncivil transportation;
• collapse of the alveoli and obstruction of the small bronchi and bronchioles;
• colonization of microbes in the bronchial tree and aggravation of the infectious inflammatory process in the bronchi.

Disturbance of content in the bronchial content of humoral protective factors

Deficiency of immunoglobulin A

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

IgA performs the following functions in the bronchopulmonary system:

• has antiviral and antimicrobial action, prevents the multiplication of viruses, reduces the ability of microbes to adhere to the mucous membrane of the bronchi;
• participates in the activation of complement in an alternative pathway, which contributes to the lysis of microorganisms;
• enhances the antibacterial effect of lysozyme and lactoferrin;
• inhibits IR-cell and antibody-dependent cellular cytotoxicity;
• has the property of connecting with tissue and foreign protein antigens, eliminating them from circulation and thus preventing the formation of autoantibodies.

IgA shows 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 secret by means of transudation from serum.

In a small amount in the bronchial secret also contains IgM, which is synthesized locally.

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

[3], [4]

Infringement of the content of complement components

The complement system is a system of serum proteins, which includes 9 components (14 proteins), which, when activated, can destroy foreign substances, primarily infectious agents.

There are 2 ways to activate complement: classical and alternative (properdinovy).

In the activation of complement in the classical pathway, immune complexes, which most often include IgM, IgG, C-reactive protein, are involved. Immune complexes with the participation of immunoglobulins A, D, E complement system do not activate.

In the classical pathway of complement activation, the successive activation of C1q, C1r, C1g components occurs 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, an active C3 complex (envelopes) is formed from the components C2 and C4, subsequently, with its participation, a so-called "membrane-blocking block" (active components C5-C6-C7-C8-C9) is formed. This protein is a transmembrane channel that is permeable to electrolytes and water. Due to the higher colloid-osmotic pressure in the microbial cell, Na ⁺ and water begin to enter inside it , as a result of which the cell swells and lyses.

An alternative pathway for complement activation does not require the participation of the early complement components C1, C2, C4. Activators of the alternative pathway may be bacterial polysaccharides, endotoxins and other factors. There is a splitting of component C3, into C3a and C3b. The latter, combined with the properdine, promotes the formation of a "membrane-blocking block" of C5-C9, and further the cytolysis of a foreign agent occurs (as in the activation along the classical pathway).

In bronchial content, most complement factors are found in a small amount, but their bronchoprotective role is very high.

The complement system of bronchial secretion has the following meaning:

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

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

With chronic bronchitis, the synthesis of complement components is impaired, which is of great importance in the progressed infectious inflammatory process in the bronchi.

Reduction of lysozyme content in bronchial secretion

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

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

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

Decrease in the content of lactoferrin in bronchial secretion

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

Lactoferrin has bactericidal and bacteriostatic effects. With chronic bronchitis, lactoferrin production and its maintenance in bronchial secretion are significantly reduced, which contributes to the maintenance of the infectious inflammatory process in the bronchopulmonary system.

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

Reduction of fibronectite in bronchial secretion

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

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

With chronic bronchitis, the content of fibronectin in the bronchial content is reduced, which can contribute to the progression of the chronic inflammatory process in the bronchi.

Violation of the content of interferon in bronchial contents

Interferons are a group of low molecular weight peptides that have antiviral, antitumor and immunoregulatory activity.

There are alpha, beta, gamma interferon. Alfa-interferon has a predominantly antiviral and antiproliferative effect and is produced by B-lymphocytes, 0-lymphocytes, 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, binding of the antigen by cells is enhanced, expression of HLA antigens, lysis of target cells, production of immunoglobulins, phagocytic activity of macrophages, oppression of growth of tumor cells, inhibition of intracellular multiplication of bacteria.

The content of interferons in bronchial secretion in chronic bronchitis is significantly reduced, which contributes to the development and maintenance of an infectious 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 liver. Normally, there is a certain balance between the praseases of bronchial secretion and antiprotease protection.

In rare cases with chronic non-inflammatory bronchitis, there may be a genetically determined decrease in antiproteolygic activity, which contributes to damage to the bronchopulmonary system by proteases. This mechanism is much more important in the development of emphysema of the lungs.

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

[10], [11], [12]

Dysfunction of local (broncho-pulmonary) and general immune system

In various departments of the bronchopulmonary system there are accumulations of lymphoid tissue - bronchus-associated lymphoid tissue. This is the source of formation of B- and T-lymphocytes. In the bronchial associated lymphoid tissue 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 as a whole can be significantly reduced, which promotes the development of autoimmune reactions, the disruption of the function of the antimicrobial and antitumor protection system. In a number of cases, the function of T-lymphocytes-helpers has been reduced and the formation of protective IgA has been disrupted. These disorders in the bronchopulmonary immune system are of great pathogenetic importance in chronic bronchitis.

[13], [14], [15], [16]

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 (ie, in the respiratory tract having a layer of cartilaginous tissue), as well as the goblet cells of the epithelium of the respiratory tract, the number of which contracts as the caliber of the airways decreases. Structural reorganization of bronchial mucosa in chronic bronchitis consists in 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 a deterioration in the rheological properties of the sputum and promotes the development of mucostasis.

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

An important factor in the pathogenesis of chronic bronchitis is the development of the classical pathogenetic triad, consisting in increasing the production of mucus (hypercrinia), qualitative changes in bronchial mucus (it becomes viscous, dense - discrinia), mucus stasis (mucostasis).

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

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

Histamine is released mainly from mast cells that are in large numbers in the submucosa near the secretory glands and in the basal membrane near the goblet cells. Under the influence of histamine, H1 and H2 secretory cell receptors are stimulated. Stimulation of H1 receptors increases the secretion of mucosal glycoproteins. Stimulation of 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 the secretion of mucus and increase the content of glycoproteins in it. Among the derivatives of arachidonic acid, leukotrienes are the most potent secretion-stimulating agents.

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

The release of these mediators of inflammation is caused by the following reasons:

• inflammatory reaction contributes to the influx of inflammatory cells (mast cells, monocytes, macrophages, neutrophils, eosinophils) in the subepithelial tissues that release inflammatory mediators in the active state - histamine, arachidonic acid derivatives, platelet activating factor, tumor necrosis factor, etc.);
• epithelial cells in themselves in response to external influences are able to release mediators of inflammation;
• exudation of plasma increases the influx of effector cells of inflammation.

Great importance in the development of chronic bronchitis belongs to hyperproduction by neutrophils of proteolytic enzymes - neutrophil elastase, etc.

Excess amount of mucus, a violation of its rheological properties (excessive viscosity) in conditions of decreased function of the ciliated epithelium (ciliary insufficiency) leads to a sharp slowdown in the evacuation of mucus and even blockage of bronchioles. The drainage function of the bronchial tree is thus sharply disrupted, while the oppression of the local bronchopulmonary defense system creates conditions for the development of bronchogenic infection, the rate of multiplication of microorganisms begins to exceed the rate of their elimination. In the future, with the existence of a pathogenetic triad (hypercrinia, discrinia, mucostasis) and further inhibition of the local defense system, 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, followed by the formation of deforming bronchitis and bronchiectasis.

[17], [18], [19], [20], [21], [22]

Pathomorphology

With chronic bronchitis there are hypertrophy and hyperplasia of the tracheobronchial glands and an increase in the number of goblet cells. There is a decrease in the number of ciliated cells, flat cell epithelial metaplasia. The thickness of the bronchial wall increases by 1.5-2 times due to hyperplasia of bronchial glands, vasodilation, edema of the mucous membrane and submucosal layer, cellular infiltration and sclerosis sites. With exacerbation of chronic bronchitis, infiltration with neutrophilic leukocytes, lymphoid and plasma cells is noted.

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