Pathogenesis of pneumonia

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

• violations of a complex multi-stage respiratory protection system against the penetration of microorganisms into the respiratory parts of the lungs;
• mechanisms of the development of local inflammation of the lung tissue;
• formation of systemic manifestations of the disease;
• formation of complications.

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

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

Ways of penetration of microorganisms into the respiratory sections of the lungs

There are three main ways of penetration of microorganisms into the respiratory parts of the lungs:

The bronchogenic pathway is the most frequent route of infection of the lung tissue. In most cases, the 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. There are pneumococci, hemophilic rod, Staphylococcus aureus, anaerobic bacteria and even Gram-negative E. Coli, Friedlander and Proteus stick.

Microaspiration of the contents of the oropharynx occurs, as is well known, in healthy people, for example, during sleep. Nevertheless, normally airways 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 secret of the oropharynx is effectively removed and the colonization of the lower respiratory tract by microorganisms does not occur.

More massive aspiration into the lower parts of the respiratory tract occurs when the mechanisms of self-cleaning fail. More often it is observed in patients of senile age, in people with mental disorders, including those who are intoxicated, with an overdose of sleeping pills or drugs, with metabolic dyscirculatory encephalopathy, convulsive syndrome, etc. In these cases, the oppression of the cough reflex and the reflex providing reflex spasm of the glottis is often observed (JV Hirschman).

The probability of dysphagia and aspiration of the contents of the oropharynx is significantly increased in patients with gastrointestinal diseases - esophagus achalasia, gastroesophageal reflux, diaphragmatic hernia, decreased tone of the esophagus and stomach with hypo- and achlorhydria.

Infringement of the act of swallowing and a high likelihood of aspiration is also observed in patients with systemic connective tissue diseases: polymyositis, systemic scleroderma, mixed connective tissue disease (Sharp's syndrome), etc.

One of the most important mechanisms for the development of nosocomial pneumonia is the use of the endotracheal tube in patients undergoing mechanical ventilation (IVL). The moment of intubation itself is characterized by the highest risk of aspiration and is the main pathogenetic mechanism for the development of intra-hospital aspirations in pneumonia in the first 48 hours of ventilation. However, the endotracheal tube itself, preventing the closure of the glottis, promotes the development of microaspirations. When the head and trunk rotate, movements of the endotracheal tube inevitably occur, contributing to the penetration of secretion into the distal parts of the respiratory tract and the dissemination of lung tissue (RG Wunderink).

An important mechanism for the colonization of respiratory tract respiratory organs by microorganisms are disorders of mucociliary transport that arise 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 elderly people

It should be remembered that pneumococci, a hemophilic rod and other microorganisms that infiltrate the distal sections of the airways, after adhesion to the surface of epithelial cells, are capable of producing factors damaging the ciliated epithelium and further slowing their movement. In patients with chronic bronchitis, the mucous trachea and bronchi are always seeded with microorganisms, primarily pneumococci and a hemophilic rod.

An important factor in the colonization of the respiratory parts of the lung are disorders of the function of lymphocytes, macrophages and neutrophils, as well as of the humoral defense, in particular IgA production. These disorders can also be aggravated by the effects of hypothermia, smoking, viral respiratory infection, hypoxia, anemia, starvation, various chronic diseases , leading to the inhibition of cellular and humoral immunity.

Thus, a decrease in the drainage function of the bronchi and other described disorders in the airway self-cleaning system, together with microaspiration of the oropharyngeal contents, create conditions for bronchogenic colonization of the respiratory part of the lungs by pathogenic and opportunistic microorganisms.

It should be borne in mind that under the influence of some endogenous and exogenous factors, the composition of the microflora of the oropharynx can vary significantly. For example, in patients with diabetes mellitus, alcoholism and other concomitant diseases, the specific gravity of gram-negative microorganisms, in particular Escherichia coli, protea, increases substantially. In addition, the effect leads to a prolonged stay of the patient in the hospital, especially in the ICU.

The most important factors contributing to the bronchogenic penetration of pathogenic microorganisms into the respiratory parts of the lungs are:

1. Microaspiration of the contents of the oropharynx, including when using the endotracheal tube in patients who are on ventilator.
2. Disorders of 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, alcoholic excesses, severe hypothermia, cold or hot air, chemical irritants, and elderly people .
3. Damage to mechanisms of nonspecific defense (including local cellular and humoral immunity).
4. Change in the composition of the microflora of the upper respiratory tract.

Air-droplet infection of the respiratory lungs is associated with the spread of pathogens with inhaled air. This way of penetration of microorganisms into lung tissue has much in common with the bronchogenic way of infection, because it largely depends on the state of the broncho-pulmonary defense system. The principal difference lies in the fact that the airborne pathway into the lungs is mostly not the conditionally pathogenic microflora contained in the aspirated secretion of the oral cavity (pneumococcus, hemophilic rod, moraxella, streptococcus, anaerobes, etc.), but pathogenic which in the oral cavity is usually not contained (legionella, mycoplasma, chlamydia, viruses, etc.).

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

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

Bronchogenic and airborne pathways of microflora penetration into the respiratory sections of the lungs are of greatest importance for the development of community-acquired pneumonia and are almost always combined with serious violations of the barrier function of the respiratory tract. Hematogenous and contagious pathways occur much less frequently and are considered as additional ways of infection of the lungs 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 effects that disrupt homeostasis and are aimed at neutralizing the damaging factor (in this case - the microorganism) or / and by delimiting the damaged tissue site from neighboring sites and the whole organism as a whole.

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

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

Alteration

The first and most important component of inflammation is the alteration (damage) of the lung tissue. Primary alteration is associated with the action 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 that adhere on 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 to the inflammation zone a large number of neutrophils, monocytes, lymphocytes and other cellular elements that are designed to neutralize the pathogen and eliminate the damage or death of the cell itself.

The leading role in this process is played by neutrophils, which ensure bacterial phagocytosis and their destruction through the activation of hydrolases and lipid peroxidation. During the phagocytosis of bacteria in neutrophils, the rate of all metabolic processes and the rate of respiration increase significantly, and oxygen is consumed primarily for the formation of peroxide compounds - hydrogen peroxide (H2O2). Radicals of the hydroxide ion (HO +), singlet oxygen (O2) and others, which have a pronounced bactericidal action. In addition, neutrophils migrating to the inflammatory focus create a high concentration of ions (acidosis), which provides favorable conditions for the action of hydrolases, eliminating dead microbial bodies.

Monocytes are also able to rapidly accumulate and inflammation focus, carrying out endocytosis in the form of pinocytoma and phagocytosis of various particles with a size of 0.1 to 10 μm, including microorganisms and viruses, gradually turning into macrophages.

Lymphocytes, lymphoid cells produce immunoglobulins IgA and IgG, whose action is directed to agglutination of bacteria and neutralization of 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 leukocyte aggression, including the released lysosomal enzymes, proteases, active metabolites of oxygen, have a pronounced damaging cytotoxic effect on alveolocytes, respiratory tract epithelium, microvessels, 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 organism to the introduction of the pathogen into the pulmonary parenchyma. It is aimed at the delimitation (localization) of infectious agents and damaged by the impact of lung tissue from the whole organism. Secondary alteration is, thus, an integral part of any inflammatory process.

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

Naturally, the morphological and functional manifestations of primary and secondary alteration of pulmonary tissue as a whole depend both on the biological properties of the pathogen of pneumonia and on the ability of elements of cellular and humoral immunity of the macroorganism to resist infection. These changes vary widely: from small structural and functional disorders of the 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 the lung tissue in the inflammatory focus, the rate of metabolic processes sharply increases, which, together with tissue decay, leads to 1) accumulation of acid products in the inflammatory focus (acidosis), 2) increased osmotic pressure (hyperosmia), 3) increase colloid osmotic pressure due to the cleavage of proteins and amino acids. These changes for backward reasons contribute to the movement of fluid from the vascular bed into the focus of inflammation (exudation) and the development of inflammatory pulmonary edema.

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

Mediators of inflammation

In the process of primary and secondary alteration, large amounts of humoral and cellular mediators of inflammation are released, which, in effect, determine all subsequent events occurring in the inflammatory focus. Humoral mediators are formed in liquid media (plasma and tissue fluid), cellular mediators are released when structures of cellular elements involved in inflammation are destroyed, or are newly formed in cells during inflammation.

Among the humoral mediators of inflammation are some complement derivatives (C5a, C3a, C3b and C5-C9 complex), as well as kinins (bradykinin, callidinum).

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

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

Both activation paths lead to the splitting of the SOC component and the formation of the fragment C3b, which performs a variety of functions: activates all other complement components, opsonizes bacteria, etc. The main bactericidal action is 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 violates its integrity. Through the formed channels, water and electrolytes rush into the cell, which leads to its death. However, the same fate awaits the damaged cells of the lung tissue itself, if they acquire the properties of a foreign agent.

Other components of complement (SZa, S5a) have the properties to increase the permeability of postcapillaries and capillaries, to affect mast cells and thereby increase the release of histamine, and also to "attract" neutrophils to the inflammatory focus (C5a), performing the function of chemotaxis.

Kininy is 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, the capillary endothelium. Under the action of the activated factor Chaguemal (factor XII of blood coagulation), prekallikreins turn into the enzyme kallikrein, which, in turn, acting on the protein kininogen, leads to the formation of bradykinin, the main effector of the kallikrein-kinin system. Simultaneously, kalinogen-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 expansion of arterioles and an increase in the permeability of microvessels. In addition, Bradykinin:

• oppresses the emigration of neutrophils to the focus of inflammation;
• stimulate the migration of lymphocytes and the secretion of some cytokinia;
• enhances the proliferation of fibroblasts and the synthesis of collagen;
• reduces the sensitivity threshold of pain receptors, if they are located in the focus of inflammation, thus contributing to the onset of pain syndrome;
• Effects on mast cells, enhancing the release of histamine;
• enhances the synthesis of prostaglandins by different types of cells.

The main proinflammatory effects of bradykinin, formed in excess in the case of tissue damage, are:

• vasodilation;
• increased vascular permeability;
• acceleration of migration to the focus of inflammation of lymphocytes and formation of some cytokines;
• increased sensitivity of pain receptors;
• increased proliferation of fibroblasts and collagen synthesis.

The action of bradykinin is completely blocked by kinases, localized and various tissues. It should be remembered that the ability to destroy bradykinia also has an angiotensin-converting enzyme (LIF), sometimes called "kininase-II."

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

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

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

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

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

• narrowing of the bronchi;
• expansion of arterioles;
• increased vascular permeability;
• stimulation of secretory activity of bronchial glands;
• stimulation of the functional activity of monocytes in the process of inflammation and inhibition of neutrophil function.

It should also be remembered about the systemic effects of increased histamine content: hypotension, tachycardia, vasodilation, face redness, headache, skin itching, etc.

Eicosanoids - are the central mediator of the inflammatory response. They are formed during the metabolism of arochidonic acid by almost all types of nuclear cells (mast cells, monocytes, basophils, neutrophils, platelets, 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 occurs in two ways: cyclooxygenase and lipoxygenase. The cyclooxygenase pathway leads to the formation of prostaglandins (PG) and thromboxia A2g (TXA2), lipoxygenase pathway to the formation of leukotrienes (LT). The main source of prostaglandins and leukotrienes are mast cells, monocytes, neutrophils and lymphocytes that migrated to the inflammatory focus. Basophils take part in the formation of only leukotrienes.

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 a reduction in the smooth muscles of the bronchi and bronchospasm, and the leukotrienes LTC4, LTD4 and LTE4 increase mucus secretion. Prostaglandin PGE2 increases the sensitivity of pain receptors to bradykinin and histamine,

The main effects of prostaglandins and leukotrienes in the inflammatory focus

Metabolites of arachidonic acid	The main effects in the focus of inflammation
Prostaglandins and thromboxane A 2
PGD 2	Bronchospasm Vascular expansion Increased vascular permeability Suppression of secretory and proliferative activity of lymphocytes
PGE 2	Bronchospasm Vascular expansion Increased vascular permeability Increased body temperature Increased sensitivity of pain receptors to bradykinin and histamine
PGF 2a	Bronchospasm Vessel constriction of the lungs
PGI	Vessel constriction of the lungs Suppression of secretory and proliferative activity of lymphocytes
TXA 2	Reduction of smooth muscles, bronchospasm Vessel constriction of the lungs Chemotaxis and adhesion of leukocytes Increased aggregation and activation of platelets
Leukotrienes
LTB 4	Chemotaxis and adhesion of leukocytes Suppression of secretory and proliferative activity of lymphocytes
LTC 4	Bronchospasm Vascular expansion Increased vascular permeability Increased secretion of mucus in the bronchi
LTD 4	Bronchospasm Vascular expansion Increased vascular permeability Increased secretion of mucus in the bronchi
LTE 4	Bronchospasm Vascular expansion Increased vascular permeability Increased secretion of mucus in the bronchi Bronchial hypertension

Interestingly, prostaglandins PGF2a. PGI and thromboxane A2 cause not vasodilation, but their constriction and, accordingly, interfere with the development of inflammatory edema. This indicates that eicosanoids have the ability to modulate the main pathophysiological processes characteristic of inflammation. For example, some arachidonic acid metabolites stimulate leukocyte chemotaxis, increasing their migration to the inflammatory focus (LTB4, TXA2, PGE2), whereas others, on the contrary, suppress neutrophil and lymphocyte activity (PGF2b).

The main pathophysiological effects of most metabolites of arachidonic acid (prostaglandins and leukotrienes) in the inflammatory focus are:

• vasodilation;
• increased vascular permeability;
• increased secretion of mucus;
• reduction of smooth muscles of the bronchi;
• increased sensitivity of pain receptors;
• increased migration of leukocytes into the focus of inflammation.

Some of the eicoanoids have opposite effects, demonstrating the important regulating role of prostaglandins and leukotrienes on the process of inflammation.

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

In the focus of inflammation, cytokines regulate the interaction of macrophages, neutrophils, lymphocytes and other cellular elements and together with other mediators determine the nature of the inflammatory response as a whole. Cytokines increase vascular permeability, promote the migration of leukocytes to the focus of inflammation and their adhesion, enhance the phagocytosis of microorganisms, as well as reparative processes in the lesion 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 mandatory participation of interleukins IL-4, IL-5, IL-6 released by T-lymphocytes. As a result, the proliferation of B-lymphocytes producing by the action of cytokines occurs. The latter are fixed on membranes of mast cells, which are "prepared" for this due to the action of interleukin IL-3.

Once the mastoid cell coated with IgG meets the corresponding antigen and the latter binds to the antibody located on its surface, the mast cell degranulates, from which a large number of inflammatory mediators are released (histamine, prostaglidins, leukotrienes, proteases, cytokines, platelet activation factor and others) that initiate the inflammatory process.

In addition to local effects observed directly in the inflammatory focus, cytokines are involved in common 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 hematopoietic growths (IL-3, IL-11), activate the coagulation system blood (TNF), participate in the appearance of fever, etc.

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

The factor of platelet activation (FAT) is formed in mast cells, neutrophils, monocytes, macrophages, eosinophils and platelets. It is a potent stimulator of platelet aggregation and subsequent activation of factor XII of coagulation of Hepatitis C (Hugemann's factor), which in turn stimulates the formation of kinins. In addition, FAT causes pronounced cellular infiltration of the mucosa of the airways, as well as hyperreactivity of the bronchi, which is accompanied by a tendency to bronchospasm.

Cationic proteins released from specific neutrophil granules possess high bactericidal activity. Due to the electrostatic interaction, they are adsorbed on the negatively charged membrane of the bacterial cell, disrupting its structure, as a result of which the death of the bacterial cell occurs. It should, however, be remembered that cationic proteins, in addition to their protective function, have the ability to damage their own endothelial cells, resulting in a significant increase in vascular permeability.

Lysosomal enzymes provide mainly destruction (lysis) of fragments of bacterial cells, as well as damaged and dead cells of the pulmonary tissue itself. The main source of lysosomal proteases (elastase, cathepsin G and collagenases) are neutrophils, monocytes and macrophages. In the center of inflammation, proteases cause a number of effects: they damage the basal membrane of the vessels, increase vascular permeability and destroy fragments of cells.

In some cases, protease damage to the connective-tissue matrix of the vascular endothelium results in a pronounced fragmentation of the endothelial cell, resulting in the development of hemorrhages and thromboses. In addition, lysosomal enzymes activate the complement system, kallikrein-kinin system, coagulation system and fibrinolysis, and also release cytokines from the cells, which supports inflammation.

Active metabolites of oxygen

The increase in the intensity of all metabolic processes in the focus of inflammation, the "respiratory explosion" of phagocytes upon their stimulation, the activation of the metabolism of arachidonic acid and other enzymatic processes in the cell are accompanied by excessive formation of free-radical oxygen forms:

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

Due to the fact that there are one or several unpaired electrons on the outer atomic or molecular orbits of active metabolites of oxygen, 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, for example, phospholipids, which are part of cell membranes. As a result of free radical oxidation, rapid destruction of unsaturated lipids, disruption of the structure and function of the cell membrane and, ultimately, cell death, occur.

It is clear that the high destructive potential of free radical metabolites of oxygen is manifested both in relation to bacterial cells and in relation to own cells of lung tissue 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 an antioxidant defense system that inhibits the formation of free radicals or inactivates peroxidation products. Among the most significant antioxidants are: superoxide dismutase; glutathione peroxidase; tocopherols (vitamin E); ascorbic acid (vitamin C).

Reduction of antioxidant protection, for example, in patients who abuse smoking, or with insufficient intake of tocopherol, ascorbic acid and selenium, contributes to the further progression and prolonged course of inflammation.

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

Disorders of microcirculation with exudation and emigration of leukocytes

A variety of vascular disorders that develop in the inflammatory focus following the action of the infectious agent are crucial in the onset of inflammatory hyperemia, edema and exudation and largely determine the clinical picture of the disease. Vascular inflammatory reactions include:

1. Short-term vasospasm, arising reflexively immediately after a damaging effect on the lung tissue of the pathogen.
2. Arterial hyperemia associated with the effect on the tone of arterioles of numerous mediators of inflammation and causing two characteristic signs of inflammation: redness and local increase in tissue temperature.
3. Venous hyperemia that accompanies the entire course of the inflammatory process and determines the main pathological disorders of microcirculation in the inflammatory focus.

Incomplete, or true inflammatory hyperemia is characterized by a significant increase in the blood filling of the inflamed part of the lung and, at the same time, marked disturbances of microcirculation due to increased blood viscosity, aggregation of red blood cells 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 occurs and increases its adhesiveness. This creates conditions for the adhesion of neutrophils, monocytes and other cellular elements to the endothelium. Eczdoteliocytes swell and round off, which is accompanied by an increase in interendothelial gaps, through which exudation and massive migration of leukocytes into the inflamed tissue occurs.

Exudation is the sweating of the protein-containing liquid part of the crope (exudate) through the vascular wall into the inflamed tissue. The three main mechanisms cause the process of exudation.

1. Increase in permeability of the vascular wall (mainly venules and capillaries), caused primarily by the influence of the pathogen itself, numerous inflammatory mediators, and microcirculation disorders
2. An increase in blood filtration pressure in vessels located in the focus of inflammation, which is a direct consequence of inflammatory hyperemia.
3. Increase in osmotic and oncotic pressure in inflamed tissue, the cause of which is the destruction of cellular elements of inflamed tissue and the destruction of high-molecular components that leave the cell. This increases the flow of water into the focus of inflammation and increases the swelling of the tissue.

All three mechanisms provide the outlet of the liquid part of the blood from the vessel and its retention in the inflammatory focus. Exudation is realized not only through the expanded interendothelial gaps, but also by the endotheliocytes themselves. The latter capture the microbubbles of the plasma and transport them towards the basal membrane, and then throw them into the tissue.

It should be remembered that the inflammatory exudate differs significantly in composition from the non-inflammatory non-inflammatory origin. This is due, first of all, to the fact that in inflammation the violation of vascular permeability is caused by the action of numerous leukocyte factors damaging the vascular wall. With non-inflammatory edema (for example, with hemodynamic or toxic pulmonary edema), leukocyte factors have virtually no effect on the vascular wall and impairment of vascular permeability is less pronounced.

A significant violation of vascular permeability in inflammation explains the fact that exudate differs, first of all, by a very high protein content (> 30 g / l). And with a small degree of impairment of permeability in exudate, albumins prevail, 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 with prolonged inflammation of T lymphocytes. For transudate, the high content of cellular elements is not characteristic.

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 mostly finely dispersed protein (albumins), a slight increase in the specific density of the liquid (up to 1.015-1.020) and a relatively small content of cellular elements (polymorphonuclear leukocytes).

Fibrinous exudate indicates a significant violation of vascular permeability in the focus of inflammation. It is characterized by a very high content of fibrinogen, which is easily transformed into fibrin in contact with damaged tissues. In this case, the filaments of fibrin give the exudate a peculiar appearance, resembling a villous film, located superficially on the mucosa of the respiratory tract or alveolar walls. The fibrin film is easily separated without disturbing the alveolocyte mucosa. Fibrinous exudate is a characteristic feature of the so-called croupous inflammation (including croupous pneumonia).

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

Hemorrhagic exudate has a high content of red blood cells, which gives the exudate a pink or red color. The appearance of red blood cells in the exudate indicates a significant damage to the vascular wall and impaired permeability.

If acute inflammation is caused by pyogenic microbes, neutrophils predominate in the exudate. In a chronic inflammatory process, the exudate contains predominantly monocytes and lymphocytes, and neutrophils are present here in small amounts.

The central event of the pathogenesis of inflammation is the release of leukocyte to the focus of inflammation. This process is initiated by a variety of chemotactic agents released by microorganisms, phagocytes and damaged cells of the lung tissue itself: bacterial peptides, some complement fragments, arachidonic acid metabolites, cytokines, granulocyte decay products, etc.

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

This helps to increase the adhesiveness of leukocytes and glue them to the endothelium - the phenomenon of the marginal standing of leukocytes develops. Leukocytes release pseudopodia, which penetrate the interendothelial cracks. Getting into the space between the endothelium layer and the basal membrane, leukocytes secrete lysosomal proteinases, which dissolve the basal membrane. As a result, leucocytes enter the focus of inflammation and "amoeba" move to its center.

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

[30], [31], [32]

Proliferation

By inflammatory proliferation refers to the multiplication of specific cellular tissue elements lost as a result of inflammation. Proliferative processes begin to predominate in later stages of inflammation, when a sufficient degree of "cleansing" of the tissue from the causative agent of pneumonia of microorganisms, and from dead leukocytes and products of alteration of the lung tissue itself is achieved in the focus. The task of "cleaning" the focus of inflammation is performed by neutrophils, monocytes and alveolar macrophages, with the help of liberated 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, as well as secreting the main intercellular substance - glycosaminoglycans. In addition, under the influence of macrophages in the focus of inflammation, proliferation of endothelial and smooth muscle cells and the formation of microvessels occur.

If the tissue is severely damaged, its defects are replaced by a proliferating connective tissue. This process underlies the formation of pismosclerosis, as one of the possible outcomes of pneumonia.