Pathogenesis of pneumonia

The development of community-acquired or hospital-acquired pneumonia occurs as a result of the implementation of several pathogenetic mechanisms, the most important of which are:

• disruption of the complex multi-stage system of protection of the respiratory organs from the penetration of microorganisms into the respiratory sections of the lungs;
• mechanisms of development of local inflammation of lung tissue;
• formation of systemic manifestations of the disease;
• formation of complications.

In each specific case, the characteristics of the pathogenesis and clinical course of pneumonia are determined by the properties of the pathogen and the state of various systems of the macroorganism involved in the inflammation.

[ 1 ], [ 2 ], [ 3 ], [ 4 ], [ 5 ], [ 6 ], [ 7 ], [ 8 ], [ 9 ], [ 10 ]

Pathways of microorganism penetration into the respiratory parts of the lungs

There are three main ways in which microorganisms enter the respiratory tract of the lungs:

The bronchogenic route is the most common route of infection of the lung tissue. In most cases, bronchogenic spread of microorganisms occurs as a result of microaspiration of the contents of the oropharynx. It is known that in a healthy person, the microflora of the oropharynx is represented by a large number of aerobic and anaerobic bacteria. Pneumococci, Haemophilus influenzae, Staphylococcus aureus, anaerobic bacteria and even gram-negative Escherichia coli, Friedlander's bacillus and Proteus are found here.

Microaspiration of the oropharyngeal contents is known to occur in healthy people, for example, during sleep. However, normally the airways located distal to the vocal cords (larynx) always remain sterile or contain a small amount of bacterial flora. This occurs as a result of the normal functioning of the defense system (mucociliary clearance, cough reflex, humoral and cell-mediated defense systems).

Under the influence of these mechanisms, the oropharyngeal secretion is effectively removed and colonization of the lower respiratory tract by microorganisms does not occur.

More massive aspiration into the lower respiratory tract occurs when self-cleaning mechanisms are impaired. This is more often observed in elderly patients, in persons with impaired consciousness, including those in a state of alcohol intoxication, in case of an overdose of sleeping pills or drugs, in case of metabolic dyscirculatory encephalopathy, convulsive syndrome, etc. In these cases, suppression of the cough reflex and the reflex providing a reflex spasm of the glottis is often observed (JV Hirschman).

The likelihood of dysphagia and aspiration of oropharyngeal contents increases significantly in patients with gastrointestinal diseases - achalasia of the esophagus, gastroesophageal reflux, diaphragmatic hernia, decreased tone of the esophagus and stomach with hypo- and achlorhydria.

Swallowing dysfunction and a high probability of aspiration are also observed in patients with systemic connective tissue diseases: polymyositis, systemic scleroderma, mixed connective tissue disease (Sharp syndrome), etc.

One of the most important mechanisms of nosocomial pneumonia development is the use of an endotracheal tube in patients on artificial lung ventilation (ALV). The moment of intubation itself is characterized by the highest risk of aspiration and is the main pathogenetic mechanism of development of hospital-acquired asiration pneumonia in the first 48 hours of ALV. However, the endotracheal tube itself, preventing the closure of the glottis, contributes to the development of microaspiration. When turning the head and body, movements of the endotracheal tube inevitably occur, contributing to the penetration of secretion into the distal parts of the respiratory tract and seeding of the lung tissue (RG Wunderink).

An important mechanism of colonization of the respiratory tract by microorganisms is the disruption of mucociliary transport, which occurs under the influence of smoking, alcohol, viral respiratory infections, exposure to cold or hot air, as well as in patients with chronic bronchitis and in the elderly.

It should be remembered that pneumococci, Haemophilus influenzae and other microorganisms that colonize the distal sections of the airways, after adhesion to the surface of epithelial cells, are themselves capable of producing factors that damage the ciliated epithelium and slow down their movement even more. In patients with chronic bronchitis, the mucous membrane of the trachea and bronchi is always colonized with microorganisms, primarily pneumococci and Haemophilus influenzae.

An important factor in the colonization of the respiratory sections of the lungs is the dysfunction of lymphocytes, macrophages and neutrophils, as well as the humoral defense link, in particular the production of IgA. These disorders can also be aggravated by hypothermia, smoking, viral respiratory infection, hypoxia, anemia, starvation, and various chronic diseases leading to the suppression of cellular and humoral immunity.

Thus, the decrease in the drainage function of the bronchi and other described disturbances in the self-cleaning system of the airways, together with microaspiration of the contents of the oropharynx, create conditions for bronchogenic seeding of the respiratory section of the lungs with pathogenic and opportunistic microorganisms.

It should be borne in mind that under the influence of some endogenous and exogenous factors, the composition of the oropharynx microflora can change significantly. For example, in patients with diabetes, alcoholism and other concomitant diseases, the proportion of gram-negative microorganisms, in particular E. coli, Proteus, increases significantly. The patient's long stay in the hospital, especially in the intensive care unit, also has this effect.

The most important factors that contribute to the bronchogenic penetration of pathogenic microorganisms into the respiratory sections of the lungs are:

1. Microaspiration of oropharyngeal contents, including when using an endotracheal tube in patients on mechanical ventilation.
2. Disturbances in the drainage function of the respiratory tract as a result of chronic inflammatory processes in the bronchi in patients with chronic bronchitis, repeated viral respiratory infections, under the influence of smoking, alcohol excesses, severe hypothermia, exposure to cold or hot air, chemical irritants, as well as in elderly and senile individuals.
3. Damage to non-specific defense mechanisms (including local cellular and humoral immunity).
4. Changes in the composition of the microflora of the upper respiratory tract.

The airborne route of infection of the respiratory parts of the lungs is associated with the spread of pathogens with inhaled air. This route of penetration of microorganisms into the lung tissue has much in common with the bronchogenic route of infection, since it largely depends on the state of the bronchopulmonary defense system. The fundamental difference is that it is not the opportunistic microflora contained in the aspirated secretion of the oral cavity (pneumococci, Haemophilus influenzae, Moraxella, streptococci, anaerobes, etc.) that enters the lungs by airborne droplets, but pathogens that are not usually found in the oral cavity (Legionella, mycoplasma, chlamydia, viruses, etc.).

The hematogenous route of microorganism penetration into the lung tissue becomes important in the presence of distant septic foci and bacteremia. This route of infection is observed in sepsis, infective endocarditis, septic thrombophlebitis of the pelvic veins, etc.

The contagious route of infection of lung tissue is associated with the direct spread of pathogens from infected organs adjacent to the lungs, for example, with mediastinitis, liver abscess, as a result of a penetrating wound to the chest, etc.

Bronchogenic and airborne routes of microflora penetration into the respiratory parts of the lungs are of the greatest importance for the development of community-acquired pneumonia and are almost always combined with serious impairments of the barrier function of the respiratory tract. Hematogenous and contagious routes are much less common and are considered additional routes of lung infection and the development of predominantly hospital (nosocomial) pneumonia.

Mechanisms of development of local inflammation of lung tissue

Inflammation is a universal reaction of the body to any influences that disrupt homeostasis and are aimed at neutralizing the damaging factor (in this case, a microorganism) or/and separating the damaged area of tissue from neighboring areas and the entire body as a whole.

The process of inflammation formation, as is known, includes 3 stages:

1. alteration (tissue damage);
2. microcirculation disorders with exudation and emigration of blood cells;
3. proliferation.

Alteration

The first and most important component of inflammation is alteration (damage) of the lung tissue. Primary alteration is associated with the effect of microorganisms on alveolocytes or epithelial cells of the respiratory tract and is determined, first of all, by the biological properties of the pathogen itself. Bacteria adhering to the surface of type II alveolocytes secrete endotoxins, proteases (hyaluronidase, metalloproteinase), hydrogen peroxide and other substances that damage the lung tissue.

Massive bacterial contamination and damage to lung tissue (primary alteration) attracts a large number of neutrophils, monocytes, lymphocytes and other cellular elements to the inflammation zone, which are designed to neutralize the pathogen and eliminate damage or death of the cell itself.

The leading role in this process is played by neutrophils, which ensure the phagocytosis of bacteria and their destruction due to the activation of hydrolases and lipid peroxidation. During the phagocytosis of bacteria in neutrophils, the rate of all metabolic processes and the intensity of respiration increase significantly, and oxygen is consumed mainly for the formation of peroxide compounds - hydrogen peroxide (H2O2). radicals of hydroxide ion (HO+), singlet oxygen (O2) and others, which have a pronounced bactericidal effect. In addition, neutrophils that migrated to the site of inflammation create a high concentration of ions (acidosis), which provides favorable conditions for the action of hydrolases that eliminate dead microbial bodies.

Monocytes are also capable of rapidly accumulating in the center of inflammation, performing endocytosis in the form of pinocytosis and phagocytosis of various particles ranging in size from 0.1 to 10 µm, including microorganisms and viruses, gradually turning into macrophages.

Lymphocytes and lymphoid cells produce immunoglobulins IgA and IgG, the action of which is aimed at agglutinating bacteria and neutralizing their toxins.

Thus, neutrophils and other cellular elements perform the most important protective function, aimed primarily at eliminating microorganisms and their toxins. At the same time, all the described factors of antimicrobial aggression of leukocytes, including released lysosomal enzymes, proteases, active oxygen metabolites, have a pronounced damaging cytotoxic effect on alveolocytes, respiratory tract epithelium, microvessels, and connective tissue elements. Such damage to the lung tissue caused by its own cellular and humoral defense factors and called "secondary alteration" is a natural reaction of the body to the introduction of a pathogen into the pulmonary parenchyma. It is aimed at limiting (localizing) infectious agents and the lung tissue damaged by them from the entire body. Secondary alteration is, therefore, an integral part of any inflammatory process.

The secondary alteration of lung tissue that began in the inflammation focus, caused by the action of neutrophils and other cellular elements migrating to the inflammation focus, no longer depends on the infectious agent, and for its development there is no need for the further presence of the microorganism in the inflammation focus. In other words, secondary alteration and the subsequent phases of inflammation develop according to their own laws, regardless of whether the causative agent of pneumonia is further present in the lung tissue or has already been neutralized.

Naturally, the morphological and functional manifestations of primary and secondary alteration of lung tissue as a whole depend on both the biological properties of the pneumonia pathogen and the ability of the elements of the cellular and humoral immunity of the macroorganism to resist infection. These changes vary widely: from minor structural and functional disorders of lung tissue to its destruction (necrobiosis) and death (necrosis). The most important role in this process is played by the state of the mediator link of inflammation.

As a result of primary and secondary alteration of lung tissue in the inflammation focus, the rate of metabolic processes increases sharply, which, together with tissue decay, leads to 1) accumulation of acidic products in the inflammation focus (acidosis), 2) increase in osmotic pressure there (hyperosmia), 3) increase in colloid-osmotic pressure due to breakdown of proteins and amino acids. These changes, for similar reasons, contribute to the movement of fluid from the vascular bed to the inflammation focus (exudation) and the development of inflammatory edema of the lung tissue.

[ 11 ], [ 12 ], [ 13 ], [ 14 ], [ 15 ], [ 16 ], [ 17 ], [ 18 ], [ 19 ]

Inflammatory mediators

During the process of primary and secondary alteration, large quantities of humoral and cellular inflammation mediators are released, which essentially determine all subsequent events occurring in the inflammatory focus. Humoral mediators are formed in liquid media (plasma and tissue fluid), cellular mediators are released during the destruction of the structures of cellular elements participating in inflammation, or are formed again in cells during the inflammation process.

Humoral mediators of inflammation include some complement derivatives (C5a, C3a, C3b and the C5-C9 complex), as well as kinins (bradykinin, kallidin).

The complement system consists of approximately 25 proteins (complement components) found in plasma and tissue fluid. Some of these components play a role in protecting lung tissue from foreign microorganisms. They destroy bacterial cells, as well as the body's own cells infected with viruses. The C3b fragment is involved in the opsopization of bacteria, which facilitates their phagocytosis by macrophages.

The key fragment of the complement is the component C3, which is activated by two pathways - classical and alternative. The classical pathway of complement activation is "launched" by immune complexes IgG, IgM, and the alternative - directly by bacterial polysaccharides and aggregates of IgG, IgA and IgE.

Both activation pathways result in the splitting of the C3 component and the formation of the C3b fragment, which performs many functions: it activates all other complement components, opsonizes bacteria, etc. The main bactericidal action is performed by the so-called membrane attack complex, consisting of several complement components (C5-C9), which is fixed on the membrane of a foreign cell, is embedded in the cell membrane and disrupts its integrity. Water and electrolytes rush into the cell through the resulting channels, which leads to its death. However, the same fate awaits damaged cells of the lung tissue itself if they acquire the properties of a foreign agent.

Other complement components (C3a, C5a) have the ability to increase the permeability of postcapillaries and capillaries, act on mast cells and thereby increase the release of histamine, and also “attract” neutrophils to the site of inflammation (C5a), performing the function of chemotaxis.

Kinins are a group of polypeptides with high biological activity. They are formed from inactive precursors present in blood plasma and tissues. Activation of the kallikrein-kinin system occurs with any tissue damage, for example, capillary endothelium. Under the influence of activated Chagemal factor (blood coagulation factor XII), prekallikreins are converted into the enzyme kallikrein, which, in turn, by acting on the protein kininogen, leads to the formation of bradykinin, the main effector of the kallikrein-kinin system. At the same time, kallidin-10 is formed from kininogen, which differs from bradykinin by the presence of an additional lysine residue in the molecule.

The main biological effect of bradykinin is a pronounced dilation of arterioles and an increase in the permeability of microvessels. In addition, bradykinin:

• inhibits the emigration of neutrophils to the site of inflammation;
• stimulate the migration of lymphocytes and the secretion of some cytokines;
• enhances fibroblast proliferation and collagen synthesis;
• reduces the sensitivity threshold of pain receptors if they are located in the site of inflammation, thereby contributing to the occurrence of pain syndrome;
• acts on mast cells, increasing the release of histamine;
• enhances the synthesis of prostaglandins by various types of cells.

The main pro-inflammatory effects of bradykinin, which is produced in excess during tissue damage, are:

• vasodilation;
• increased vascular permeability;
• acceleration of migration of lymphocytes to the site of inflammation and the formation of certain cytokines;
• increased sensitivity of pain receptors;
• enhancing the processes of fibroblast proliferation and collagen synthesis.

The action of bradykinin is completely blocked by kininases localized in various tissues. It should be remembered that the ability to destroy bradykinin is also possessed by angiotensin-converting enzyme (ACE), sometimes called "kininase-II".

Numerous cellular mediators of inflammation are represented by vasoactive amines, arachidonic acid metabolites, lysosomal enzymes, cytokines, active oxygen metabolites, neuropeptides, etc.

Histamine is the most important cellular mediator of inflammation. It is formed from L-histidine by the enzyme histidine decarboxylase. The main source of histamine are mast cells and, to a lesser extent, basophils and thrombocytes. The effects of histamine are realized through two currently known types of membrane receptors: H1- H2. Stimulation of H1 receptors causes contraction of bronchial smooth muscles, increased vascular permeability and narrowing of venules, and stimulation of H2 receptors increases secretion by bronchial glands, increases vascular permeability and dilates arterioles.

In the development of inflammation, the vascular effects of histamine are the most significant. Since the peak of its action occurs within 1-2 minutes after release from mast cells, and the duration of action does not exceed 10 minutes, histamine, as well as the neurotransmitter serotonin, are considered the main mediators of initial microcirculatory disorders in the inflammation focus and a rapid increase in vascular permeability. Interestingly, by acting on the receptors of the vascular wall, histamine causes dilation of arterioles, and through H1 receptors - narrowing of venules, which is accompanied by an increase in intracapillary pressure and an increase in vascular permeability.

In addition, by acting on the H2 receptors of neutrophils, histamine to a certain extent limits their functional activity (anti-inflammatory effect). By acting on the H1 receptors of monocytes, histamine, on the contrary, stimulates their proinflammatory activity.

The main effects of histamine released from mast cell granules upon activation are:

• bronchial constriction;
• dilation of arterioles;
• increased vascular permeability;
• stimulation of secretory activity of bronchial glands;
• stimulation of the functional activity of monocytes during inflammation and inhibition of neutrophil function.

One should also remember the systemic effects of elevated histamine levels: hypotension, tachycardia, vasodilation, facial flushing, headache, itching of the skin, etc.

Eicosanoids are the central mediator link of the inflammatory reaction. They are formed in the process of arohidonic acid metabolism by almost all types of nuclear cells (mast cells, monocytes, basophils, neutrophils, thrombocytes, eosinophils, lymphocytes, epithelial and endothelial cells) upon their stimulation.

Arachidonic acid is formed from phospholipids of cell membranes under the action of phospholipase A2. Further metabolism of arachidonic acid is carried out in two ways: cyclooxygenase and lipoxygenase. The cyclooxygenase pathway leads to the formation of prostaglandins (PG) and thromboxane A2g (TXA2), the lipoxygenase pathway leads to the formation of leukotrienes (LT). The main source of prostaglandins and leukotrienes are mast cells, monocytes, neutrophils and lymphocytes that have migrated to the site of inflammation. Basophils participate in the formation of leukotrienes only.

Under the influence of prostaglandins PGD2, PGE2 and leukotrienes LTC4, LTD4 and LTE4, there is a significant expansion of arterioles and an increase in vascular permeability, which contributes to the development of inflammatory hyperemia and edema. In addition, PGD2, PGE2, PGF2b, thromboxane A2 and leukotrienes LTQ, LTD4 and LTE4, together with histamine and acetylcholine, cause contraction of bronchial smooth muscles and bronchospasm, and leukotrienes LTC4, LTD4 and LTE4 - an increase in mucus secretion. Prostaglandin PGE2 increases the sensitivity of pain receptors to bradykinin and histamine,

The main effects of prostaglandins and leukotrienes in the inflammation focus

Arachidonic acid metabolites	Main effects in the inflammation focus
Prostaglandins and thromboxane A 2
PGD 2	Bronchospasm Vasodilation Increased vascular permeability Suppression of secretory and proliferative activity of lymphocytes
PGE 2	Bronchospasm Vasodilation Increased vascular permeability Increased body temperature Increased sensitivity of pain receptors to bradykinin and histamine
PGF -2a	Bronchospasm Narrowing of the pulmonary vessels
PGI	Narrowing of the pulmonary vessels Suppression of secretory and proliferative activity of lymphocytes
TXA 2	Smooth muscle contraction, bronchospasm Narrowing of the pulmonary vessels Chemotaxis and adhesion of leukocytes Increased platelet aggregation and activation
Leukotrienes
LTB 4	Chemotaxis and adhesion of leukocytes Suppression of secretory and proliferative activity of lymphocytes
LTC 4	Bronchospasm Vasodilation Increased vascular permeability Increased mucus secretion in the bronchi
LTD 4	Bronchospasm Vasodilation Increased vascular permeability Increased mucus secretion in the bronchi
LTE 4	Bronchospasm Vasodilation Increased vascular permeability Increased mucus secretion in the bronchi Bronchial hyperactivity

It is interesting that prostaglandins PGF2a, PGI and thromboxane A2 cause not vasodilation, but their constriction and, accordingly, prevent the development of inflammatory edema. This indicates that eicosanoids have the ability to modulate the main pathophysiological processes characteristic of inflammation. For example, some metabolites of arachidonic acid stimulate leukocyte chemotaxis, enhancing their migration to the site of inflammation (LTB4, TXA2, PGE2), while others, on the contrary, suppress the activity of neutrophils and lymphocytes (PGF2b).

The main pathophysiological effects of most arachidonic acid metabolites (prostaglandins and leukotrienes) at the site of inflammation are:

• vasodilation;
• increased vascular permeability;
• increased mucus secretion;
• contraction of the smooth muscles of the bronchi;
• increased sensitivity of pain receptors;
• increased migration of leukocytes to the site of inflammation.

Some eicosanoids have opposite effects, demonstrating the important regulatory role of prostaglandins and leukotrienes on the inflammatory process.

Cytokines are a group of polypeptides formed during stimulation of leukocytes, endothelial and other cells and determining not only many local pathophysiological changes occurring in the inflammation focus, but also a number of general (systemic) manifestations of inflammation. Currently, about 20 cytokines are known, the most important of which are interleukins 1-8 (IL 1-8), tumor necrosis factor (TNFa) and interferons. The main sources of cytokines are macrophages, T-lymphocytes, monocytes and some other cells.

In the inflammation focus, cytokines regulate the interaction of macrophages, neutrophils, lymphocytes and other cellular elements and, together with other mediators, determine the nature of the inflammatory reaction as a whole. Cytokines increase vascular permeability, promote leukocyte migration to the inflammation focus and their adhesion, enhance phagocytosis of microorganisms, as well as reparative processes in the damage focus. Cytokines stimulate the proliferation of T- and B-lymphocytes, as well as the synthesis of antibodies of different classes.

Such stimulation of B-lymphocytes occurs with the obligatory participation of interleukins IL-4, IL-5, IL-6, released by T-lymphocytes. As a result, under the influence of cytokines, proliferation of B-lymphocytes occurs, producing. The latter are fixed on the membranes of mast cells, which are “prepared” for this due to the action of interleukin IL-3.

As soon as the IgG-coated mast cell encounters the corresponding antigen, and the latter binds to the antibody located on its surface, degranulation of the mast cell occurs, from which a large number of inflammatory mediators (histamine, prostaglandins, leukotrienes, proteases, cytokines, platelet activating factor, etc.) are released, initiating the inflammatory process.

In addition to local effects observed directly at the site of inflammation, cytokines participate in general systemic manifestations of inflammation. They stimulate hepatocytes to produce proteins of the acute phase of inflammation (IL-1, IL-6, IL-11, TNF, etc.), affect the bone marrow, stimulating all hematopoiesis sprouts (IL-3, IL-11), activate the blood coagulation system (TNFa), participate in the appearance of fever, etc.

In the inflammation focus, cytokines increase vascular permeability, promote the migration of leukocytes to the inflammation focus, enhance the phagocytosis of microorganisms, reparative processes in the damage focus, stimulate the synthesis of antibodies, and also participate in general systemic manifestations of inflammation.

Platelet-activating factor (PAF) is produced in mast cells, neutrophils, monocytes, macrophages, eosinophils, and thrombocytes. It is a potent stimulator of platelet aggregation and subsequent activation of blood coagulation factor XII (Hageman factor), which in turn stimulates the formation of kinins. In addition, PAF causes pronounced cellular infiltration of the respiratory mucosa, as well as bronchial hyperreactivity, which is accompanied by a tendency to bronchospasm.

Cationic proteins released from specific granules of neutrophils have high bactericidal properties. Due to electrostatic interaction, they are adsorbed on the negatively charged membrane of the bacterial cell, disrupting its structure, which results in the death of the bacterial cell. However, it should be remembered that cationic proteins, in addition to their protective function, have the ability to damage their own endothelial cells, which significantly increases vascular permeability.

Lysosomal enzymes mainly ensure the destruction (lysis) of bacterial cell debris, as well as damaged and dead cells of the lung tissue itself. The main source of lysosomal proteases (elastase, cathepsin G and collagenases) are neutrophils, monocytes and macrophages. At the site of inflammation, proteases cause a number of effects: they damage the vascular basement membrane, increase vascular permeability and destroy cell debris.

In some cases, damage to the connective tissue matrix of the vascular endothelium by proteases leads to severe fragmentation of the endothelial cell, which may result in the development of hemorrhages and thromboses. In addition, lysosomal enzymes activate the complement system, the kallikrein-kinin system, the coagulation system and fibrinolysis, and release cytokines from cells, which maintains inflammation.

Active oxygen metabolites

An increase in the intensity of all metabolic processes in the inflammation site, the “respiratory explosion” of phagocytes during their stimulation, activation of arachidonic acid metabolism and other enzymatic processes in the cell are accompanied by excessive formation of free radical forms of oxygen:

• superoxide anion (O');
• hydroxide radical (HO');
• singlet oxygen (O'3);.
• hydrogen peroxide (H2O2), etc.

Due to the fact that the outer atomic or molecular orbitals of active oxygen metabolites contain one or more unpaired electrons, they have an increased reactivity to interact with other molecules, causing the so-called free-radical (or peroxide) oxidation of biomolecules. Of particular importance is the free-radical oxidation of lipids, such as phospholipids, which are part of cell membranes. As a result of free-radical oxidation, unsaturated lipids are rapidly destroyed, the structure and function of the cell membrane are disrupted, and, ultimately, the cell dies.

It is clear that the high destructive potential of free-radical oxygen metabolites is manifested both in relation to bacterial cells and in relation to the body's own lung tissue cells and phagocytes. The latter circumstance indicates the participation of free-radical oxidation in the inflammatory process.

It should also be remembered that the intensity of free-radical oxidation of lipids, carbohydrates and proteins is normally regulated by the antioxidant defense system, which inhibits the formation of free radicals or inactivates peroxidation products. The most significant antioxidants include: superoxide dismutase; glutathione peroxidase; tocopherols (vitamin E); ascorbic acid (vitamin C).

A decrease in antioxidant protection, for example, in patients who abuse smoking, or with insufficient intake of tocopherol, ascorbic acid and selenium, contributes to further progression and protracted inflammation.

[ 20 ], [ 21 ], [ 22 ], [ 23 ], [ 24 ], [ 25 ], [ 26 ], [ 27 ], [ 28 ], [ 29 ]

Microcirculation disorders with exudation and emigration of leukocytes

Various vascular disorders that develop in the inflammation focus following exposure to an infectious agent are of decisive importance in the development of inflammatory hyperemia, edema and exudation and largely determine the clinical picture of the disease. Vascular inflammatory reactions include:

1. A short-term spasm of blood vessels that occurs reflexively immediately after the damaging effect of an infecting agent on the lung tissue.
2. Arterial hyperemia associated with the effect of numerous inflammatory mediators on the tone of arterioles and causing two characteristic signs of inflammation: redness and local increase in tissue temperature.
3. Venous hyperemia, which accompanies the entire course of the inflammatory process and determines the main pathological disturbances of microcirculation in the inflammation site.

Incomplete or true inflammatory hyperemia is characterized by a significant increase in the blood filling of the inflamed area of the lung and, simultaneously, by pronounced microcirculation disorders due to increased blood viscosity, aggregation of erythrocytes and platelets, a tendency to thrombosis, slowing of blood flow and even blood stasis in some branches of microvessels. As a result, swelling of the vascular endothelium and an increase in its adhesiveness occur. This creates conditions for the adhesion of neutrophils, monocytes and other cellular elements to the endothelium. Endothelial cells swell and become rounded, which is accompanied by an increase in interendothelial gaps through which exudation and massive migration of leukocytes into the inflamed tissue occur.

Exudation is the exudation of protein-containing liquid part of the blood (exudate) through the vascular wall into the inflamed tissue. Three main mechanisms determine the process of exudation.

1. Increased permeability of the vascular wall (primarily venules and capillaries), caused primarily by the impact of the pneumonia pathogen itself, numerous inflammatory mediators, as well as microcirculation disorders
2. An increase in blood filtration pressure in the vessels located in the site of inflammation, which is a direct consequence of inflammatory hyperemia.
3. Increased osmotic and oncotic pressure in the inflamed tissue, caused by the destruction of cellular elements of the inflamed tissue and the destruction of high-molecular components released from the cell. This increases the flow of water into the inflammation site and increases tissue edema.

All three mechanisms ensure the exit of the liquid part of the blood from the vessel and its retention in the inflammatory focus. Exudation is carried out not only through the widened interendothelial gaps, but also actively by the endothelial cells themselves. The latter capture plasma microbubbles and transport them towards the basement membrane, and then throw them into the tissue.

It should be remembered that the inflammatory exudate differs significantly in composition from the transudate of non-inflammatory origin. This is primarily due to the fact that during inflammation, the disturbance of vascular permeability is caused by the action of numerous leukocyte factors that damage the vascular wall. In non-inflammatory edema (for example, in hemodynamic or toxic pulmonary edema), leukocyte factors have virtually no effect on the vascular wall and the disturbance of vascular permeability is expressed to a lesser extent.

Significant impairment of vascular permeability during inflammation is explained by the fact that the exudate is distinguished, first of all, by a very high protein content (>30 g/l). Moreover, with a small degree of impairment of permeability, albumins predominate in the exudate, and with more significant damage to the vascular wall - globulins and even fibrinogen.

The second difference between exudate and transudate is the cellular composition of the pathological effusion. Exudate is characterized by a significant content of leukocytes, mainly neutrophils, monocytes, macrophages, and in case of prolonged inflammation, T-lymphocytes. Transudate is not characterized by a high content of cellular elements.

Depending on the protein and cellular composition, several types of exudate are distinguished:

1. serous;
2. fibrinous;
3. purulent;
4. putrefactive;
5. hemorrhagic;
6. mixed.

Serous exudate is characterized by a moderate increase (30-50 g/l) of mainly finely dispersed protein (albumin), a slight increase in the specific density of the fluid (up to 1.015-1.020) and a relatively low content of cellular elements (polymorphonuclear leukocytes).

Fibrinous exudate indicates a significant disruption of vascular permeability in the inflammation focus. It is characterized by a very high content of fibrinogen, which is easily transformed into fibrin upon contact with damaged tissues. Fibrin threads give the exudate a unique appearance, reminiscent of a villous film located superficially on the mucous membrane of the respiratory tract or the walls of the alveoli. The fibrin film is easily separated without disrupting the mucous membrane of the alveolocytes. Fibrinous exudate is a characteristic sign of so-called croupous inflammation (including croupous pneumonia).

Purulent exudate is characterized by a very high content of protein and polymorphonuclear leukocytes. It is typical for purulent lung diseases (abscess, bronchiectasis, etc.) and often accompanies inflammation caused by streptococci. If pathogenic anaerobes join this bacterial microflora, the exudate acquires a putrefactive character - it has a dirty green color and a very unpleasant, sharp odor.

Hemorrhagic exudate is characterized by a high content of erythrocytes, which gives the exudate a pink or red color. The appearance of erythrocytes in the exudate indicates significant damage to the vascular wall and impaired permeability.

If acute inflammation is caused by pyogenic microbes, neutrophils predominate in the exudate. In chronic inflammation, the exudate contains mainly monocytes and lymphocytes, and neutrophils are present here in small quantities.

The central event in the pathogenesis of inflammation is the release of leukocytes into the inflammation site. This process is initiated by various chemotactic agents released by microorganisms, phagocytes and damaged cells of the lung tissue itself: bacterial peptides, some complement fragments, arachidonic acid metabolites, cytokines, granulocyte breakdown products, etc.

As a result of the interaction of chemotactic agents with phagocyte receptors, the latter are activated, and all metabolic processes in the phagocytes are intensified. The so-called "respiratory explosion" occurs, characterized by a rare increase in oxygen consumption and the formation of its active metabolites.

This contributes to the increase of leukocyte adhesiveness and their gluing to the endothelium - the phenomenon of marginal standing of leukocytes develops. Leukocytes release pseudopodia, which penetrate into the interendothelial gaps. Getting into the space between the endothelium layer and the basement membrane, leukocytes secrete lysosomal proteinases, which dissolve the basement membrane. As a result, leukocytes get into the inflammation site and "amoeba-like" move to its center.

During the first 4-6 hours from the onset of inflammation, neutrophils penetrate into the inflammation site from the vascular bed, after 16-24 hours - monocytes, which here turn into macrophages, and only then lymphocytes.

[ 30 ], [ 31 ], [ 32 ]

Proliferation

Inflammatory proliferation is understood as the multiplication of specific cellular elements of tissue lost as a result of inflammation. Proliferative processes begin to prevail at later stages of inflammation, when a sufficient degree of tissue "cleansing" from the causative microorganisms of pneumonia, as well as from dead leukocytes and products of alteration of the lung tissue itself, has been achieved in the focus. The task of "cleansing" the focus of inflammation is performed by neutrophils, monocytes and alveolar macrophages, with the help of released lysosomal enzymes (proteinases) and cytokines.

Proliferation of lung tissue occurs due to mesenchymal elements of the stroma and elements of the lung parenchyma. An important role in this process is played by fibroblasts, synthesizing collagen and elastin, and secreting the main intercellular substance - glycosaminoglycans. In addition, under the influence of macrophages, proliferation of endothelial and smooth muscle cells and neoplasm of microvessels occur in the inflammation focus.

With significant tissue damage, its defects are replaced by proliferating connective tissue. This process underlies the formation of pneumosclerosis, as one of the possible outcomes of pneumonia.