Chronic obstructive bronchitis - Causes and pathogenesis

Etiological factors of chronic obstructive bronchitis. These are smoking (active and passive), air pollution (environmental aggression), industrial (professional) hazards, severe congenital deficiency of a1-antitrypsin, respiratory viral infections, bronchial hyperreactivity. There are absolute and probable risk factors for the development of chronic obstructive bronchitis.

The most important etiologic factor is smoking. However, it should be noted that smoking itself is not enough to develop COPD. It is known that COPD occurs in only 15% of long-term smokers. According to the "Dutch hypothesis", a genetic predisposition to damage to the respiratory tract is necessary for the development of chronic obstructive bronchitis when smoking.

Risk factors for chronic obstructive bronchitis

The main risk factor for the development of COPD in 80-90% of cases is tobacco smoking. Among "smokers" chronic obstructive pulmonary disease develops 3-9 times more often than among non-smokers. At the same time, mortality from COPD is determined by the age at which smoking was started, the number of cigarettes smoked and the duration of smoking. It should be noted that the problem of smoking is especially relevant for Ukraine, where the prevalence of this bad habit reaches 60-70% among men and 17-25% among women.

In this case, the impact of tobacco smoke on the lungs is important not only as one of the most important factors that disrupt the function of the mucociliary transport system, the cleansing and protective function of the bronchi, but also as a factor in the occurrence of chronic inflammation of the bronchial mucosa. The long-term irritating effect of tobacco smoke on the alveolar tissue and the surfactant system contributes to the disruption of the elasticity of the lung tissue and the occurrence of pulmonary emphysema.

The second risk factor for the development of COPD is occupational hazards, in particular work in production associated with the inhalation of dust containing cadmium, silicon and some other substances.

Professional groups with an increased risk of developing chronic obstructive pulmonary disease include:

• miners;
• builders;
• workers of metallurgical enterprises;
• railroad workers;
• workers engaged in the processing of grain, cotton and paper production, and others.

The third risk factor is repeated acute respiratory viral infections (ARVI), which also contribute to the disruption of the cleansing and protective function of the bronchi, seeding the bronchial mucosa with pathogenic and opportunistic microorganisms that initiate a chronic inflammatory process in the bronchi. In patients with already developed COPD, repeated ARVI accelerates the occurrence of pulmonary ventilation disorders and the formation of broncho-obstructive syndrome and respiratory failure.

Hereditary predisposition to chronic obstructive pulmonary disease also plays a significant role. Currently, the only proven and well-studied genetic pathology leading to the development of COPD is a1-antitrypsin deficiency, which leads to the development of pulmonary emphysema and chronic obstructive syndrome. However, this genetic deficiency among patients with chronic obstructive bronchitis and COPD occurs in less than 1% of cases. Most likely, there are other, as yet unstudied, genetic defects that contribute to the formation of broncho-obstructive syndrome, pulmonary emphysema and the development of respiratory failure. This is indicated, in particular, by the fact that not all smokers or those who have occupational hazards develop COPD.

In addition to the listed factors, a certain significance is apparently attached to being male, age 40-50 years, disorders of the local and general immune system, hyperreactivity of the bronchi to various irritating and damaging factors and some others, although the role of many of these factors in the development of COPD has not yet been proven.

A list of some risk factors for the development of COPD, given in the standards of the European Respiratory Society (ERS, GOLD, 2000).

Risk factors for COPD (according to ERS, GOLD, 2000)

Probability of the value of factors	External factors	Internal factors
Installed	Smoking. Occupational hazards (cadmium, silicon)	α1-antitrypsin deficiency
Tall	Pollution of ambient air (especially SO2, NJ2, 03). Other occupational hazards, poverty, low socioeconomic status. Passive smoking in childhood	Prematurity. High IgE level. Bronchial hyperreactivity. Familial nature of the disease.
Possible	Adenoviral infection. Vitamin C deficiency	Genetic predisposition [blood group A (II), no IgA]

The main pathogenetic factors of chronic obstructive bronchitis are dysfunction of the local bronchopulmonary defense system, structural reorganization of the bronchial mucosa (hypertrophy of the mucous and serous glands, replacement of the ciliated epithelium with goblet cells), development of the classical pathogenetic triad (hypercrinia, dyscrinia, mucostasis) and the release of inflammatory mediators and cytokines.

In addition, mechanisms of bronchial obstruction are included. They are divided into two groups: reversible and irreversible.

Group I - reversible mechanisms of bronchial obstruction:

• bronchospasm; it is caused by excitation of m-cholinergic receptors and receptors of the non-adrenergic, non-cholinergic nervous system;
• inflammatory edema, infiltration of the mucous and submucous membranes of the bronchi;
• obstruction of the respiratory tract with mucus due to impaired expectoration. As the disease progresses, this mechanism becomes increasingly pronounced, as the ciliated epithelium of the bronchi is transformed into mucus-forming (i.e. goblet cells). The number of goblet cells increases 10-fold over 5-10 years of the disease. Gradually, the rate of daily accumulation of mucus in the bronchial tree exceeds the rate of its removal.

Group II - irreversible mechanisms of bronchial obstruction (these mechanisms are based on morphological disorders):

• stenosis, deformation and obliteration of the bronchial lumen;
• fibroplastic changes in the bronchial wall;
• expiratory collapse of small bronchi due to decreasing production of surfactant and gradually developing pulmonary emphysema;
• expiratory prolapse of the membranous part of the trachea and large bronchi into their lumen.

The insidiousness of obstructive lung diseases is that in the absence of systematic treatment, reversible mechanisms are replaced by irreversible ones, unnoticed by the patient and the doctor, and the disease gets out of control after 12-15 years.

Pathomorphology of chronic obstructive bronchitis

In the large bronchi, characteristic changes are observed:

• enlargement of submucosal glands;
• goblet cell hyperplasia;
• predominance of mononuclear cells and neutrophils in the mucous membrane;
• atrophic changes in cartilage as the disease progresses.

Small bronchi and bronchioles also undergo characteristic morphological changes:

• the appearance and increase in the number of goblet cells;
• increased amount of mucus in the lumen of the bronchi;
• inflammation, increase in the mass of the muscular membrane, fibrosis, obliteration, narrowing of the lumen.

Formation of COPD

At the initial stage of the disease, the impact of the described factors, some of which can be attributed to etiological factors (smoking, industrial and household dust, infections, etc.), on the bronchial mucosa, interstitial tissue and alveoli leads to the formation of a chronic inflammatory process that affects all of the listed structures. In this case, all cellular elements of neutrophils, macrophages, mast cells, platelets, etc. are activated.

The main role in the development of inflammation is given to neutrophils, the concentration of which in the area of chronic irritation of the bronchial mucosa increases several times. Then penetrating into the intercellular space, neutrophils secrete cytokines, prostaglandins, leukotrienes and other proinflammatory substances that contribute to the formation of chronic inflammation of the bronchial mucosa, hyperplasia of goblet cells, including in places not typical for their localization, i.e. in the distal (small) bronchi. In other words, the described processes lead to the formation of a universal response of the body - inflammation to chronic irritation of the bronchial mucosa.

Thus, at the initial stages of the disease development, its pathogenetic mechanisms resemble the mechanisms of formation of chronic non-obstructive bronchitis. The fundamental differences are that with COPD:

1. the inflammation affects bronchi of different sizes, including the smallest bronchioles, and
2. The activity of inflammation is significantly higher than in chronic non-obstructive bronchitis.

Formation of pulmonary emphysema

The formation of pulmonary emphysema is a key moment in the development of COPD and the progression of respiratory failure characteristic of this disease. As is known, the destruction of elastic fibers of the lung tissue, which develops mainly as a result of the pathogenic action of neutrophils, which accumulate in large quantities in the intercellular space, is of decisive importance in this process.

Against the background of the long-term irritating effect of tobacco smoke and other volatile pollutants, seeding of the mucous membrane with viruses and/or microbes, the content of neutrophils in the distal parts of the respiratory system increases 10-fold. At the same time, the release of proteases (elastase) and free oxygen radicals by neutrophils, which have a strong damaging (destructive) effect on all molecular components of tissues and a cytopathogenic effect, sharply increases. At the same time, the local antiprotease and antioxidant potential is quickly depleted, which leads to the destruction of structural elements of the alveoli and the formation of pulmonary emphysema. In addition, various components of tobacco smoke inactivate the alpha1-antiprotease inhibitor, further reducing the antiprotease potential of tissues.

The main reason for the destruction of the elastic framework of the lung tissue is a pronounced imbalance in the protease-antiprotease and oxidant-antioxidant systems, caused by the pathogenic functioning of neutrophils that accumulate in large quantities in the distal parts of the lungs.

In addition, a shift in the relationship between damage and reparation processes is important, which are regulated, as is known, by a large number of proinflammatory and anti-inflammatory mediators. Disturbance of the balance of these processes also contributes to the destruction of the elastic framework of the lung tissue.

Finally, impaired mucociliary clearance, hypercrinia and dyscrinia of mucus create conditions for colonization by microflora, which further activates neutrophils, macrophages, and lymphocytes, which also enhances the destructive potential of cellular elements of inflammation.

All the described elements of chronic inflammation lead to the destruction of the alveolar walls and interalveolar septa, an increase in the airiness of the lung tissue and the formation of pulmonary emphysema.

Since in COPD inflammation primarily affects the terminal and respiratory bronchioles, destruction of the alveoli and increased airiness of the lung tissue are often focal, localized primarily in the central parts of the acinus, which are surrounded by macroscopically slightly changed pulmonary parenchyma. This centroacinar form of emphysema is typical for patients with the bronchitis type of chronic obstructive bronchitis. In other cases, a panacinar form of emphysema is formed, typical for patients with the emphysematous type of chronic obstructive bronchitis.

Broncho-obstructive syndrome

Broncho-obstructive syndrome, which is a characteristic and obligatory sign of chronic obstructive bronchitis and COPD, is formed, as is known, due to reversible and irreversible components of bronchial obstruction. At the initial stages of the disease, the reversible component of bronchial obstruction predominates, which is caused by three main mechanisms:

• inflammatory swelling of the bronchial mucosa;
• hypersecretion of mucus;
• spasm of the smooth muscles of the small bronchi.

In patients with COPD, especially in the acute phase of the disease, there is a pronounced narrowing of the lumen of small bronchi and bronchioles with a diameter of less than 2 mm, up to the occlusion of individual peripheral respiratory tracts with mucous plugs. There is also hypertrophy of the smooth muscles of the small bronchi and their tendency to spastic contraction, which further reduces the total lumen of the airways and contributes to an increase in overall bronchial resistance.

The causes and mechanisms of bronchospasm in chronic obstructive bronchitis, bronchial asthma or other diseases of the airways are different. However, it should be borne in mind that the bacterial and viral-bacterial infection itself and the chronic inflammatory process in the bronchi are usually accompanied by a decrease in sensitivity and loss of beta2-adrenergic receptors, stimulation of which is known to be accompanied by a bronchodilating effect.

In addition, patients with COPD have an increased tone of the wandering pepper. A tendency to bronchospasm is more characteristic of patients with bronchial asthma. However, in patients with chronic obstructive bronchitis, hyperreactivity of the small bronchi also has a certain significance in the pathogenesis of broncho-obstructive syndrome, although the term "asthmoid" bronchitis or bronchitis with an "asthmoid component" that was widely used in the past is not recommended for use at present.

Further progression of the disease leads to an increasing predominance of the irreversible component of bronchial obstruction, which is determined by the developing pulmonary emphysema and structural changes in the respiratory tract, primarily peribronchial fibrosis.

The most important cause of irreversible bronchial obstruction in patients with chronic obstructive bronchitis and pulmonary emphysema is early expiratory closure of the bronchi, or expiratory collapse of small bronchi. This is primarily due to a decrease in the supporting function of the pulmonary parenchyma, which has lost its elasticity, for small airways - bronchioles. The latter are, as it were, immersed in the lung tissue, and the alveoli are tightly adjacent to their walls, the elastic recoil of which normally keeps these airways open throughout inhalation and exhalation. Therefore, a decrease in the elasticity of the lung tissue in patients with pulmonary emphysema leads to a collapse of the small bronchi in the middle or even at the beginning of exhalation, when the volume of the lungs decreases and the elastic recoil of the lung tissue quickly falls.

In addition, the insufficiency of bronchoalveolar surfactant is important, the synthesis of which is significantly reduced in COPD patients who abuse smoking. The lack of surfactant leads, as is known, to an increase in the surface tension of the alveolar tissue and even greater "instability" of the small airways.

Finally, peribronchial fibrosis, which develops in patients with COPD as a result of chronic inflammation, and other structural changes in the airways (thickening of the walls and deformation of the bronchi), are also of great importance in the development and progression of broncho-obstructive syndrome, but their role in the formation of the irreversible component of obstruction is less than the role of pulmonary emphysema.

In general, a significant predominance of the irreversible component of bronchial obstruction in patients with COPD, as a rule, means the onset of the final stage of the disease, characterized by rapid progression of respiratory and pulmonary-cardiac failure.

Respiratory failure

Slow progression of respiratory failure is the third mandatory sign of COPD. Chronic obstructive respiratory failure ultimately leads to severe gas exchange disorders and is the main cause of decreased exercise tolerance, performance, and death in patients with COPD.

Let us recall that from a practical point of view, there are two main forms of respiratory failure:

Parenchymatous (hypoxemic), developing mainly as a result of a sharp ventilation-perfusion relationship in the lungs and an increase in intrapulmonary right-to-left heart shunting of blood, which leads to arterial hypoxemia (PaO2 < 80 mm Hg).

Ventilatory (hypercapnic) form of respiratory failure, which occurs as a result of a primary disruption of effective pulmonary ventilation (alveolar hypoventilation), which is accompanied by both a decrease in the removal of CO2 from the body (hypercapnia) and a disruption of blood oxygenation (hypoxemia).

For patients with COPD at a certain stage of the disease, the most typical is a combination of arterial hypoxemia and hypercapnia, i.e. a mixed form of respiratory failure. Several main mechanisms can be identified that determine gas exchange and ventilation disorders in patients with COPD:

1. Bronchial obstruction resulting from bronchial mucosal edema, bronchospasm, mucus hypersecretion and expiratory collapse of small bronchi in patients with concomitant pulmonary emphysema. Airway obstruction leads to the development of hypoventilated or completely non-ventilated zones, as a result of which the blood flowing through them is insufficiently oxygenated, resulting in a decrease in PaO2, i.e. arterial hypoxemia develops. Thus, broncho-obstructive syndrome itself significantly complicates alveolar ventilation, which is further aggravated by the development of microatelectasis in areas of critical bronchial narrowing.
2. A decrease in the total area of the functioning alveolar-capillary membrane in patients with severe pulmonary emphysema. As a result of the destruction of the interalveolar septa, the volume of the alveoli increases, and their total surface area decreases significantly.
3. Decreased ventilation as a result of a decrease in the reserve volume of inspiration, typical for patients with pulmonary emphysema, which occurs due to a change in configuration, an increase in the volume of the chest and an increase in its rigidity.
4. Severe fatigue of the respiratory muscles, primarily the diaphragm, developing as a result of a significant increase in the load on the respiratory muscles in patients with broncho-obstructive syndrome and pulmonary emphysema.
5. Decreased function of the diaphragm as a result of its flattening, which is typical for patients with pulmonary emphysema,
6. Impaired diffusion of gases at the level of the alveolar-capillary membrane due to its thickening, impaired microcirculation and desolation of peripheral vessels.

As a result of the implementation of some of these mechanisms, ventilation-perfusion relations in the lungs are disrupted, as a result of which insufficiently oxygenated blood flows out of the lungs, which is accompanied by a decrease in PaO2. Indeed, the destruction of the respiratory tract leads to the emergence of hypoventilated or completely non-ventilated zones, as a result of which the blood flowing through them is insufficiently oxygenated. As a result, PaO2 decreases and arterial hypoxemia develops.

Further progression of structural and functional changes in the lungs leads to a decrease in the efficiency of pulmonary ventilation (for example, as a result of impaired respiratory muscle function), which is accompanied by an increase in the ventilation form of respiratory failure with the development of hypercapnia (an increase in PaCO2 greater than 45 mm Hg).

The mixed form of respiratory failure is especially pronounced during periods of exacerbation of the disease, when, on the one hand, bronchial patency is sharply impaired, and on the other hand, the weakness (fatigue) of the respiratory muscles (diaphragm) increases, arising against the background of a sharp increase in the load on them.

Let us recall that the severity of respiratory failure is usually assessed based on the oxygen tension (PaO2) and carbon dioxide (PaCO2) in arterial blood.

Assessment of the severity of respiratory failure (arterial blood gas tension expressed in mm Hg)

Degree of DN	Parenchymatous DN	Ventilation DN
Moderate	Ra0 2 > 70	RaCO 2 < 50
Moderate severity	Ra0 2 = 70-50	RaCO2 = 50-70
Heavy	Ra0 2 < 50	RaCO 2 > 70 Hypercapnic coma

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