Causes and pathogenesis of pulmonary emphysema

In 1965, Eriksson described a1-antitrypsin deficiency. At the same time, a hypothesis was made about the existence of a connection between the development of emphysema and a1-antitrypsin deficiency. In an experiment on animals, a model of pulmonary emphysema was reproduced by introducing extracts of proteolytic enzymes from plants into the lungs.

Primary diffuse pulmonary emphysema

Genetic alpha1-antitrypsin deficiency

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

The highest concentration of alpha1-antitrypsin is found in blood serum and about 10% of the serum level is determined on the surface of the epithelial cells of the respiratory tract.

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

• normal - with a physiological level of concentration of a1-antitrypsin in the blood serum;
• deficient - the concentration level of trypsin inhibitor decreases to 65% of the norm;
• "zero" -a1-antitrypsin is not detected in the blood serum;
• In serum, the content of alpha1-antitrypsin is normal, but its activity in relation to elastase is reduced.

PI alleles are also subdivided depending on the electrophoretic mobility of the glycoprotein a1-antitrypsin:

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

The main share of the gene pool (over 95%) is made up of three subtypes of the normal allele “M” - M1, M2, M3.

Human pathology caused by the PI gene occurs in deficiency and null alleles. The main clinical manifestations of a1-antitrypsin deficiency are pulmonary emphysema and juvenile liver cirrhosis.

In a healthy person, neutrophils and alveolar macrophages in the lungs secrete proteolytic enzymes (primarily elastase) in quantities sufficient to develop emphysema, but this is prevented by alpha1-antitrypsin, which is present in the blood, bronchial secretions, and other tissue structures.

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

The effects of tobacco smoke

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

It is still unclear why smoking causes emphysema in only 10-15% of smokers. In addition to alpha1-antitrypsin deficiency, unknown factors (possibly genetic) probably play a role in predisposing smokers to emphysema.

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Impact of aggressive environmental factors

"Emphysema is to a certain extent an environmentally conditioned disease" (A. G. Chuchalin, 1998). Aggressive factors of the polluted external environment (pollutants) cause damage not only to the respiratory tract, but also to the alveolar walls, contributing to the development of pulmonary emphysema. Among the pollutants, sulfur and nitrogen dioxides are of the greatest importance; their main generators are thermal power plants and transport. In addition, black smoke and ozone play a major role in the development of pulmonary emphysema. Increased ozone concentrations are associated with the use of freon in everyday life (refrigerators, household aerosols, perfumes, aerosol dosage forms). In hot weather, a photochemical reaction of nitrogen dioxide (a product of combustion of transport fuel) with ultraviolet radiation occurs in the atmosphere, ozone is formed, which causes the development of inflammation of the upper respiratory tract.

The mechanism of development of pulmonary emphysema under the influence of 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 the destruction of the elastic framework of the pulmonary alveoli;
• increased production of inflammatory reaction mediators - leukotrienes and damaging cytokines.

Occupational hazards, presence of persistent or recurrent bronchopulmonary infection

In elderly people, in whom pulmonary emphysema is detected especially often, the simultaneous influence of several etiological factors over many years of life usually has an effect. In some cases, mechanical stretching of the lungs plays a certain role (in brass band musicians, glassblowers).

Pathogenesis

The main general mechanisms of development of pulmonary emphysema are:

• disruption of the normal ratio of protease/alpha1-antitrypsin and oxidants/antioxidants towards the predominance of proteolytic enzymes and oxidants that damage the alveolar wall;
• disruption of surfactant synthesis and function;
• fibroblast dysfunction (according to the hypothesis of Times et al., 1997).

Fibroblasts play an important role in the process of lung tissue reparation. It is known that structuring and restructuring of lung tissue is carried out by the interstitium and its two main components - fibroblasts and extracellular matrix. Extracellular matrix is synthesized by fibroblasts, it connects bronchi, vessels, nerves, alveoli into a single functional block. In this way, lung tissue is structured. Fibroblasts interact with immune system cells and extracellular matrix by synthesizing 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 basement membrane. Elastin provides elastic properties of the lung tissue. The connection between different molecules of the extracellular matrix is provided by proteoglycans. The structural connection between collagen and elastin is provided by the proteoglycans decorin and dermatan sulfate; the connection between the fourth type of collagen and laminin in the basement membrane is provided by the proteoglycan heparan sulfate.

Proteoglycans influence the functional activity of receptors on the cell surface and participate in the processes of lung tissue reparation.

The early phase of lung tissue reparation is associated with fibroblast proliferation. Neutrophils then migrate to the damaged lung tissue site, where they actively participate in the depolymerization of extracellular matrix molecules. These processes are regulated by various cytokines produced by alveolar macrophages, neutrophils, lymphocytes, epithelial cells, and fibroblasts. Cytokines are involved in the reparative process - platelet growth factors, granulocyte/macrophage colony-stimulating factor. A cytokine depot is formed in the extracellular matrix and regulates the proliferative activity of fibroblasts.

Thus, in the development of pulmonary emphysema, a major role is played by the disruption of fibroblast function and adequate processes of reparation of damaged lung tissue.

The main pathophysiological consequences of emphysema are:

• collapse of small non-cartilaginous bronchi during exhalation and the development of obstructive pulmonary ventilation disorders;
• progressive reduction in the functioning surface of the lungs, which leads to a reduction in 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 the expansion of the alveoli, respiratory tract, a general increase in the airiness of the lung tissue, degeneration of the elastic fibers of the alveolar walls, and desolation of the capillaries.

The anatomical classification of pulmonary 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 by the fact that the respiratory bronchiole, which is the proximal part of the acinus, is abnormally enlarged and damaged. There are two forms of proximal acinar emphysema: centrilobular and emphysema in miners' pneumoconiosis. In the centrilobular form of proximal acinar emphysema, the respiratory bronchiole changes proximal to the acinus. This creates the effect of a central location in the lung lobule. The distal lung tissue is not changed.

Miners' pneumoconiosis is characterized by a combination of interstitial pulmonary fibrosis and focal areas of emphysema.

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

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

The irregular form of emphysema is characterized by a variety of enlargement of 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. A bulla is an emphysematous area of the lung with a diameter of more than 1 cm.

Primary emphysema to a certain extent includes involutional (senile) emphysema of the lungs. It is characterized by the expansion of the alveoli and respiratory tract without reduction of the vascular system of the lungs. These changes are considered a manifestation of involution, aging.

With involutional pulmonary emphysema, there are no significant disturbances in bronchial patency; hypoxemia and hypercapnia do not develop.

Secondary pulmonary emphysema

Secondary pulmonary emphysema may be focal or diffuse. The following forms of focal emphysema are distinguished: periscar (perifocal), infantile (lobar), paraseptal (intermediate) and unilateral emphysema of the lung or lobe.

Pericardial emphysema of the lungs - occurs around foci of previous pneumonia, tuberculosis, sarcoidosis. Regional bronchitis plays the main role in the development of focal emphysema of the lungs. Pericardial emphysema of the lungs is usually localized in the area of the apex of the lungs.

Infantile lobar emphysema is an emphysematous change in one lobe of the lung in young children, usually due to atelectasis in other lobes. The upper lobe of the left lung and the middle lobe of the right lung are most often affected. Infantile lobar emphysema manifests itself as severe dyspnea.

McLeod syndrome (unilateral emphysema) - usually develops after unilateral bronchiolitis or bronchitis suffered in childhood.

Paraseptal emphysema is a focus of emphymatously altered lung tissue adjacent to a compacted connective tissue septum or pleura. It usually develops as a result of focal bronchitis or bronchiolitis. Clinically, it is manifested by the formation of bullae and spontaneous pneumothorax.

Of much greater importance is secondary diffuse pulmonary emphysema. The main cause of its development is chronic bronchitis.

It is known that the narrowing of small bronchi and the increase in bronchial resistance occur both during inhalation and exhalation. In addition, during exhalation, positive intrathoracic pressure creates additional compression of the already poorly passable bronchi and causes a delay of inspired air in the alveoli and an increase in pressure in them, which, naturally, leads to the gradual development of pulmonary emphysema. The spread of the inflammatory process from small bronchi to the respiratory bronchioles and alveoli is also of significant importance.

Local obstruction of small bronchi leads to overstretching of small areas of lung tissue and formation of thin-walled cavities - bullae, located subpleurally. With multiple bullae, lung tissue is compressed, which further aggravates secondary obstructive gas exchange disorders. Rupture of a bulla leads to spontaneous pneumothorax.

In secondary diffuse emphysema, the capillary network of the lungs is reduced, and precapillary pulmonary hypertension develops. In turn, pulmonary hypertension promotes fibrosis of functioning small arteries.