Causes and pathogenesis of emphysema

In 1965, Eriksson described the deficiency of a1-antitrypsin. At the same time, it was suggested that there is a connection between the development of emphysema and the deficit of a1-antitrypsin. In an animal experiment, a model of lung emphysema was reproduced by introducing extracts of proteolytic enzymes from plants into the lungs.

Primary diffuse emphysema

Genetically determined deficiency of α1-antitrypsin

A1-antitrypsin is the main inhibitor of serine proteases, which include trypsin, chymotrypsin, neutrophil elastase, tissue kallikrein, factor X- and plasminogen. The a1-antitrypsin gene is located on the long arm of chromosome 14 and is called the proteinase inhibitor (PI) gene. The PI gene is expressed in two types of cells - macrophages and hepatocytes.

The highest concentration of a1-antitrypsin is found in serum and about 10% of the serum level is determined on the surface of epithelial cells of the respiratory tract.

Currently, there are 75 alleles of the PI gene. They are divided into 4 groups:

• normal - with a physiological level of concentration in serum of blood a1-antitrypsin;
• deficient - the concentration level of the trypsin inhibitor is reduced to 65% of the norm;
• "Zero" -al-antitrypsin in serum is not determined;
• in serum, the content of a-antitrypsin is normal, but its activity against elastase is reduced.

PI alleles are also subdivided depending on the electrophoretic mobility of the α1-antitrypsin glycoprotein:

• option "A" - is located closer to the anode;
• option "- cathode;
• option "M" - the most frequent.

The main share of the gene pool (over 95%) is made up of three subtypes of the normal allele "M" - M1, M2, MZ.

The pathology of a person due to the PI gene occurs in scarce and zero alleles. The main clinical manifestations of a1-antitrypsin deficiency are emphysema and juvenile cirrhosis of the liver.

In a healthy person, neutrophils and alveolar macrophages in the lungs secrete proteolytic enzymes (primarily elastase) in an amount sufficient for the development of emphysema, but this is prevented by alpha1-antitrypsin, which is present in the blood, bronchial secretion and other tissue structures.

In case of genetically determined deficiency of alpha1-antitrypsin, as well as its lack due to smoking, aggressive etiologic factors, occupational hazards, the shift in the proteolysis / alpha1 antitrypsin system occurs towards proteolysis, which causes damage to the alveolar walls and the development of emphysema.

Effects of tobacco smoke

Smoking is considered one of the most aggressive factors in the development of chronic obstructive pulmonary disease in general and emphysema in particular. The development of emphysema in smokers is due to the fact that tobacco smoke causes the migration of neutrophils to the terminal section of the respiratory tract. Neutrophils produce large amounts of proteolytic enzymes elastase and cathepsin, which have a destructive effect on the elastic base of the alveoli.

In addition, chronic smoking in alveolar macrophages accumulates tar of tobacco smoke, and the formation of alpha-1 antitrypsin in them sharply decreases.

Smoking also causes an imbalance in the oxidant / antioxidant system with a predominance of oxidants, which has a damaging effect on the alveolar walls and promotes the development of emphysema.

It is still not clear why smoking causes the development of emphysema only in 10-15% of smokers. In addition to deficiency of alpha1-antitrypsin, some unknown factors (possibly genetic ones) that predispose smoking to developing emphysema probably play a role.

[1], [2], [3], [4], [5]

The impact of aggressive environmental factors

"Emphysema to a certain extent is a disease environmentally conditioned" (AG Chuchalin, 1998). Aggressive factors polluted environment (pollutants) cause damage not only to the respiratory tract, but also alveolar walls, contributing to the development of emphysema. Among the pollutants, sulfur dioxide and nitrogen dioxide are of the greatest importance, their main generators are thermal stations and transport. In addition, black smoke and ozone play an important role in the development of emphysema. Elevated ozone concentrations are associated with the use of freon in their daily lives (refrigerators, household aerosols, perfumes, aerosol dosage forms). In hot weather, the photochemical reaction of nitrogen dioxide (the combustion product of transport fuel) with the ultraviolet takes place in the atmosphere, ozone is formed, which causes the development of inflammation of the upper respiratory tract.

The mechanism of the development of emphysema due to long-term exposure to atmospheric pollutants is as follows:

• direct damaging effect on the alveolar membranes;
• activation of proteolytic and oxidative activity in the bronchopulmonary system, which causes destruction of the elastic framework of the pulmonary alveoli;
• increased production of mediators of inflammatory reactions - leukotrienes and damaging cytokines.

Occupational hazards, the presence of persistent or recurrent bronchopulmonary infection

In elderly people, whose emphysema is detected especially often, the simultaneous effect of several etiological factors during many years of life is affected. In some cases a certain role is played by mechanical stretching of the lungs (in musicians of brass bands, glass blowers).

Pathogenesis

The main common mechanisms for the development of emphysema are:

• violation of the normal ratio of protease / alpha1-antitrypsin and oxidants / antioxidants to the predominance of wall-damaging alveoli of proteolytic enzymes and oxidants;
• disruption of synthesis and function of surfactant;
• dysfunction of fibroblasts (according to the hypothesis of Times et al., 1997).

Fibroblasts play an important role in the process of repair of pulmonary tissue. It is known that the structuring and restructuring of lung tissue is due to interstitial and its two main components - fibroblasts and extracellular matrix. The extracellular matrix is synthesized by fibroblasts, it binds the bronchi, vessels, nerves, and alveoli into a single functional block. Thus, the lung tissue is structured. Fibroblasts interact with cells of the immune system and extracellular matrix through the synthesis of cytokines.

The main components of the extracellular matrix are collagen and elastin. The first and third types of collagen stabilize the interstitial tissue, the fourth type of collagen is part of the basal membrane. Elastin provides elastic properties of lung tissue. The relationship between the various molecules of the extracellular matrix is provided by proteoglycans. The structural relationship between collagen and elastin is provided by proteoglycans with decorin and dermatan sulfate; The relationship between the fourth type of collagen and laminin in the basal membrane is carried by proteoglycan heparan sulfate.

Proteoglycans affect the functional activity of receptors on the cell surface and are involved in repair of lung tissue.

The early phase of repair of pulmonary tissue is associated with the proliferation of fibroblasts. Then neutrophils migrate to the damaged pulmonary tissue site, where they take an active part in the depolymerization of extracellular matrix molecules. These processes are regulated by various cytokines produced by alveolar macrophages, neutrophils, lymphocytes, epithelial cells, fibroblasts. The reparative process involves cytokines - platelet growth factors, colony-stimulating factor of granulocytes / macrophages. The cytokine depot is formed in the extracellular matrix and regulates the proliferative activity of fibroblasts.

Thus, in the development of emphysema, a major role is played by dysfunction of fibroblasts and adequate repair processes of damaged lung tissue.

The main pathophysiological consequences of emphysema are:

• collapse (collapse) of small, free-running bronchial tubes on exhalation and development of violations of pulmonary ventilation of the obstructive type;
• a progressive decrease in the functioning surface of the lungs, which leads to the reduction of alveolar-capillary membranes, a sharp decrease in oxygen diffusion and the development of respiratory failure;
• Reduction of the capillary network of the lungs, which leads to the development of pulmonary hypertension.

Pathomorphology

Emphysema of the lungs is characterized by expansion of the alveoli, respiratory passages, a general increase in the airiness of the lung tissue, degeneration of the elastic fibers of the alveolar walls, and the desolation of the capillaries.

The anatomical classification of emphysema is based on the degree of involvement of the acinus in the pathological process. The following anatomical variants are distinguished:

• proximal acinar emphysema;
• panacinar emphysema;
• distal emphysema;
• irregular emphysema.

The proximal acinar form is characterized in that the respiratory bronchiola, which is the proximal part of the acinus, is abnormally enlarged and damaged. Two forms of proximal acinar emphysema are known: centrolobular and emphysema in pneumoconiosis of miners. In the centrilobular form of proximal acinar emphysema, respiratory bronchioles change proximally to the acinus. This creates the effect of a central location in the lobe of the lung. The distally located lung tissue is not changed.

Pneumoconiosis of miners is characterized by a combination of interstitial pulmonary fibrosis and focal sites of emphysema.

Panacinar (diffuse, generalized, alveolar) emphysema is characterized by the involvement of the whole acinus in the process.

Distal acinar emphysema is characterized by involvement in the pathological process of predominantly alveolar courses.

The irregular (irregular) form of emphysema is characterized by a variety of increases in acini and their destruction and is combined with a pronounced cicatricial process in the lung tissue. This causes the irregular nature of emphysema.

A special form of emphysema is bullous. Bulla is the emphysema of the lung with a diameter of more than 1 cm.

To a certain extent, involuntary (senile) emphysema of the lungs can be referred to primary emphysema. It is characterized by the expansion of the alveoli and respiratory passages without reduction of the vascular system of the lungs. These changes are considered a manifestation of involution, aging.

With involute emphysema, there are no significant violations of bronchial permeability, hypoxemia and hypercapnia do not develop.

Secondary emphysema of the lungs

Secondary emphysema may be focal or diffuse. The following forms of focal emphysema are distinguished: near-scarlet (perifocal), infant (lobar), paraseptal (interstitial) and unilateral emphysema of the lung or lobe.

Circumbar pulmonary emphysema - occurs around the foci of pneumonia, tuberculosis, and sarcoidosis. The main role in the development of focal emphysema of the lungs is played by regional bronchitis. Circumbar pulmonary emphysema is usually localized in the region of the apex of the lungs.

Infantile fractional emphysema is an emphysema change in one lobe of the lung in young children, usually due to atelectasis in other lobes. Most often affects the upper lobe of the left lung and the middle lobe of the right. Infantious lobar emphysema manifests itself as pronounced dyspnea.

MacLeod syndrome (unilateral emphysema) - usually develops after a childhood suffering from unilateral bronchiolitis or bronchitis.

Paraseptal emphysema is the focus of emphysema-modified lung tissue adjacent to a tight connective tissue septum or pleura. Usually develops as a result of focal bronchitis or bronchiolitis. Clinically manifested by the formation of bullae and spontaneous pneumothorax.

Significantly more important is secondary diffuse emphysema of the lungs. The main cause of its development is chronic bronchitis.

It is known that narrowing of small bronchi and an increase in bronchial resistance occurs both during inspiration and during exhalation. In addition, with exhalation, the positive intrathoracic pressure creates an additional compression of the already poorly passable bronchi and causes delayed inspiratory air in the alveoli and increased pressure in them, which naturally leads to the gradual development of emphysema. It is also important to spread the inflammatory process from the small bronchi to the respiratory bronchioles and alveoli.

Local obstruction of small bronchi leads to overstretching of small areas of lung tissue and the formation of thin-walled cavities - bullae, located subpleurally. With multiple bullae, pulmonary tissue is compressed, further exacerbating secondary obstructive disturbances of gas exchange. The rupture of bulla leads to spontaneous pneumothorax.

With secondary diffuse emphysema, there is a reduction in the capillary network of the lungs, precapillary pulmonary hypertension develops. In turn, pulmonary hypertension contributes to the fibrosis of functioning small arteries.