The concept of systemic inflammatory response syndrome. View of modern medicine
GBOU VPO KrasGMU them. prof. V.F. Voyno-Yasenetsky Ministry of Health of Russia
Department of Pathophysiology with the Course of Clinical Pathophysiology named after V.V. Ivanova
INTRODUCTORY LECTURE
by discipline " clinical pathophysiology"
for clinical residents of all specialties
TOPIC: "Etiopathogenesis of systemic inflammatory response syndrome"
Subject Index:OD.O.00.
Head of Department________________ MD Ruksha T.G.
Compiled by:
Doctor of Medical Sciences, Associate Professor Artemyev S.A.
Krasnoyarsk
Purpose of the lecture:
to systematize knowledge about the etiology and pathogenesis of inflammation
LECTURE PLAN:
Inflammation, definition
Stages of inflammation
Physico-chemical changes in the cell during alteration
Exudation and emigration of blood cells to the focus of inflammation
Phagocytosis
Inflammation- a typical pathological process that occurs in response to the action of a damaging factor. Inflammation is characterized by the following successive stages:
alteration
microcirculation disorders
exudation
emigration
phagocytosis
proliferation
Systemic manifestations of inflammation include fever, hematopoietic tissue reactions with the development of leukocytosis, increased erythrocyte sedimentation rate, accelerated metabolism, changes in immunological reactivity, and intoxication of the body.
Etiology of inflammation
An inflammatory agent (phlogogen - from Latin phlogosis - inflammation, a synonym for the term inflammatio) can be any factor that can cause tissue damage:
Physical factors (ultraviolet radiation, ionizing radiation, thermal effects)
Chemical factors (acids, alkalis, salts)
Biological factors (viruses, fungi, tumor cells, insect toxins)
The pathogenesis of inflammation
Alteration
The initial stage of inflammation - alteration develops immediately after the action of the damaging factor.
Alteration is changes in tissues that occur immediately after exposure to a damaging factor, are characterized by a metabolic disorder in the tissue, a change in its structure and function. Distinguish between primary and secondary alteration.
Primary alteration is the result of the damaging effect of the inflammatory agent itself, therefore, its severity, other things being equal (reactivity of the organism, localization), depends on the properties of the phlogogen.
Secondary alteration is a consequence of the impact on the connective tissue, microvessels and blood released into the extracellular space of lysosomal enzymes and active oxygen metabolites. Their source is activated immigrated and circulating phagocytes, partly - resident cells.
Characteristic of all metabolisms is an increase in the intensity of catabolic processes, their predominance over anabolism reactions. On the part of carbohydrate metabolism, an increase in glycolysis and glycogenolysis is noted, which ensures an increase in ATP production. However, due to an increase in the level of respiratory chain uncouplers, most of the energy is dissipated in the form of heat, which leads to energy deficiency, which in turn induces anaerobic glycolysis, the products of which - lactate, pyruvate - lead to the development of metabolic acidosis.
Changes in lipid metabolism are also characterized by the predominance of catabolic processes - lipolysis, which causes an increase in the concentration of free fatty acids and intensification of LPO. The level of keto acids increases, which also contributes to the development of metabolic acidosis.
On the part of protein metabolism, increased proteolysis is recorded. The synthesis of immunoglobulins is activated.
The above features of the flow of metabolic reactions to the alteration stage lead to the following physicochemical changes in the cell:
metabolic acidosis
An increase in catabolic processes leads to the accumulation of excess acid products of catabolism: lactic, pyruvic acid, amino acids, IVFA and CT, which causes depletion of the buffer systems of cells and intercellular fluid, leads to an increase in the permeability of membranes, including lysosomal ones, and the release of hydrolases into the cytosol and intercellular substance.
Hyperosmia - increased osmotic pressure
Caused by increased catabolism, breakdown of macromolecules, hydrolysis of salts. Hyperosmia leads to hyperhydration of the focus of inflammation, stimulation of leukocyte emigration, changes in the tone of the walls of blood vessels, and the formation of a feeling of pain.
Hyperonkia - an increase in oncotic pressure in the tissue
It is caused by an increase in protein concentration in the focus of inflammation due to increased enzymatic and non-enzymatic hydrolysis of proteins and the release of proteins from the blood to the focus of inflammation due to increased permeability of the vascular wall. The consequence of hyperonkia is the development of edema in the focus of inflammation.
Change in the surface charge of cells
It is caused by a violation of the water-electrolyte balance in the inflamed tissue due to violations of the transmembrane ion transport and the development of electrolyte imbalance. A change in the surface charge of cells causes a change in the excitability threshold, induces the migration of phagocytes and cell cooperation due to a change in the magnitude of their surface charge.
Changes in the colloidal state of the intercellular substance and hyaloplasm of cells in the focus of inflammation.
Due to enzymatic and non-enzymatic hydrolysis of macromolecules and phase changes in microfilaments, it leads to an increase in phase permeability.
Reducing the surface tension of cell membranes
Caused by exposure to surfactant cell membranes (phospholipids, VFA, K + , Ca ++). Facilitates cell mobility and potentiates adhesion during phagocytosis.
Inflammatory mediators
Inflammatory mediators - biologically active substances responsible for the occurrence or maintenance of inflammatory phenomena.
1. Biogenic amines. This group includes two factors - histamine and serotonin. They are formed by mast cells and basophils.
Action histamine is realized on cells through binding to specialized H-receptors. There are three varieties of them - H 1, H 2, H 3. The first two types of receptors are responsible for the implementation of the biological action, H 3 - for inhibitory effects. In inflammation, the effects mediated through the H1 receptors of endothelial cells predominate. The action of histamine is manifested in the expansion of blood vessels and an increase in their permeability. Histamine acts on nerve endings to cause pain. Histamine also promotes the emigration of leukocytes by increasing the adhesiveness of endothelial cells, stimulates phagocytosis.
Serotonin in moderate concentrations causes the expansion of arterioles, narrowing of venules and contributes to the development of venous stasis. In high concentrations, it promotes spasm of arterioles.
To education kinins leads to the activation of serum and tissue factors, carried out by a cascade mechanism. Kinins dilate arterioles and venules in the focus of inflammation, increase vascular permeability, increase exudation, stimulate the formation of eicosanoids, and cause a sensation of pain.
System fibrinolysis includes a number of plasma proteins with protease activity that cleave the fibrin clot and promote the formation of vasoactive peptides.
complement system. Complement system includes a group of whey proteins that sequentially activate each other according to the cascade principle, resulting in the formation of opsonizing agents and peptide factors involved in the development of inflammatory and allergic reactions. The participation of the complement system in inflammation is manifested at several stages of its development: during the formation of a vascular reaction, the implementation of phagocytosis, and the lysis of pathogenic microorganisms. The result of the activation of the complement system is the formation of a lytic complex that violates the integrity of the cell membrane, primarily bacterial.
Eicosanoids are inflammatory mediators that play an important role in the development of a vascular reaction and the emigration of leukocytes to the site of inflammation. They are derivatives of arachidonic acid, which is part of cell membranes and is cleaved from lipid molecules under the influence of the phospholipase A 2 enzyme.
Leukotrienes appear in the focus of inflammation in 5-10 minutes. Mainly released by mast cells and basophils, constrict small vessels, increase their permeability, enhance the adhesion of leukocytes to the endothelium, serve as chemotactic agents.
Prostaglandins accumulate in the focus of inflammation 6-24 hours after the onset of its development. PGI2 inhibits platelet aggregation, preventing blood clotting, causing vasodilation. PGE2 dilates small vessels, causes pain, regulates the production of other mediators.
Thromboxane TXA2 causes narrowing of venules, aggregation of plates, secretion of active products by platelets, and is a source of pain.
Acute phase proteins are about 30 blood plasma proteins involved in the body's inflammatory response to various damage. Acute phase proteins are synthesized in the liver, their concentration depends I t on the stage of the disease and / or on the extent of damage (hence the value of tests for OP proteins for laboratory diagnosis of the acute phase of the inflammatory response).
C-reactive protein (CRP): during inflammation, the concentration of CRP in the blood plasma increases - by 10-100 times and there is a direct relationship between changes in the level of CRP and severity and dynamics clinical manifestations inflammation. The higher the concentration of CRP, the higher the severity of the inflammatory process, and vice versa. That is why CRP is the most specific and sensitive clinical and laboratory indicator of inflammation and necrosis. That is why the measurement of CRP concentration is widely used to monitor and control the effectiveness of therapy for bacterial and viral infections, chronic inflammatory diseases, oncological diseases, complications in surgery and gynecology, etc. However, different causes of inflammatory processes increase CRP levels in different ways.
With bacterial infections, with exacerbation of certain chronic inflammatory diseases (for example, rheumatoid arthritis) and tissue damage (surgical operations, acute myocardial infarction), CRP concentrations increase to 40-100 mg/l (and sometimes up to 200 mg/l).
Severe generalized infections, burns, sepsis - increase CRP almost prohibitively - up to 300 mg / l and more.
Orosomucoid has antiheparin activity, with an increase in its concentration in serum, platelet aggregation is inhibited.
fibrinogen not only the most important of the blood coagulation proteins, but also the source of the formation of fibrinopeptides with anti-inflammatory activity.
ceruloplasmin- a polyvalent oxidizing agent (oxidase), it inactivates superoxide anionic radicals formed during inflammation, and thus protects biological membranes.
Haptoglobin not only is it able to bind hemoglobin with the formation of a complex with peroxidase activity, but rather effectively inhibits cathepsins C, B, and L. Haptoglobin can also participate in the utilization of some pathogenic bacteria.
A number of acute phase proteins have antiprotease activity. it proteinase inhibitor (α -antitrypsin), antichymotrypsin, α-macroglobulin. Their role is to inhibit the activity of elastase-like and chymotrypsin-like proteinases that enter inflammatory exudates from granulocytes and cause secondary tissue damage. The initial stages of inflammation are usually characterized by decline levels of these inhibitors, but this is followed by an increase in their concentration caused by an increase in their synthesis. Specific inhibitors of proteolytic cascade systems, complement, coagulation, and fibrinolysis regulate changes in the activity of these important biochemical pathways under conditions of inflammation. And therefore, if proteinase inhibitors decrease in septic shock or acute pancreatitis, this is a very poor prognostic sign.
bacterial infection . This is where the highest levels are observed. SRP (100 mg/l and above). At effective therapy the concentration of CRP decreases the very next day, and if this does not happen, taking into account changes in CRP levels, the question of choosing another antibacterial treatment is decided.
Sepsis in newborns . If sepsis is suspected in newborns, the concentration of CRP is more 12 mg/l is an indication for immediate initiation of antimicrobial therapy. But it should be borne in mind that in some newborns, a bacterial infection may not be accompanied by a sharp increase in the concentration of CRP.
Viral infection . With it, CRP can increase only slightly ( less than 20 mg/l), which is used to differentiate a viral infection from a bacterial one. In children with meningitis CRP in concentration above 20 mg/l- this is an unconditional basis for starting antibiotic therapy.
Neutropenia . With neutropenia in an adult patient, the level of CRP more than 10 mg/l may be the only objective indication of a bacterial infection and the need for antibiotics.
Postoperative complications . If CRP remains high (or increases) within 4-5 days after surgery, this indicates the development of complications (pneumonia, thrombophlebitis, wound abscess).
I- infection - infection
R– response – response of the patient
O– organ dysfunction – dysfunction of organs
Some authors believe that in polytrauma, SIRS and MODS are phenomena of the same order - SIRS is a mild form of MODS.
Chemokine CXCL8 is a predictor of poor outcome and development of MODS
IL-12, tumor necrosis factor-α are predictors of a favorable outcome.
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Procoagulant system Anticoagulant system
SEPSIS tissue factor IAP-1 Protein C Plasminogen activators Plasminogen Plasmin Fibrin Inhibition of fibrinolysis INCREASED THROMBO FORMATION Procoagulant mechanisms Thrombosis of small vessels Increased fibrinogen levels Impaired tissue perfusion Thrombin Prothrombin Factor VIIa Factor X Factor X Va factor |
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Rice. 2. The mechanism of development of hemostasis disorders in sepsis. |
Systemic inflammatory response syndrome (SIRS)
The cumulative effects of damage mediators form a generalized systemic inflammatory response or systemic inflammatory response syndrome. , clinical manifestations which are:
- body temperature is more than 38 o C or less than 36 o C;
- heart rate more than 90 per minute;
- frequency respiratory movements more than 20 per minute or arterial hypocapnia less than 32 mm Hg. st;
- leukocytosis more than 12,000 mm or leukopenia less than 4,000 mm, or the presence of more than 10% of immature forms of neutrophils.
Pathogenesis of systemic inflammatory response syndrome (SIRS)
The presence of a traumatic or purulent focus causes the production of inflammatory mediators.
At the first stage local production of cytokines.
At the second stage insignificant concentrations of cytokines enter the bloodstream, which, however, can activate macrophages and platelets. The developing acute phase reaction is controlled by pro-inflammatory mediators and their endogenous antagonists, such as interleukin-1, 10, 13 antagonists; tumor necrosis factor. Due to the balance between cytokines, mediator receptor antagonists and antibodies in normal conditions prerequisites are created for wound healing, destruction of pathogenic microorganisms, maintenance of homeostasis.
Third stage characterized by a generalized inflammatory response. In the event that the regulatory systems are unable to maintain homeostasis, the destructive effects of cytokines and other mediators begin to dominate, which leads to:
impaired permeability and function of the capillary endothelium,
an increase in blood viscosity, which can induce the development of ischemia, which, in turn, can cause reperfusion disorders and the formation of heat shock proteins
activation of the blood coagulation system
deep dilatation of blood vessels, exudation of fluid from the bloodstream, severe blood flow disorders.
In Western literature, the term SIRS is used to define the clinical syndrome formerly referred to as "sepsis", and the diagnosis of "sepsis" is used only in SIRS with documented infection.
Differential diagnosis of non-infectious and infectious (septic) systemic inflammatory response syndrome:
It is believed that in septic SIRS, the most informative indicators of the intensity of inflammation are the levels of CRP, tumor necrosis factor-α and IL-6.
Acute Respiratory Distress Syndrome (ARDS)
For the first time about this syndrome became known during the Vietnam War, when soldiers who survived severely wounded died suddenly within 24-48 hours from acute respiratory failure.
The reasons development ARDS:
Lung infections
Fluid aspiration
Conditions after a heart and lung transplant
Inhalation of toxic gases
Pulmonary edema
shock states
Autoimmune diseases
Pathogenesis of acute respiratory distress syndrome (ARDS)
starting torque ARDS most often is the embolization of microvessels of the lungs with aggregates of blood cells, drops of neutral fat, particles of damaged tissues, microclots of donor blood against the background of the toxic effects of biologically active substances formed in tissues (including lung tissue) - prostaglandins, kinins, etc. The key cytokine in development of ARDS is IL-1β, which, even in small doses, can cause an inflammatory process in the lungs. Locally produced under the influence of IL-1β and tumor necrosis factor-α, the chemokine CXCL8 causes the migration of neutrophils to the lungs, which produce cytotoxic substances that cause damage to the alveolar epithelium, alveolar-capillary membranes and increase the permeability of the walls of the capillaries of the lungs, which ultimately leads to the development of hypoxemia .
Manifestations of ARDS:
Shortness of breath: tachypnea is characteristic of distress syndrome
MOD increase
Decrease in lung volumes (total lung capacity, residual volume lungs, VC, functional residual lung capacity)
Hypoxemia, acute respiratory alkalosis
An increase in cardiac output (in the terminal stage of the syndrome - a decrease)
Multiple Organ/Multiorgan Dysfunction Syndrome (MODS, MOF)
Term MODS(multiple organ dysfunction syndrome) has replaced MOF(multiple organ failure), as it focuses on the course of the dysfunction process, and not on its outcome.
In development MODS distinguish 5 stages:
1. local reaction in the area of injury or primary site of infection
2. initial system response
3. massive systemic inflammation that manifests as SIRS
4. Excessive immunosuppression according to the type of compensatory anti-inflammatory response syndrome
5. immunological disorders.
The pathogenesis of the syndrome of multiple organ lesions (MODS, MOF)
Multiple organ lesions develop as a result of mechanical tissue trauma, microbial invasion, endotoxin release, ischemia-reperfusion and are the cause of death in 60-85% of patients. One of the important causes of damage is the production of inflammatory mediators predominantly by macrophages (tumor necrosis factor-α, IL-1, -4, 6, 10, chemokine CXCL8, adhesive molecules - selectins, ICAM-1, VCAM-1), which leads to activation and migration of leukocytes that produce cytotoxic enzymes, reactive metabolites of oxygen, nitrogen, causing damage to organs and tissues.
Conclusions:
AT inflammation is characterized by the following successive stages:
alteration
microcirculation disorders
exudation
emigration
phagocytosis
proliferation
Treatment of inflammation is based on etiotropic, pathogenetic and symptomatic therapy.
Recommended reading
Main
Litvitsky P.F. Pathophysiology. GEOTAR-Media, 2008
Voynov V.A. Atlas of Pathophysiology: Textbook. - M .: Medical Information Agency, 2004. - 218s.
3. Dolgikh V.T. General pathophysiology: textbook.-R-on-Don: Phoenix, 2007.
4. Efremov A.A. Pathophysiology. Basic concepts: textbook.- M.: GEOTAR-Media, 2008.
5. Pathophysiology: a guide to practical exercises: textbook / ed. V.V.Novitsky.- M.: GEOTAR-Media, 2011.
Electronic resources
1. Frolov V.A. General pathophysiology: E-course on pathophysiology: textbook.- M.: MIA, 2006.
2.Electronic catalog of KrasSMU
Also known as SIRS, systemic inflammatory response syndrome (SIRS) is a pathological condition associated with heightened dangers serious consequences for the patient. SIRS is possible against the background of surgical interventions, which are currently extremely widespread, in particular if we are talking about malignant pathologies. Otherwise, except for the operation, the patient cannot be cured, but the intervention can provoke SIRS.
Question Features
Since the systemic inflammatory response syndrome in surgery occurs more often in patients who have been prescribed treatment against the background of general weakness, illness, the likelihood severe course due to side effects of other therapeutic methods used in a particular case. Regardless of where the injury caused by the operation is located, an early rehabilitation period is associated with increased risks of secondary damage.
As is known from pathological anatomy, the systemic inflammatory response syndrome is also due to the fact that any operation provokes inflammation in an acute form. The severity of such a reaction is determined by the severity of the event, a number of auxiliary phenomena. The more unfavorable the background of the operation, the more difficult the VSSO will be.
What and how?
Systemic inflammatory response syndrome is a pathological condition that indicates itself tachypnea, fever, heart rhythm disturbance. Analyzes show leukocytosis. In many ways, this response of the body is due to the peculiarity of the activity of cytokines. Pro-inflammatory cellular structures that explain SIRS and sepsis form the so-called secondary wave of mediators, due to which systemic inflammation does not subside. This is associated with the danger of hypercytokinemia, a pathological condition in which damage is done to the tissues and organs of one's own body.
The problem of determining and predicting the likelihood of a systemic inflammatory response syndrome, in the ICD-10 encrypted with the R65 code, in the absence of suitable method evaluation of the initial state of the patient. There are several options and gradations that allow you to determine how bad the patient's state of health, but none of them is linked to the risks of SIRS. It is taken into account that in the first 24 hours after the intervention, SIRS appears without fail, but the intensity of the condition varies - this is determined by a complex of factors. If the phenomenon is severe, prolonged, the likelihood of complications, pneumonia, increases.
About terms and theory
Systemic inflammatory response syndrome, coded as R65 in the ICD-10, was considered in 1991 at a conference that brought together leading experts in intensive care and pulmonology. It was decided to recognize SIRS as a key aspect, reflecting any inflammatory process of an infectious nature. Such a systemic reaction is associated with the active distribution of cytokines, and it is not possible to take this process under control by the forces of the body. Inflammatory mediators are generated in the primary focus infection, from where they move to the tissues around, thus getting into circulatory system. The processes proceed with the involvement of macrophages, activators. Other tissues of the body, remote from the primary focus, become the area of generation of similar substances.
According to the pathophysiology of the systemic inflammatory response syndrome, histamine is most often used. Similar effects have factors that activate platelets, as well as those associated with necrotic tumor processes. Perhaps the participation of adhesive molecular structures of the cell, parts of the complement, nitric oxides. SIRS can be explained by the activity of toxic products of oxygen transformation and lipid peroxidation.
Pathogenesis
The systemic inflammatory response syndrome, fixed by the R65 code in the ICD-10, is observed when a person’s immunity cannot take control and extinguish the active systemic spread of factors that initiate inflammatory processes. There is an increase in the content of mediators in the circulatory system, which leads to a failure of fluid microcirculation. The endothelium of capillaries becomes more permeable, toxic components from the bed penetrate through the cracks of this tissue into the cells surrounding the vessels. Over time, inflamed foci appear remote from the primary area, a gradually progressive insufficiency of the work of various internal structures is observed. As a result of such a process - DIC syndrome, paralysis of immunity, insufficiency of functioning in a multiple organ form.
As shown by numerous studies on the occurrence of systemic inflammatory response syndrome in obstetrics, surgery, oncology, such a response appears both when an infectious agent enters the body, and as a response to a certain stress factor. SIRS can be triggered or by a person's injury. In some cases, the root cause is an allergic reaction to a medication, ischemia of certain parts of the body. To some extent, SIRS is such a universal response of the human body to unhealthy processes occurring in it.
Subtleties of the question
Studying the systemic inflammatory response syndrome in obstetrics, surgery, and other branches of medicine, scientists paid special attention to the rules for determining such a condition, as well as the intricacies of using various terminologies. In particular, it makes sense to talk about sepsis if an infectious focus becomes the cause of inflammation in a systemic form. In addition, sepsis is observed if the functioning of some parts of the body is disrupted. Sepsis can be diagnosed only with the obligatory selection of both signs: SSVR, infection of the body.
If manifestations are observed that allow one to suspect dysfunction of internal organs and systems, that is, the reaction has spread wider than the primary focus, a severe variant of the course of sepsis is detected. When choosing a treatment, it is important to remember the possibility of transient bacteremia, which does not lead to a generalization of the infectious process. If this has become the cause of SIRS, organ dysfunction, it is necessary to choose a therapeutic course indicated for sepsis.
Categories and severity
Focusing on the diagnostic criteria for the systemic inflammatory response syndrome, it is customary to distinguish four forms of the condition. Key signs that allow you to talk about SIRS:
- fever above 38 degrees or temperature less than 36 degrees;
- the heart is reduced with a frequency of more than 90 acts per minute;
- breathing in frequency exceeds 20 acts per minute;
- with IVL RCO2 less than 32 units;
- leukocytes in the analysis are defined as 12 * 10 ^ 9 units;
- leukopenia 4*10^9 units;
- new leukocyte forms more than 10% of the total.
To be diagnosed with SIRS, the patient must have two or more of these signs.
About Options
If a patient has two or more signs of the above manifestations of the systemic inflammatory response syndrome, and studies show a focus of infection, analysis of blood samples gives an idea of the pathogen that caused the condition, sepsis is diagnosed.
In case of insufficiency that develops according to a multi-organ scenario, with acute failures in the patient's mental status, lactic acidosis, oliguria, pathologically greatly reduced blood pressure in the arteries, a severe form of sepsis is diagnosed. The condition can be maintained through intensive therapeutic approaches.
Septic shock is detected if sepsis develops in a severe form, low blood pressure is observed in a stable variant, perfusion failures are stable and cannot be controlled by classical methods. In SIRS, hypotension is considered to be a condition in which the pressure is less than 90 units or less than 40 units relative to the initial state of the patient, when there are no other factors that can provoke a decrease in the parameter. It is taken into account that the intake of certain medications may be accompanied by manifestations indicating organ dysfunction, a problem of perfusion, while the pressure is maintained adequately.
Could it be worse?
The most severe variant of the course of the systemic inflammatory response syndrome is observed if the patient has impaired functionality of a pair or more organs necessary to maintain viability. This condition is called multiple organ failure syndrome. This is possible if SIRS is very difficult, while drug and instrumental methods do not allow to control and stabilize homeostasis, with the exception of methods and methods of intensive treatment.
Development concept
Currently, a two-phase concept is known in medicine that describes the development of SIRS. The cytokine cascade becomes the basis of the pathological process. At the same time, cytokines that initiate inflammatory processes are activated, and with them mediators that inhibit the activity of the inflammatory process. In many ways, how the systemic inflammatory response syndrome will proceed and develop is determined precisely by the balance of these two components of the process.
SIRS progresses in stages. The first in science is called induction. This is the period during which the focus of inflammation is local, due to a normal organic reaction to the impact of some aggressive factor. The second stage is a cascade, in which too many inflammatory mediators are generated in the body that can penetrate the circulatory system. At the third stage, secondary aggression takes place, directed at one's own cells. This explains the typical pattern of the course of the systemic inflammatory response syndrome, early manifestations of insufficient organ functionality.
The fourth stage is immunological paralysis. At this stage of development, a deeply depressed state of immunity is observed, the work of the organs is very much disturbed. The fifth and final stage is the terminal one.
Can something help?
If it is necessary to alleviate the course of the systemic inflammatory response syndrome, the clinical recommendation is to monitor the patient's condition by regularly taking vital signs. important organs and the use of medications. If necessary, the patient is connected to special equipment. Recently, medications designed specifically for the relief of SIRS in its various manifestations look especially promising.
Drugs effective in SIRS are based on diphosphopyridine nucleotide and also include inosine. Some versions of the release contain digoxin, lisinopril. Combination medications, chosen at the discretion of the attending physician, inhibit SIRS, regardless of what caused the pathological process. Manufacturers assure that a pronounced effect can be achieved in the shortest possible time.
Is an operation necessary?
In SIRS, additional surgery may be prescribed. Its necessity is determined by the severity of the condition, its course and development forecasts. As a rule, it is possible to carry out an organ-preserving intervention, during which the area of suppuration is drained.
More about medicines
Revealing medicinal features diphosphopyridine nucleotide, combined with inosine, gave doctors new opportunities. Such a drug, as practice has shown, is applicable in the work of cardiologists and nephrologists, surgeons and pulmonologists. Preparations with this composition are used by anesthesiologists, gynecologists, endocrinologists. Currently, drugs are used in surgical operations on the heart and blood vessels, if necessary, to assist the patient in the intensive care unit.
Such a wide area of use is associated with the general symptoms of sepsis, the consequences of burns, manifestations of diabetes occurring in a decompensated handicap, shock on the background of trauma, DFS, necrotic processes in the pancreas and many other severe pathological uprisings. The symptom complex inherent in SIRS, and effectively stopped by diphosphopyridine nucleotide in combination with inosine, includes weakness, pain, and sleep disturbances. The drug alleviates the condition of a patient who has a headache and dizziness, symptoms of encephalopathy appear, the skin turns pale or yellow, the rhythm and frequency of heart contractions are disturbed, and blood flow fails.
Relevance of the issue
As shown statistical studies, SIRS is currently one of the most common options for the development of severe hypoxia, a strong destructive activity of cells in individual tissues. In addition, such a syndrome with a high degree of probability develops against the background of chronic intoxication. The pathogenesis and etiology of conditions leading to SIRS differ greatly.
With any shock, SIRS is always observed. The reaction becomes one of the aspects of sepsis, a pathological condition caused by trauma or burns. It cannot be avoided if the person has had a TBI or surgery. As observations have shown, SIRS is diagnosed in patients with diseases of the bronchi, lungs, uremia, oncology, and surgical pathological conditions. It is impossible to exclude SIRS if an inflammatory or necrotic process develops in the pancreas, abdominal cavity.
As specific studies have shown, SIRS is also observed in a number of more favorably developing diseases. As a rule, with them, this condition does not threaten the patient's life, but lowers its quality. We are talking about a heart attack, ischemia, hypertension, preeclampsia, burns, osteoarthritis.
- generalized activation of the basic mechanisms, which in classical inflammation are localized in the focus of inflammation;
- the leading role of the reaction of microvessels in all vital organs and tissues;
- lack of biological expediency for the organism as a whole;
- systemic inflammation has self-development mechanisms and is the main driving force pathogenesis of critical complications, namely: shock states of various genesis and the syndrome of multiple organ failure, which are the main causes of lethal outcomes.
XVIII. PATHOPHYSIOLOGY OF TUMOR GROWTH
In every science there is a small number of such tasks and problems that can potentially be solved, but this solution has either not been found or, due to a fatal set of circumstances, has been lost. For many centuries, these problems have attracted the interest of scientists. When trying to solve them, outstanding discoveries are made, new sciences are born, old ideas are revised, new theories appear and die. Examples of such tasks and problems are: in mathematics - the famous Fermat's theorem, in physics - the problem of finding the elementary structure of matter, in medicine - the problem of tumor growth. This section is devoted to this problem.
It is more correct to speak not about the problem of tumor growth, but about the problems of tumor growth, since here we are faced with several problems.
First, the tumor is a biological problem, since it is the only disease known to us that is so widespread in nature and occurs in almost the same form in all species of animals, birds, and insects, regardless of their level of organization and habitat. Tumors (osteomas) have already been found in fossil dinosaurs that lived 50 million years ago. Neoplasms are also found in plants - in the form of crown galls in trees, potato "cancer", etc. But there is another side: the tumor consists of the cells of the body itself, therefore, having understood the laws of the emergence and development of the tumor, we will be able to understand many biological laws growth, division, reproduction and differentiation of cells. Finally, there is a third side: the tumor
is an autonomous proliferation of cells, therefore, in the study of the occurrence of tumors, it is impossible to bypass the laws of biological integration of cells.
Secondly, the tumor is a social problem, if only because it is a disease of mature and old age: malignant tumors occur most often at the age of 45–55 years. In other words, highly qualified workers who are still in the period of active creative activity die of malignant neoplasms.
Thirdly, the tumor is an economic problem, since the death of oncological patients is usually preceded by a long and painful illness, therefore, there is a need for specialized medical institutions for a large number of patients, the training of specialized medical personnel, the creation of complex and expensive equipment, the maintenance of research institutions, maintenance of intractable patients.
Fourthly, the tumor is a psychological problem: the appearance of a cancer patient significantly changes the psychological climate in the family and in the team where he works.
The tumor, finally, is also a political problem, since all people on earth, regardless of their race, skin color, social and political structure in their countries. It is not for nothing that practically all countries, establishing political and scientific contacts among themselves, always create bilateral and multilateral programs to combat cancer.
For any tumor, one of the following Greek or Latin terms is used: tumor, blastoma, neoplasm, oncos. When it is necessary to emphasize that we are talking about a malignant growth of a tumor, then the word malignus is added to one of the listed terms, with benign growth - the word benignus.
In 1853, R. Virchow's first work was published, outlining his views on the etiology and pathogenesis of tumors. Since that moment, the cellular direction in oncology has taken a dominant position. "Omnis cellula ex cellula". A tumor cell, like any cell in the body, is formed only from cells. With his statement, R. Virchow put an end to all theories about the emergence of tumors from fluids, lymph, blood, blasts, all kinds of
sty humoral theories. Now the focus is on the tumor cell, and the main task is to study the causes that cause the transformation of a normal cell into a tumor cell, and the ways in which this transformation occurs.
The second major event in oncology was the publication in 1877 of M.A. Novinsky for a master's degree in veterinary sciences with a description of his experiments on transplanting three microsarcomas of dogs into other dogs. The author used young animals for these experiments and grafted into them small pieces not from decaying (as was usually done before), but from living parts of canine tumors. This work marked, on the one hand, the emergence of experimental oncology, and, on the other hand, the emergence of the method of tumor transplantation, i.e. transplantation of spontaneously occurring and induced tumors. The improvement of this method made it possible to determine the main conditions for successful vaccination.
1. For vaccination, live cells must be taken.
2. The number of cells may vary. There are reports of successful inoculation of even one cell, but still, the more cells we inject, the more likely successful tumor inoculation.
3. Repeated vaccinations succeed sooner, and tumors reach large sizes, i.e. if you grow a tumor on an animal, take cells from it and inoculate them in another animal of the same species, then they take root better than in the first animal (the first owner).
4. Autologous transplantation is best performed, i.e. tumor transplantation to the same host, but to a new location. Syngeneic transplantation is also effective; grafting of the tumor onto animals of the same inbred line as the original animal. Tumors take root worse in animals of the same species, but of a different line (allogeneic transplantation), and tumor cells take root very poorly when transplanted into an animal of another species (xenogenic transplantation).
Along with tumor transplantation, the method of explantation is also of great importance for understanding the characteristics of malignant growth; cultivation of tumor cells outside the body. Back in 1907, R.G. Harrison showed the possibility of growing cells on artificial nutrient media, and soon, in 1910, A. Carrel and M. Burrows published data on the possibility of in vitro cultivation of malignant tissues. This method made it possible to study tumor cells of various animals.
and even a person. The latter include the Hela strain (from epic
dermoid cervical cancer), Hep-1 (also obtained from the cervix), Hep-2 (laryngeal cancer), etc.
Both methods are not without drawbacks, among which the most significant are the following:
with repeated vaccinations and crops in culture, the properties of the cells change;
the ratio and interaction of tumor cells with stromal and vascular elements, which are also part of the tumor growing in the body, are disturbed;
the regulatory influence of the organism on the tumor is removed (when the tumor tissue is cultivated in vitro).
With the help of the described methods, we can still study the properties of tumor cells, the characteristics of their metabolism, and the effect of various chemical and medicinal substances on them.
The occurrence of tumors is associated with the action on the body of various factors.
1. Ionizing radiation. In 1902, A. Frieben in Hamburg described skin cancer on the back of the hand in an employee in a factory manufacturing X-ray tubes. This worker spent four years checking the quality of the pipes by looking through his own hand.
2. Viruses. In the experiments of Ellerman and Bang (C. Ellerman, O. Bang)
in 1908 and P. Rous in 1911 established the viral etiology of leukemia and sarcoma. However, at that time, leukemia was not considered a neoplastic disease. And although these scientists have created a new, very promising direction in the study of cancer, their work for a long time were ignored and underestimated. Only in 1966, 50 years after the discovery, P. Raus was awarded the Nobel Prize.
Along with numerous viruses that cause tumors in animals, viruses that act as an etiological factor for the induction of tumors in humans have been isolated. Of the RNA-containing retroviruses, these include the HTLV-I virus (eng. hu man T-cell lymphotropic virus type I), developmental a type of human T-cell leukemia. In a number of its properties, it is similar to the human immunodeficiency virus (HIV), which causes the development of acquired immunodeficiency syndrome (AIDS). DNA-containing viruses whose participation in the development of human tumors has been proven include human papillomavirus (cervical cancer), hepatitis B and C viruses (liver cancer), Epstein-Barr virus (in addition to infectious mononucleosis, is an etiological factor for lymphoma Burkitt and nasopharyngeal carcinoma).
3. Chemicals. In 1915, the work of Yama Giwa and Ichikawa (K. Yamagiwa and K. Ichikawa) was published. Pilot study atypical epithelial proliferation”, which described the development of a malignant tumor in rabbits under the influence of long-term lubrication of the skin of the inner surface of the ear with coal tar. Later, a similar effect was obtained by smearing the backs of mice with this resin. Undoubtedly, this observation was a revolution in experimental oncology, since the tumor was induced in the body of an experimental animal. This is how the method of tumor induction appeared. But at the same time, the question arose: what is the active principle, which of the many substances that make up the resin serves as a carcinogen?
The subsequent years of development of experimental and clinical oncology are characterized by the accumulation of factual data, which since the beginning of the 60s. 20th century began to be generalized into more or less coherent theories. Nevertheless, even today we can say that we know quite a lot about tumor growth, but we still do not understand everything about it and are still far from the final solution of oncological problems. But what do we know today?
Tumor, neoplasm– pathological cell proliferation uncontrolled by the body with relative autonomy of metabolism and significant differences in structure and properties.
A tumor is a clone of cells that originated from the same parent cell and have the same or similar properties. Academician R.E. Kavetsky proposed to distinguish three stages in tumor development: initiation, stimulation and progression.
Initiation stage
The transformation of a normal cell into a tumor cell is characterized by the fact that it acquires new properties. These "new" properties of a tumor cell should be correlated with changes in the genetic apparatus of the cell, which are triggers for carcinogenesis.
Physical carcinogenesis. Changes in the DNA structure leading to the development of a tumor can be caused by various physical factors, and ionizing radiation should be put in the first place here. Under the influence of radioactive substances, gene mutations occur, some of which can lead to the development of a tumor. As for other physical factors, such as mechanical irritation, thermal effects (chronic burns), polymeric substances (metal foil, synthetic foil),
they stimulate (or activate) the growth of the already induced, i.e. an already existing tumor.
chemical carcinogenesis. Changes in the structure of DNA can also be caused by various chemicals, which served as the basis for the creation of theories of chemical carcinogenesis. For the first time, the possible role of chemicals in tumor induction was pointed out in 1775 by Dr. English doctor Percivall Pott, who described scrotum cancer in chimney sweeps and linked the occurrence of this tumor with exposure to soot from the chimneys of English houses. But only in 1915 this assumption was experimentally confirmed in the works of Japanese researchers Yamagiwa and Ichikawa (K. Yamagiwa and K. Ichikawa), who caused a malignant tumor in rabbits with coal tar.
At the request of the English researcher J.W. Cook, in 1930, 2 tons of resin were subjected to fractional distillation at a gas plant. After repeated distillation, crystallization, and preparation of characteristic derivatives, 50 g of some unknown compound was isolated. It was 3,4-benzpyrene, which, as was established by biological tests, turned out to be quite suitable for research as a carcinogen. But 3,4-benzpyrene is not one of the very first pure carcinogens. Even earlier (1929) Cooke had already synthesized 1,2,5,6-dibenzathracene, which also turned out to be an active carcinogen. Both compounds, 3,4-benzpyrene and 1,2,5,6 dibenzoatracene, belong to the class of polycyclic hydrocarbons. Representatives of this class contain benzene rings as the main building block, which can be combined into numerous ring systems in various combinations. Later, other groups of carcinogens were identified, such as aromatic amines and amides, chemical dyes widely used in industry in many countries; nitroso compounds are aliphatic cyclic compounds that necessarily have an amino group in their structure (dimethylnitrosamine, diethylnitrosamine, nitrosomethylurea, etc.); aflatoxins and other products of vital activity of plants and fungi (cicasine, safrole, ragwort alkaloids, etc.); heterocyclic aromatic hydrocarbons (1,2,5,6-dibenzacridine, 1,2,5,6 and 3,4,5,6-dibenzcarbazole, etc.). Consequently, carcinogens differ from each other in chemical structure, but nevertheless they all have a number of common properties.
1. From the moment of action of a carcinogen until the appearance of a tumor, a certain latent period passes.
2. The action of a chemical carcinogen is characterized by a summation effect.
3. The influence of carcinogens on the cell is irreversible.
4. There are no subthreshold doses for carcinogens, i.e. any, even a very small dose of a carcinogen causes a tumor. However, at very low doses of a carcinogen, the latent period can exceed the lifespan of a person or animal, and the organism dies from a cause other than a tumor. This can also explain the high frequency of tumor diseases in the elderly (a person is exposed to low concentrations of carcinogens, therefore, the latent period is long and the tumor develops only in old age).
5. Carcinogenesis is an accelerated process, i.e., having started under the action of a carcinogen, it will not stop, and the cessation of the action of a carcinogen on the body does not stop the development of a tumor.
6. Essentially, all carcinogens are toxic; able to kill the cell. This means that at particularly high daily doses of carcinogens, cells die. In other words, the carcinogen interferes with itself: at high daily doses, a larger amount of the substance is required to produce a tumor than at low ones.
7. The toxic effect of a carcinogen is directed primarily against normal cells, as a result of which “resistant” tumor cells gain advantages in selection when exposed to a carcinogen.
8. Carcinogenic substances can replace each other (the phenomenon of syncarcinogenesis).
There are two options for the appearance of carcinogens in the body: intake from outside (exogenous carcinogens) and formation in the body itself (endogenous carcinogens).
Exogenous carcinogens. Only a few of the known exogenous carcinogens without changing their chemical structure capable of causing the formation of a tumor, i.e. are initially carcinogenic. Among the polycyclic hydrocarbons, benzene itself, naphthalene, anthracene, and phenanthracene are non-carcinogenic. Perhaps the most carcinogenic are 3,4-benzpyrene and 1,2,5,6-dibenzanthracene, while 3,4-benzpyrene plays a special role in the human environment. Oil residues, exhaust fumes, street dust, fresh earth in the field, cigarette smoke and even smoked products contain in some cases a significant amount of this carcinogenic hydrocarbon. Aromatic amines themselves are not carcinogenic at all, which has been proven by direct experiments (Georgiana
Bonser). Consequently, the bulk of carcinogenic substances should be formed in the body of an animal and a person from substances coming from outside. There are several mechanisms for the formation of carcinogens in the body.
First, inactive carcinogenic substances can be activated in the body during chemical transformations. At the same time, some cells are capable of activating carcinogenic substances, while others are not. Carcinogens, which can do without activation and which do not have to pass through metabolic processes in the cell in order to manifest their destructive properties, should be considered as an exception. Sometimes, activating reactions are referred to as a process of toxication, since the formation of genuine toxins occurs in the body.
Secondly, a violation of detoxification reactions, during which toxins are neutralized, including carcinogens, will also contribute to carcinogenesis. But even if not disturbed, these reactions can contribute to carcinogenesis. For example, carcinogens (particularly aromatic amines) are converted into esters (glycosides) of glucuronic acid and then excreted by the kidneys through the ureter into the bladder. And urine contains glucuronidase, which, by destroying glucuronic acid, promotes the release of carcinogens. Apparently, this mechanism plays an important role in the occurrence of bladder cancer under the influence of aromatic amines. Glucuronidase has been found in human and dog urine, but is absent in mice and rats, and as a consequence, humans and dogs are prone to bladder cancer, while mice and rats
Endogenous carcinogens. In the human and animal body, there are a lot of various "raw materials" for the emergence of substances that may have carcinogenic activity - these are bile acids, and vitamin D, and cholesterol, and a number of steroid hormones, in particular sex hormones. All these are ordinary components of the animal organism in which they are synthesized, undergo significant chemical changes, and are utilized by tissues, which is accompanied by a change in their chemical structure and the elimination of the remains of their metabolism from the body. At the same time, as a result of this or that metabolic disorder, instead of a normal, physiological product, say, a steroid structure, some very close, but still different product arises, with a different effect on tissues - this is how endogenous carcinogenic substances arise. As you know, people get cancer most often in 40-60 years. This age has
biological features - this is the age of menopause in the broadest sense of the term. During this period, there is not so much a cessation of the function of the gonads as their dysfunction, leading to the development of hormone-dependent tumors. special attention deserve therapeutic measures with the use of hormones. Cases of development malignant tumors mammary gland with immoderate prescription of natural and synthetic estrogens, not only in women (with infantilism), but also in men. It does not at all follow from this that estrogens should not be prescribed at all, however, indications for their use in necessary cases and especially the doses of the administered drugs must be well thought out.
The mechanism of action of carcinogens . It has now been established that at around 37°C (i.e. body temperature) DNA breaks are constantly occurring. These processes proceed at a fairly high rate. Consequently, the existence of a cell, even under favorable conditions, is possible only because the DNA repair (repair) system usually has time to eliminate such damage. However, under certain conditions of the cell, and primarily during its aging, the balance between the processes of DNA damage and repair is disturbed, which is the molecular genetic basis for the increase in the frequency of tumor diseases with age. Chemical carcinogens can accelerate the development of the process of spontaneous (spontaneous) DNA damage due to an increase in the rate of DNA break formation, suppress the activity of mechanisms that restore normal structure DNA, as well as change the secondary structure of DNA and the nature of its packaging in the nucleus.
There are two mechanisms of viral carcinogenesis.
The first is induced viral carcinogenesis. The essence of this mechanism is that the virus that existed outside the body enters the cell and causes tumor transformation.
The second is "natural" viral carcinogenesis. The virus that causes tumor transformation enters the cell not from the outside, but is a product of the cell itself.
induced viral carcinogenesis. Currently, more than 150 oncogenic viruses are known, which are divided into two large groups: DNA and RNA-containing. Their main common property is the ability to transform normal cells into tumor cells. RNA-containing oncoviruses (oncornaviruses) represent a larger unique group.
When a virus enters a cell, different variants of their interaction and relationships between them are possible.
1. Complete destruction of the virus in the cell - in this case, there will be no infection.
2. Complete reproduction of viral particles in the cell, i.e. replication of the virus in the cell. This phenomenon is called a productive infection and is most often encountered by infectious disease specialists. An animal species in which the virus circulates under normal conditions, being transmitted from one animal to another, is called a natural host. Natural host cells infected with a virus and productively synthesizing viruses are called permissive cells.
3. As a result of the action of protective cellular mechanisms on the virus, it is not fully reproduced; the cell is not able to completely destroy the virus, and the virus cannot fully ensure the reproduction of viral particles and destroy the cell. This often occurs when the virus enters the cells of a non-natural host, but of an animal of another species. Such cells are called nonpermissive. Consequently, the cell genome and part of the viral genome simultaneously exist and interact in the cell, which leads to a change in the properties of the cell and can lead to its tumor transformation. It has been established that productive infection and cell transformation under the action of DNA-containing oncoviruses are usually mutually exclusive: cells of the natural host are mainly infected productively (permissive cells), while cells of another species are more often transformed (non-permissive cells).
AT it is now generally accepted that abortive infection, i.e. interruption of the full cycle of oncovirus reproduction at any stage is an obligatory factor causing the tumor
cell transformation. Such interruption of the cycle can occur when a full infectious virus infects genetically resistant cells, when a defective virus infects permissive cells, and, finally, when a full virus infects susceptible cells under unusual (non-permissive) conditions, for example, at high temperature (42°C).
Cells transformed with DNA-containing oncoviruses, as a rule, do not replicate (do not reproduce) the infectious virus, but in such neoplastically altered cells, a certain function of the viral genome is constantly realized. It turned out that it is precisely this abortive form of the relationship between the virus and the cell that creates favorable conditions for embedding, incorporating the viral genome into the cellular one. To resolve the issue of the nature of the incorporation of the virus genome into the DNA of a cell, it is necessary to answer the following questions: when, where, and how does this integration take place?
The first question is when? – refers to the phase of the cell cycle during which the process of integration is possible. This is possible in the S phase of the cell cycle, because during this period individual DNA fragments are synthesized, which are then combined into a single strand using the DNA ligase enzyme. If among such fragments of cellular DNA there are also fragments of a DNA containing oncovirus, then they can also be included in the newly synthesized DNA molecule and it will have new properties that change the properties of the cell and lead to its tumor transformation. It is possible that the DNA of an oncovirus, having penetrated into a normal cell not in the S-phase, is first in a state of “rest” in anticipation of the S-phase, when it mixes with fragments of the synthesized cellular DNA, in order to then be included in the cellular DNA with the help of DNA- ligases.
The second question is where? – refers to the place where the DNA of the oncogene virus is incorporated into the cell genome. Experiments have shown that it occurs in regulatory genes. The inclusion of the oncovirus genome in the structural genes is unlikely.
The third question is how is the integration going?
follows logically from the previous one. The minimal structural unit of DNA from which information is read out, the transcripton, is represented by the regulatory and structural zones. The reading of information by DNA-dependent RNA polymerase starts from the regulatory zone and proceeds towards the structural zone. The point from which the process begins is called the promoter. If a DNA virus is included in a transcripton, it contains two
motors are cellular and viral, and information reading starts from the viral promoter.
AT case of integration of oncovirus DNA between the regulatory
and structural zones RNA polymerase starts transcription from the viral promoter, bypassing the cellular promoter. As a result, a heterogeneous chimeric messenger RNA is formed, part of which corresponds to the virus genes (starting from the viral promoter), and the other part corresponds to the structural gene of the cell. Consequently, the structural gene of the cell is completely out of control of its regulatory genes; regulation is lost. If an oncogenic DNA virus is included in the regulatory zone, then part of the regulatory zone will still be translated, and then the loss of regulation will be partial. But in any case, the formation of chimeric RNA, which serves as the basis for enzyme protein synthesis, leads to a change in cell properties. According to available data, up to 6–7 viral genomes can integrate with cellular DNA. All of the above referred to DNA-containing oncogenic viruses, the genes of which are directly incorporated into the DNA of the cell. But they cause a small number of tumors. Much more tumors are caused by RNA-containing viruses, and their number is greater than that of DNA-containing ones. At the same time, it is well known that RNA cannot be incorporated into DNA by itself; therefore, carcinogenesis caused by RNA-containing viruses must have a number of features. Proceeding from the chemical impossibility of incorporating the viral RNA of oncornaviruses into cellular DNA, the American researcher H.M. Temin, Nobel Prize in 1975, based on his experimental data, suggested that oncornaviruses synthesize their own viral DNA, which is included in the cellular DNA in the same way as in the case of DNA-containing viruses. Temin called this form of DNA synthesized from viral RNA a provirus. It is probably appropriate to recall here that Temin's proviral hypothesis appeared in 1964, when the central position of molecular biology that the transfer of genetic
information goes according to the scheme DNA RNA protein. Temin's hypothesis introduced a fundamentally new stage into this scheme - DNA RNA. This theory, met by the majority of researchers with obvious mistrust and irony, nevertheless, was in good agreement with the main position of the virogenetic theory on the integration of the cellular and viral genomes, and, most importantly, explained it.
It took six years for Temin's hypothesis to receive experimental confirmation, thanks to the discovery of
ment, carrying out the synthesis of DNA on RNA, - reverse transcriptase. This enzyme has been found in many cells and has also been found in RNA viruses. It was found that the reverse transcriptase of RNA containing tumor viruses differs from conventional DNA polymerases; information about its synthesis is encoded in the viral genome; it is present only in virus-infected cells; reverse transcriptase has been found in human tumor cells; it is necessary only for tumor transformation of the cell and is not required to maintain tumor growth. When the virus enters the cell, its reverse transcriptase begins to work and the synthesis of a complete copy of the viral genome occurs - a DNA copy, which is a provirus. The synthesized provirus is then incorporated into the genome of the host cell, and then the process develops in the same way as in the case of DNA-containing viruses. In this case, the provirus can be included entirely in one place in the DNA, or, after decomposing into several fragments, it can be included in various sections cellular DNA. Now, when the synthesis of cellular DNA is activated, the synthesis of viruses will always be activated.
In the body of the natural host, the complete copying of the viral genome and the synthesis of the complete virus occur from the provirus. In a non-natural organism, the provirus is partially lost and only 30–50% of the complete viral genome is transcribed, which contributes to tumor cell transformation. Consequently, in the case of RNA-containing viruses, tumor transformation is associated with abortive (interrupted) infection.
Until now, we have considered viral carcinogenesis from the standpoint of classical virology, i.e. they proceeded from the fact that the virus is not a normal component of the cell, but enters it from the outside and causes its tumor transformation, i.e. induces tumor formation; therefore, such carcinogenesis is called induced viral carcinogenesis.
products of a normal cell (or, as they are called, endogenous viruses). These viral particles have all the features characteristic of oncornaviruses. At the same time, these endogenous viruses are, as a rule, apathogenic for the organism, and often they are not even infectious at all (i.e., they are not transmitted to other animals), only some of them have weak oncogenic properties.
To date, endogenous viruses have been isolated from normal cells of almost all bird species and all mouse strains, as well as rats, hamsters, guinea pigs, cats, pigs, and monkeys. It has been established that any cell can practically be a virus producer; such a cell contains the necessary information for the synthesis of an endogenous virus. The part of the normal cellular genome encoding the structural components of the virus is called the virogen (virogens).
Two main properties of virogens are inherent in all endogenous viruses: 1) ubiquitous distribution - moreover, one normal cell may contain information for the production of two or more endogenous viruses that differ from each other; 2) vertical hereditary transmission, i.e. from mother to offspring. The virogen can be included in the cellular genome not only as a single block, but also individual genes or their groups that make up the virogen as a whole can be included in different chromosomes. It is not difficult to imagine (since there is no single functioning structure) that in most cases normal cells containing a virogen in their composition do not form a complete endogenous virus, although they can synthesize its individual components in various quantities. All the functions of endogenous viruses under physiological conditions have not yet been fully elucidated, but it is known that they are used to transfer information from a cell to a cell.
The participation of endogenous viruses in carcinogenesis is mediated by various mechanisms. In accordance with the concept of R.J. Huebner and Y.J. Todaro (Hubner - Todaro) virogen contains a gene (or genes) responsible for the tumor transformation of the cell. This gene is called an oncogene. Under normal conditions, the oncogene is in an inactive (repressed) state, since its activity is blocked by repressor proteins. Carcinogenic agents (chemical compounds, radiation, etc.) lead to derepression (activation) of the corresponding genetic information, resulting in the formation of virions from the virus precursor contained in the chromosome, which can cause the transformation of a normal cell into a tumor cell. H.M. Temin based on detailed tumor studies
The study of cell transformation by the Rous sarcoma virus postulated that the virogen does not contain oncogenes; genes that determine the transformation of a normal cell into a tumor cell. These genes arise as a result of mutations in certain regions of cellular DNA (protoviruses) and the subsequent transfer of genetic information along a pathway that includes reverse transcription (DNA RNA DNA). Out of contemporary ideas about the molecular mechanisms of carcinogenesis, it can be argued that the mutation of a prooncogene is not the only way of its transformation into an oncogene. The inclusion (insertion) of a promoter (the DNA region that RNA polymerase binds to initiate gene transcription) near the protooncogene can lead to the same effect. In this case, the role of a promoter is played either by DNA copies of certain sections of oncornoviruses, or by mobile genetic structures or “jumping” genes, i.e. DNA segments that can move and integrate into different parts of the cell genome. The transformation of a proto-oncogene into an oncogene may also be due to amplification (lat.amplificatio - distribution, increase
- this is an increase in the number of protooncogenes that normally have a small trace activity, as a result of which the total activity of protooncogenes increases significantly) or translocation (movement) of a protooncogene to a locus with a functioning promoter. For the study of these mechanisms, the Nobel Prize in 1989.
received J.M. Bishop and H.E. Varmus.
Thus, the theory of natural oncogenesis considers viral oncogenes as genes of a normal cell. In this sense, Darlington's catchy aphorism (C.D. Darlington) "A virus is a freaked out gene" most accurately reflects the essence of natural oncogenesis.
It turned out that viral oncogenes, the existence of which was pointed out by L.A. Silber, encode proteins that are regulators of the cell cycle, processes of cell proliferation and differentiation, and apoptosis. Currently, more than a hundred oncogenes are known that encode components of intracellular signaling pathways: tyrosine and serine/threonine protein kinases, GTP-binding proteins of the Ras-MAPK signaling pathway, nuclear transcription regulatory proteins, as well as growth factors and their receptors.
The protein product of the v-src gene of the Rous sarcoma virus functions as a tyrosine protein kinase, the enzymatic activity of which determines the oncogenic properties of v-src. Protein products five other viral oncogenes (fes/fpc ,yes ,ros ,abl ,fgr ) also turned out to be tyrosine new protein kinases. Tyrosine protein kinases are enzymes that phosphorylate various proteins (enzymes, regulatory
chromosome proteins, membrane proteins, etc.) by tyrosine residues. Tyrosine protein kinases are currently considered as the most important molecules that provide the transduction (transmission) of an external regulatory signal to intracellular metabolism; in particular, the important role of these enzymes in the activation and further triggering of the proliferation and differentiation of T- and B-lymphocytes through their antigen-recognizing receptors has been proven. One gets the impression that these enzymes and the signaling cascades triggered by them are intimately involved in the regulation of the cell cycle, the processes of proliferation and differentiation of any cells.
It turned out that normal, non-retrovirus-infected cells contain normal cell genes related to viral oncogenes. This relationship was originally established as a result of the discovery of homology in the nucleotide sequences of the transforming Rous sarcoma virus oncogene v-src (viral src ) and the normal chicken c-src gene (cellular src ). Apparently, the Rous sarcoma virus was the result of recombinations between c-src and the ancient standard avian retrovirus. This mechanism, recombination between the viral gene and the host gene, is an obvious explanation for the formation of transforming viruses. For this reason, the functions of normal genes and their role in nonviral neoplasms are of great interest to researchers. In nature normal forms oncogenes are very conservative. For each of them there are human homologues, some of them are present in all eukaryotic organisms up to and including invertebrates and yeasts. Such conservatism indicates that these genes perform vital functions in normal cells, and the oncogenic potential is acquired by genes only after functionally significant changes (such as those that occur upon recombination with a retrovirus). These genes are referred to as proto-oncogenes.
Some of these genes, grouped into the ras family of cellular oncogenes, were discovered by cell transfection with DNA taken from human tumor cells. Activation of ras genes is common in some chemically induced rodent epithelial carcinomas, suggesting activation of these genes by chemical carcinogens. The important role of ras genes in the regulation of activation, proliferation, and differentiation of normal, non-tumor cells, in particular, T-lymphocytes, has been proven. Other human protooncogenes have also been identified that perform the most important functions in normal nontumor cells. Study of the proteins encoded by the virus
oncogenes and their normal cellular homologues, clarifies the mechanisms of functioning of these genes. Proteins encoded by the ras protooncogene are associated with the inner surface of the cell membrane. Their functional activity, which consists in the binding of GTP, is a manifestation of functional activity GTP-binding or G-proteins. The ras genes are phylogenetically ancient; they are present not only in the cells of mammals and other animals, but also in yeast. The main function of their products is to trigger a mitogen-activated signaling pathway that is directly involved in the regulation of cell proliferation and includes sequential cascade activation of MAPKKK (a kinase that phosphorylates MAPKK; in vertebrates, serine-threonine protein kinase Raf), MAPKK (a kinase that phosphorylates MAPK; in in vertebrates - protein kinase MEK; from English mitogen-activated and extracellularly activated kinase) and MAPK (from English mitogen-activated protein kinase; in vertebrates - protein kinase ERK; from English extracellular signal-regulated kinase) protein kinases. Therefore, it may turn out that transforming Ras proteins belong to the class of altered G proteins that transmit a constitutive growth signal.
Proteins encoded by three other oncogenes - myb, myc, fos - are located in the cell nucleus. In some, but not all cells, the normal myb homologue is expressed during the Gl phase of the cell cycle. The functioning of the other two genes seems to be closely related to the mechanisms of action of the growth factor. When stunted fibroblasts are exposed to platelet-derived growth factor, expression of a specific set of genes (estimated at 10 to 30), including the c-fos and c-myc proto-oncogenes, begins to be expressed, and cellular mRNA levels of these genes increase. Expression of c-myc is also stimulated in resting T- and B-lymphocytes after exposure to the corresponding mitogens. After the cell enters the growth cycle, c-myc expression remains almost constant. After the cell loses the ability to divide (for example, in the case of postmitotic differentiated cells), c-myc expression ceases.
An example of protooncogenes that function as growth factor receptors are genes encoding epidermal growth factor receptors. In humans, these receptors are represented by 4 proteins, designated as HER1, HER2, HER3 and HER4 (from the English human epidermal growth factor receptor). All receptor variants have a similar structure and consist of three domains: extracellular ligand-binding, transmembrane lipophilic, and intracellular
th, which has the activity of tyrosine protein kinase and is involved in signal transduction into the cell. A sharply increased expression of HER2 was found in breast cancer. Epidermal growth factors stimulate proliferation, prevent the development of apoptosis, and stimulate angiogenesis and tumor metastasis. The high therapeutic efficacy of monoclonal antibodies against the extracellular domain of HER2 (drug trastuzumab, which has passed clinical trials in the USA) in the treatment of breast cancer has been proven.
Therefore, protooncogenes can normally function as regulators of the "activation" of cell growth and differentiation and serve as nuclear targets for signals generated by growth factors. When altered or deregulated, they can provide a defining stimulus for unregulated cell growth and abnormal differentiation, which is characteristic of neoplastic conditions. The data discussed above indicate the most important role of protooncogenes in the functioning of normal cells and in the regulation of their proliferation and differentiation. "Breakdown" of these mechanisms of intracellular regulation (as a result of the action of retroviruses, chemical carcinogens, radiation, etc.) can lead to malignant transformation of the cell.
In addition to proto-oncogenes that control cell proliferation, damage to growth-inhibiting tumor suppressor genes plays an important role in tumor transformation.
(eng. growth-inhibiting cancer-suppressor genes), performing the function of anti-oncogenes. In particular, many tumors have mutations in the gene encoding the synthesis of the p53 protein (p53 tumor suppressor protein), which triggers signaling pathways in normal cells that are involved in the regulation of the cell cycle (stopping the transition from the G1 phase to the S phase of the cell cycle) , induction of apoptosis processes, inhibition of angiogenesis. In tumor cells of retinoblastoma, osteosarcomas, and small cell lung cancer, there is no synthesis of the retinoblastoma protein (pRB protein) due to a mutation of the RB gene encoding this protein. This protein is involved in the regulation of the G1 phase of the cell cycle. An important role in the development of tumors is also played by the mutation of the bcl-2 genes (English anti-apoptotic protein B-cell lymphoma 2),
leading to inhibition of apoptosis.
For the occurrence of a tumor, no less important than the factors that cause it is the selective sensitivity of cells to these factors. It has been established that an indispensable prerequisite for the appearance of a tumor is the presence in the initial tissue of a population of dividing
moving cells. This is probably why mature brain neurons of an adult organism, which have completely lost the ability to divide, never form a tumor, in contrast to the glial elements of the brain. Therefore, it is clear that all factors that promote tissue proliferation also contribute to the emergence of neoplasms. The first generation of dividing cells of highly differentiated tissues is not an exact copy of parental, highly specialized cells, but turns out to be like a “step back” in the sense that it is characterized by a lower level of differentiation and some embryonic features. Later, in the process of division, they differentiate in a strictly determined direction, “ripening” to the phenotype inherent in the given tissue. These cells have a less rigid program of behavior than cells with a complete phenotype; in addition, they may be incompetent to some regulatory influences. Naturally, the genetic apparatus of these cells more easily switches to the path of tumor transformation,
and they serve as direct targets for oncogenic factors. Having turned into neoplasm elements, they retain some features that characterize the stage of ontogenetic development at which they were caught by the transition to a new state. From these positions, it becomes clear hypersensitivity to oncogenic factors of embryonic tissue, entirely consisting of immature, dividing
and differentiating elements. It also largely determines the phenomenontransplacental blastomogenesis: doses of blastomogenic chemical compounds, harmless to the pregnant female, act on the embryo, which leads to the appearance of tumors in the cub after birth.
Stage of stimulation of tumor growth
The stage of initiation is followed by the stage of stimulation of tumor growth. At the initiation stage, one cell degenerates into a tumor cell, but a whole series of cell divisions is still needed to continue tumor growth. During these repeated divisions, cells with different abilities for autonomous growth are formed. Cells that obey the regulatory influences of the body are destroyed, and cells that are most prone to autonomous growth acquire growth advantages. There is a selection, or selection of the most autonomous cells, and hence the most malignant. The growth and development of these cells is influenced by various factors – some of them accelerate the process, while others, on the contrary, inhibit it, thereby preventing the development of a tumor. Factors that in themselves
are not capable of initiating a tumor, are not able to cause tumor transformation, but stimulate the growth of tumor cells that have already arisen, are called cocarcinogens. These primarily include factors that cause proliferation, regeneration or inflammation. These are phenol, carbolic ether, hormones, turpentine, healing wounds, mechanical factors, mitogens, cell regeneration, etc. These factors cause tumor growth only after or in combination with a carcinogen, for example, cancer of the lip mucosa in pipe smokers (cocarcinogenic mechanical factor), cancer of the esophagus and stomach (mechanical and thermal factors), bladder cancer (the result of infection and irritation), primary liver carcinoma (most often based on liver cirrhosis), lung cancer (in cigarette smoke, except for carcinogens - benzpyrene and nitrosamine, contain phenols acting as cocarcinogens). concept co carcinogenesis should not be confused with the concept syncarcinogenesis, which we talked about earlier. Synergistic action of carcinogens is understood as syncarcinogenesis, i.e. substances that can cause, induce a tumor. These substances are capable of replacing each other in tumor induction. Cocarcinogenesis refers to factors that contribute to carcinogenesis, but are not carcinogenic in and of themselves.
Tumor progression stage
Following initiation and stimulation, the stage of tumor progression begins. Progression is a steady increase in the malignant properties of a tumor during its growth in the host organism. Since a tumor is a clone of cells originating from a single parent cell, therefore, both the growth and progression of the tumor obey the general biological laws of clonal growth. First of all, several cell pools, or several groups of cells, can be distinguished in a tumor: a pool of stem cells, a pool of proliferating cells, a pool of non-proliferating cells, and a pool of lost cells.
Stem cell pool. This population of tumor cells has three properties: 1) the ability to self-maintenance, i.e. the ability to persist indefinitely in the absence of cell supply: 2) the ability to produce differentiated cells; 3) the ability to restore the normal number of cells after damage. Only stem cells have an unlimited proliferative potential, while non-stem proliferating cells inevitably die after a series of divisions. Sle
Consequently, stem cells in tumors can be defined as cells capable of unlimited proliferation and resumption of tumor growth after injury, metastasis, and inoculation into other animals.
Pool of proliferating cells. The proliferative pool (or growth fraction) is the proportion of cells currently participating in proliferation, i.e. in the mitotic cycle. The concept of a proliferative pool in tumors has become widespread in recent years. It is of great importance in connection with the problem of treating tumors. This is due to the fact that many active antitumor agents act mainly on dividing cells, and the size of the proliferative pool may be one of the factors determining the development of tumor treatment regimens. When studying the proliferative activity of tumor cells, it turned out that the duration of the cycle in such cells is shorter, and the proliferative pool of cells is larger than in normal tissue, but at the same time, both of these indicators never reach the values characteristic of regenerating or stimulated normal tissue. We have no right to speak about a sharp increase in the proliferative activity of tumor cells, since normal tissue can proliferate and proliferate during regeneration more intensively than the tumor grows.
Pool of non-proliferating cells . Represented by two types of cells. On the one hand, these are cells that are capable of dividing, but have exited the cell cycle and entered the G stage. 0 , or a phase in which. The main factor determining the appearance of these cells in tumors is insufficient blood supply, leading to hypoxia. The stroma of tumors grows more slowly than the parenchyma. As tumors grow, they outgrow their own blood supply, which leads to a decrease in the proliferative pool. On the other hand, the pool of non-proliferating cells is represented by maturing cells; some of the tumor cells are capable of maturation and maturation to mature cell forms. However, during normal proliferation in an adult organism in the absence of regeneration, there is an equilibrium between dividing and maturing cells. In this state, 50% of the cells formed during division are differentiated, which means that they lose the ability to reproduce. In tumors, the pool of maturing cells decreases; less than 50% of cells differentiate, which is a prerequisite for progressive growth. The mechanism of this disruption remains unclear.
The pool of lost cells. The phenomenon of cell loss in tumors has been known for a long time, it is determined by three different processes: cell death, metastasis, maturation and sloughing of cells (more typical for tumors of the gastrointestinal tract and skin). Obviously, for most tumors, the main mechanism of cell loss is cell death. In tumors, it can proceed in two ways: 1) in the presence of a zone of necrosis, cells continuously die at the border of this zone, which leads to an increase in the amount of necrotic material; 2) death of isolated cells away from the necrosis zone. Four main mechanisms can lead to cell death:
1) internal defects of tumor cells, i.e. cell DNA defects;
2) maturation of cells as a result of the preservation in tumors of a process characteristic of normal tissues; 3) insufficiency of blood supply resulting from the lag of vascular growth from tumor growth (the most important mechanism of cell death in tumors); 4) immune destruction of tumor cells.
The state of the above pools of cells that make up the tumor determines the tumor progression. The laws of this tumor progression were formulated in 1949 by L. Foulds as six rules for the development of irreversible qualitative changes in a tumor, leading to the accumulation of malignancy (malignancy).
Rule 1. Tumors arise independently of each other (the processes of malignancy proceed independently of each other in different tumors in the same animal).
Rule 2. Progression in this tumor does not depend on the dynamics of the process in other tumors of the same organism.
Rule 3. The processes of malignancy do not depend on tumor growth.
Notes:
a) during the primary manifestation, the tumor may be at a different stage of malignancy; b) irreversible qualitative changes that occur in
tumors are independent of tumor size.
Rule 4. The progression of the tumor can be carried out either gradually or abruptly, suddenly.
Rule 5. The progression of the tumor (or the change in the properties of the tumor) goes in one (alternative) direction.
Rule 6. Tumor progression does not always reach its end point of development during the life of the host.
From the foregoing, it follows that tumor progression is associated with the continuous division of tumor cells, in the process of
After that, cells appear that differ in their properties from the original tumor cells. First of all, this concerns biochemical shifts in the tumor cell: not so much new biochemical reactions or processes arise in the tumor, but there is a change in the ratio between the processes occurring in the cells of normal, unaltered tissue.
In tumor cells, a decrease in respiration processes is observed (according to Otto Warburg, 1955, respiratory failure is the basis of tumor cell transformation). The lack of energy resulting from a decrease in respiration forces the cell to somehow make up for energy losses. This leads to the activation of aerobic and anaerobic glycolysis. The reasons for the increase in the intensity of glycolysis are an increase in the activity of hexokinase and the absence of cytoplasmic glycerophosphate dehydrogenase. It is believed that about 50% of the energy needs of tumor cells are covered by glycolysis. The formation of glycolysis products (lactic acid) in the tumor tissue causes acidosis. The breakdown of glucose in the cell also proceeds along the pentose phosphate pathway. Of the oxidative reactions in the cell, the breakdown of fatty acids and amino acids is carried out. In the tumor, the activity of anabolic enzymes of nucleic acid metabolism is sharply increased, which indicates an increase in their synthesis.
Most tumor cells proliferate. Due to increased cell proliferation, protein synthesis is enhanced. However, in the tumor cell, in addition to the usual cellular proteins, new proteins begin to be synthesized that are absent in the normal original tissue, this is a consequence of dedifferentiation tumor cells, in their properties they begin to approach embryonic cells and progenitor cells. Tumor-specific proteins are similar to embryonic proteins. Their determination is important for the early diagnosis of malignant neoplasms. As an example, Yu.S. Tatarinov and G.I. Abelev is a fetoprotein that is not detected in the blood serum of healthy adults, but is found with great constancy in some forms of liver cancer, as well as in excessive liver regeneration under conditions of damage. The effectiveness of their proposed reaction was confirmed by the WHO verification. Another protein isolated by Yu.S. Tatarinov, is a trophoblastic 1-glycoprotein, an increase in the synthesis of which is observed in tumors and pregnancy. An important diagnostic value is the determination of carcinoembryonic proteins.
kov with different molecular weight, cancer embryonic antigen, etc.
At the same time, damage to the DNA structure leads to the fact that the cell loses the ability to synthesize some proteins that it synthesized under normal conditions. And since enzymes are proteins, the cell loses a number of specific enzymes and, as a result, a number of specific functions. In turn, this leads to alignment or leveling of the enzymatic spectrum of various cells that make up the tumor. Tumor cells have a relatively uniform enzyme spectrum, which reflects their dedifferentiation.
A number of properties specific to tumors and their constituent cells can be identified.
1. Uncontrolled cell proliferation. This property is an essential feature of any tumor. The tumor develops at the expense of the body's resources and with the direct participation of humoral factors. host organism, but this growth is not caused or conditioned by his needs; on the contrary, the development of a tumor not only does not maintain the body's homeostasis, but also has a constant tendency to disturb it. This means that by uncontrolled growth they mean growth that is not due to the needs of the body. At the same time, local and systemic limiting factors can affect the tumor as a whole, slow down the growth rate, and determine the number of cells proliferating in it. Slowdown of tumor growth can also proceed along the path of increased destruction of tumor cells (as, for example, in mouse and rat hepatomas, which lose up to 90% of divided cells during each mitotic cycle). Today we no longer have the right to speak, as our predecessors did 10–20 years ago, that tumor cells are generally not sensitive to regulatory stimuli and influences. Thus, until recently it was believed that tumor cells completely lose their ability to contact inhibition; are not amenable to the inhibiting division of the influence of neighboring cells (a dividing cell, upon contact with a neighboring cell, under normal conditions, stops dividing). It turned out that the tumor cell still retains the ability to contact inhibition, only the effect occurs at a higher concentration of cells than normal and upon contact of the tumor cell with normal cells.
The tumor cell also obeys the proliferation inhibitory action of proliferation inhibitors formed by mature cells (for example, cytokines and low molecular weight regulators). Affect tumor growth and cAMP, cGMP, prostaglandins: cGMP
stimulates cell proliferation, while cAMP inhibits it. In the tumor, the balance is shifted towards cGMP. Prostaglandins affect the proliferation of tumor cells through a change in the concentration of cyclic nucleotides in the cell. Finally, serum growth factors, which are called poetins, can influence tumor growth. various metabolites delivered to the tumor by blood.
The cells and intercellular substance, which form the basis of the tumor microenvironment, have a great influence on the proliferation of tumor cells. So a tumor that grows slowly in one place of the body, being transplanted to another place, begins to grow rapidly. For example, benign Shoup rabbit papilloma, being transplanted into the same animal, but into other parts of the body (muscles, liver, spleen, stomach, under the skin), turns into a highly malignant tumor, which, infiltrating and destroying adjacent tissues, quickly leads to death of the organism.
In human pathology, there are stages when the cells of the mucous membrane enter the esophagus and take root in it. Such "dystopic" tissue tends to form tumors.
Tumor cells, however, lose the upper "limit" on the number of their divisions (the so-called Hayflick limit). Normal cells divide up to a certain maximum limit (in mammals under cell culture conditions, up to 30–50 divisions), after which they die. Tumor cells acquire the ability to endless division. The result of this phenomenon is the immortalization (“immortality”) of a given cell clone (with a limited life span of each individual cell, its component).
Therefore, unregulated growth should be considered a fundamental feature of any tumor, while all the following features, which will be discussed, are secondary - the result of tumor progression.
2. Anaplasia (from Greek ana - opposite, opposite and plasis - formation), cataplasia. Many authors believe that anaplasia, or a decrease in the level of tissue differentiation (morphological and biochemical characteristics) after its neoplastic transformation, is a characteristic feature of a malignant tumor. Tumor cells lose their ability to form specific tissue structures and produce specific substances, which is characteristic of normal cells. Cataplasia is a complex phenomenon, and it cannot be explained only by the preservation of immaturity traits corresponding to the stage of cell ontogeny at which it was overtaken by nonplastic transformation. This process involves tumor
cells are not to the same extent, which often leads to the formation of cells that have no analogues in normal tissue. In such cells, there is a mosaic of preserved and lost features of cells of a given level of maturity.
3. Atypism. Anaplasia is associated with atypism (from Greek a – negation and typicos – exemplary, typical) of tumor cells. There are several types of atypia.
Atypism of reproduction, due to the unregulated growth of cells mentioned earlier and the loss of the upper limit or "limit" of the number of their divisions.
Atypism of differentiation, manifested in partial or complete inhibition of cell maturation.
Morphological atypism, which is divided into cellular and tissue. In malignant cells, there is a significant variability in the size and shape of cells, the size and number of individual cell organelles, the content of DNA in cells, the shape
and number of chromosomes. In malignant tumors, along with cell atypism, there is tissue atypism, which is expressed in the fact that, compared with normal tissues, malignant tumors have a different shape and size of tissue structures. For example, the size and shape of glandular cells in tumors from glandular tissue adenocarcinomas differ sharply from the original normal tissues. Tissue atypism without cellular atypism is typical only for benign tumors.
Metabolic and energy atypism, which includes: intensive synthesis of oncoproteins (“tumor-like”, or “tumor” proteins); decrease in the synthesis and content of histones (transcription suppressor proteins); education not characteristic of mature
cells of embryonic proteins (including -fetoprotein); change in the method of ATP resynthesis; the appearance of substrate “traps”, which are manifested by increased uptake and consumption of glucose for energy production, amino acids for building the cytoplasm, cholesterol for building cell membranes, as well as β-tocopherol and other antioxidants for protection against free radicals and stabilization of membranes; a decrease in the concentration of the intracellular messenger cAMP in the cell.
Physicochemical atypism, which is reduced to an increase in the content of water and potassium ions in tumor cells against the background of a decrease in the concentration of calcium and magnesium ions. At the same time, an increase in the water content facilitates the diffusion of metabolic substrates
inside the cells and its products out; a decrease in the content of Ca2+ reduces intercellular adhesion, and an increase in the concentration of K+ prevents the development of intracellular acidosis caused by increased glycolysis and accumulation of lactic acid in the growing peripheral zone of the tumor, since there is an intensive exit from the decaying structures of K+ and protein.
Functional atypism, characterized by a complete or partial loss of the ability of tumor cells to produce specific products (hormones, secretions, fibers); or inadequate, inappropriate enhancement of this production (for example, an increase in insulin synthesis by insuloma, a tumor from the cells of the pancreatic islets of Langerhans); or "perversion" of the noted function (synthesis by tumor cells in breast cancer of the hormone thyroid gland- calciotonin or synthesis by tumor cells of lung cancer of the hormones of the anterior pituitary gland - adrenocorticotropic hormone, antidiuretic hormone, etc.). Functional atypism is usually associated with biochemical atypism.
Antigenic atypism, which manifests itself in antigenic simplification or, conversely, in the appearance of new antigens. In the first case, the tumor cells lose the antigens that were present in the original normal cells (for example, the loss of the organ-specific liver h-antigen by tumor hepatocytes), and in
the second is the emergence of new antigens (for example, -fetoprotein).
Atypism of the "interaction" of tumor cells with the body, which consists in the fact that the cells do not participate in the coordinated interconnected activity of the organs and tissues of the body, but, on the contrary, violate this harmony. For example, a combination of immunosuppression, a decrease in antitumor resistance, and potentiation of tumor growth by the immune system leads to the escape of tumor cells from the immune surveillance system. Secretion of hormones and other biologically active substances by tumor cells, deprivation of the body of essential amino acids and antioxidants, tumor stress effect, etc. aggravate the situation.
4. Invasiveness and destructive growth. The ability of tumor cells to grow (invasiveness) into the surrounding healthy tissues (destructive growth) and destroy them are characteristic features of all tumors. The tumor induces the growth of connective tissue, and this leads to the formation of the underlying tumor stroma, as it were, a "matrix", without which tumor development is impossible. Neoplasm cells
The connective tissue bath, in turn, stimulates the reproduction of tumor cells that grow into it, releasing some biologically active substances. The properties of invasiveness are, strictly speaking, nonspecific for malignant tumors. Similar processes can be observed in ordinary inflammatory reactions.
Infiltrating tumor growth leads to destruction of normal tissues adjacent to the tumor. Its mechanism is associated with the release of proteolytic enzymes (collagenase, cathepsin B, etc.), toxic substances, competition with normal cells for energy and plastic material (in particular, for glucose).
5. Chromosomal abnormalities. They are often found in tumor cells and may be one of the mechanisms of tumor progression.
6. Metastasis(from Greek meta - middle, statis - position). The spread of tumor cells by separation from the main focus is the main sign of malignant tumors. Usually, the activity of a tumor cell does not end in the primary tumor, sooner or later the tumor cells migrate from the compact mass of the primary tumor, are carried by the blood or lymph, and settle somewhere in the lymph node or in another tissue. There are a number of reasons for migrating.
An important reason for settling is a simple lack of space (overpopulation leads to migration): the internal pressure in the primary tumor continues to increase until cells start to be pushed out of it.
Cells entering mitosis become rounded and largely lose their connections with surrounding cells, partly due to disruption of the normal expression of cell adhesion molecules. Since a significant number of cells are dividing in the tumor at the same time, their contacts in this small area are weakened, and such cells can more easily fall out of the total mass than normal ones.
In the course of progression, tumor cells increasingly acquire the ability to grow autonomously, as a result of which they break away from the tumor.
There are the following ways of metastasis: lymphogenous, hematogenous, hematolymphogenic, "cavitary" (transfer of tumor cells by fluids in body cavities, for example, cerebrospinal fluid), implantation (direct transition of tumor cells from the tumor surface to the surface of a tissue or organ).
Whether a tumor will metastasize, and if so, when, is determined by the properties of the tumor cells and their immediate environment. However, where the released cell will migrate, where it will settle, and when a mature tumor is formed from it, a significant role belongs to the host organism. Clinicians and experimenters have long noted that metastases in the body spread unevenly, apparently giving preference to certain tissues. Thus, the spleen almost always escapes this fate, while the liver, lungs, and lymph nodes are favorite sites for metastasizing cells to settle. The addiction of some tumor cells to certain organs sometimes reaches extreme expression. For example, mouse melanoma has been described with a particular affinity for lung tissue. During transplantation of such mouse melanoma, in the paw of which the lung tissue was previously implanted, the melanoma grew only in the lung tissue, both in the implanted area and in the normal lung of the animal.
In some cases, tumor metastasis begins so early and with such a primary tumor that it overtakes its growth and all the symptoms of the disease are due to metastases. Even at autopsy, it is sometimes impossible to find the primary source of metastasis among the many tumor foci.
The very fact of the presence of tumor cells in the lymphatic and blood vessels does not predetermine the development of metastases. Numerous cases are known when at a certain stage of the course of the disease, most often under the influence of treatment, they disappear from the blood and metastases do not develop. Most of the tumor cells circulating in the vascular bed die after a certain period of time. Another part of the cells die under the action of antibodies, lymphocytes, and macrophages. And only the most insignificant part of them finds favorable conditions for their existence and reproduction.
Distinguish intraorganic, regional and distant metastases. Intraorganic metastases are detached tumor cells that are fixed in the tissues of the same organ in which the tumor has grown, and have given secondary growth. Most often, such metastasis occurs by the lymphogenous route. Regional metastases are called, which are located in the lymph nodes adjacent to the organ in which the tumor has grown. At the initial stages of tumor growth, the lymph nodes react with increasing hyperplasia of the lymphoid tissue and reticular cellular elements. As the tumor progresses, sensitized lymphoid cells migrate from the regional lymph node to more distant ones.
With the development of metastases in the lymph nodes, the proliferative and hyperplastic processes in them decrease, dystrophy of the cellular elements of the lymph node and the reproduction of tumor cells occur. The lymph nodes are enlarged. Distant metastases mark the dissemination or generalization of the tumor process and are beyond the scope of radical therapeutic action.
7. Recurrence(from lat. recedivas - return; re-development disease). It is based on: a) incomplete removal of tumor cells during treatment, b) implantation of tumor cells into the surrounding normal tissue, c) transfer of oncogenes into normal cells.
The listed properties of tumors determine the features of tumor growth, the features of the course of a tumor disease. In the clinic, it is customary to distinguish two types of tumor growth: benign and malignant, which have the following properties.
For benign growth typical, as a rule, slow tumor growth with tissue expansion, absence of metastases, preservation of the structure of the original tissue, low mitotic activity of cells, and the prevalence of tissue atypism.
For malignant growth usually characterized by rapid growth with destruction of the original tissue and deep penetration into the surrounding tissues, frequent metastasis, significant loss of the structure of the original tissue, high mitotic and amitotic activity of cells, the predominance of cellular atypia.
A simple enumeration of the features of benign and malignant growth indicates the conventionality of such a division of tumors. A tumor that is different benign growth, localized in vital organs, is no less, if not more dangerous for the body than a malignant tumor localized far from vital organs. Moreover, benign tumors, especially those of epithelial origin, can become malignant. It is often possible to trace the malignancy of benign growths in humans.
From the point of view of the mechanisms of tumor progression, benign growth (i.e., a benign tumor) is a stage in this progression. It cannot be argued that a benign tumor in all cases serves as an obligatory stage in the development of a malignant tumor, but the undoubted fact that this is often the case justifies the idea of a benign tumor as one of the initial phases of progression. Tumors are known to
throughout the life of the organism do not become malignant. These are, as a rule, very slowly growing tumors, and it is possible that their malignancy takes time longer than the life span of the organism.
Principles of classification of tumors
According to the clinical course, all tumors are divided into benign and malignant.
According to the histogenetic principle, which is based on determining whether a tumor belongs to a specific tissue source of development, tumors are distinguished:
epithelial tissue;
connective tissue;
muscle tissue;
melanin-forming tissue;
nervous system and membranes of the brain;
blood systems;
teratoma.
According to the histological principle, which is based on the severity of atypia, mature tumors (with a predominance of tissue atypism) and immature ones (with a predominance of cellular atypism) are distinguished.
According to the oncological principle, tumors are characterized according to the International Classification of Diseases.
According to the prevalence of the process, the characteristics of the primary focus, metastases to the lymph nodes and distant metastases are taken into account. The international TNM system is used, where T (tumor)
– characteristics of the tumor, N (nodus) – the presence of metastases in the lymph nodes, M (metastasis) – the presence of distant metastases.
The immune system and tumor growth
Tumor cells change their antigenic composition, which has been repeatedly shown (in particular, in the works of Academician L.A. Zilber, who founded the first scientific laboratory of tumor immunology in our country in the 1950s). Consequently, the process must inevitably include the immune system, one of the most important functions of which is censorship, i.e. detection and destruction of the “foreign” in the body. Tumor cells that have changed their antigenic composition represent this “foreign” subject to destruction.
niyu. Tumor transformation occurs constantly and relatively often during life, but immune mechanisms eliminate or suppress the reproduction of tumor cells.
Immunohistochemical analysis of tissue sections of various human and animal tumors shows that they are often infiltrated with cells of the immune system. It has been established that in the presence of T-lymphocytes, NK-cells or myeloid dendritic cells in the tumor, the prognosis is much better. For example, the frequency of five-year survival in patients with ovarian cancer in the case of detection of T lymphocytes in a tumor removed during surgery is 38%, and in the absence of T-lymphocyte infiltration of the tumor, only 4.5%. In patients with gastric cancer, the same indicator with tumor infiltration by NK cells or dendritic cells is 75% and 78%, respectively, and with low infiltration by these cells, 50% and 43%, respectively.
Conventionally, two groups of mechanisms of antitumor immunity are distinguished: natural resistance and the development of an immune response.
The leading role in the mechanisms of natural resistance belongs to NK cells, as well as activated macrophages and granulocytes. These cells have natural and antibody dependent cellular cytotoxicity towards tumor cells. Due to the fact that the manifestation of this action does not require long-term differentiation and antigen-dependent proliferation of the corresponding cells, the mechanisms of natural resistance form the first echelon of the antitumor defense of the body, since they are always included in it immediately.
The main role in the elimination of tumor cells during the development of the immune response is played by effector T-lymphocytes, which form the second defense echelon. It should be emphasized that the development of an immune response ending in an increase in the number of cytotoxic T-lymphocytes (synonym: T-killers) and T-effectors of delayed-type hypersensitivity (synonym: activated pro-inflammatory Th1-lymphocytes) requires from 4 to 12 days. This is due to the processes of activation, proliferation and differentiation of cells of the corresponding clones of T-lymphocytes. Despite the duration of the development of the immune response, it is he who provides the second echelon of the body's defense. The latter, due to the high specificity of antigen-recognizing receptors of T-lymphocytes, a significant increase (by thousands or hundreds of thousands of times) in the number of cells of the corresponding clones as a result of proliferation and differentiation
predecessors, is much more selective and effective. By analogy with the current weapons systems of the armies of various countries, the mechanisms of natural resistance can be compared with tank armies, and effector T-lymphocytes with high-precision space-based weapons.
Along with an increase in the number of effector T lymphocytes and their activation, the development of an immune response to tumor antigens as a result of the interaction of T and B lymphocytes leads to clonal activation, proliferation, and differentiation of B lymphocytes into plasma cells producing antibodies. The latter, in most cases, do not inhibit the growth of tumors; on the contrary, they can enhance their growth (the phenomenon of immunological enhancement associated with the “shielding” of tumor antigens). At the same time, antibodies can participate in antibody dependent cellular cytotoxicity. Tumor cells with fixed IgG antibodies are recognized by NK cells through the receptor for the IgG Fc fragment (Fc RIII, CD16). In the absence of a signal from the killer inhibitory receptor (in the case of a simultaneous decrease in the expression of class I histocompatibility molecules by tumor cells as a result of their transformation), NK cells lyse the target cell coated with antibodies. Antibody dependent cellular cytotoxicity can also involve natural antibodies that are present in the body in low titer before contact with the corresponding antigen, i.e. before the development of an immune response. The formation of natural antibodies is a consequence of the spontaneous differentiation of the corresponding clones of B-lymphocytes.
The development of a cell-mediated immune response requires a complete presentation of antigenic peptides in combination with molecules of the major histocompatibility complex I (for cytotoxic T-lymphocytes) and class II (for Th1 lymphocytes) and additional costimulatory signals (in particular, signals involving CD80/CD86). T-lymphocytes receive this set of signals when interacting with professional antigen-presenting cells (dendritic cells and macrophages). Therefore, the development of an immune response requires infiltration of the tumor not only by T lymphocytes, but also by dendritic and NK cells. Activated NK cells lyse tumor cells that express ligands for killer-activating receptors and have reduced expression of class I major histocompatibility complex molecules (the latter act as a ligand for killer-inhibitory receptors). Activation of NK cells also leads to the secretion of IFN-, TNF-,
granulocyte-monocyte colony stimulating factor (GM-CSF), chemokines. In turn, these cytokines activate dendritic cells, which migrate to regional lymph nodes and trigger the development of an immune response.
At normal functioning immune system, the probability of survival of single transformed cells in the body is very low. It increases in some congenital immunodeficiency diseases associated with impaired function of natural resistance effectors, exposure to immunosuppressive agents, and aging. Influences that suppress the immune system contribute to the occurrence of tumors, and vice versa. The tumor itself has a pronounced immunosuppressive effect, sharply inhibits immunogenesis. This action is realized through the synthesis of cytokines (IL-10, transforming growth factor-), low molecular weight mediators (prostaglandins), activation of CD4+ CD25+ FOXP3+ regulatory T-lymphocytes. The possibility of a direct cytotoxic effect of tumor cells on cells of the immune system has been experimentally proven. In view of the foregoing, the normalization of the functions of the immune system in tumors is a necessary component in the complex pathogenetic treatment.
Treatment, depending on the type of tumor, its size, spread, presence or absence of metastases, includes surgery, chemotherapy and radiation therapy, which themselves can have an immunosuppressive effect. Correction of the functions of the immune system with immunomodulators should be carried out only after the end of radiation therapy and / or chemotherapy (the risk of developing drug-induced immunological tolerance to tumor antigens as a result of the destruction of antitumor clones of T-lymphocytes when their proliferation is activated before the appointment of cytostatics). In the absence of subsequent chemotherapy or radiation therapy, the use of immunomodulators in the early postoperative period (for example, myelopid lymphotropic, imunofan, polyoxidonium) can significantly reduce the number of postoperative complications.
Currently, approaches to immunotherapy of neoplasms are being intensively developed. Methods of active specific immunotherapy are being tested (introduction of vaccines from tumor cells, their extracts, purified or recombinant tumor antigens); active non-specific immunotherapy (administration of BCG vaccine, vaccines based on Corynebacterium parvum and other microorganisms to obtain an adjuvant effect and switch
Determination and assessment of the severity of the treatment of this disease are available to any medical institution. The concept of "systemic inflammatory response syndrome" as a term is accepted by the international community of doctors of various specialties in most countries of the world.
Symptoms of the development of systemic inflammatory response syndrome
The frequency of the disease in patients reaches 50% according to statistics. However, in patients with high temperature body (this is one of the symptoms of the syndrome) located in the intensive care unit, systemic inflammatory response syndrome is observed in 95% of patients.
The syndrome may last only a few days, but it can also exist for a longer time, until the level of cytokines and nitric monoxide (NO) in the blood decreases, until the balance between pro-inflammatory and anti-inflammatory cytokines is restored, and the immune system functions to control the production of cytokines.
With a decrease in hypercytokinemia, the symptoms of a systemic inflammatory response may gradually subside, in these cases the risk of developing complications decreases sharply, and recovery can be expected in the coming days.
Symptoms of severe systemic inflammatory response syndrome
In a severe form of the disease, there is a direct correlation between the content of cytokines in the blood and the severity of the patient's condition. Pro- and anti-inflammatory mediators may eventually mutually reinforce their pathophysiological effects, creating a growing immunological dissonance. It is under these conditions that inflammatory mediators begin to have a damaging effect on the cells and tissues of the body.
The complex complex interaction of cytokines and cytokine-neutralizing molecules in the systemic inflammatory response syndrome probably determines the clinical manifestations and course of sepsis. Even a severe systemic response syndrome to inflammation cannot be considered as sepsis if the patient does not have a primary focus of infection (gate of entry), bacteremia, confirmed by the isolation of bacteria from the blood during multiple cultures.
Sepsis as a sign of systemic response syndrome to inflammation
Sepsis as a clinical symptom of the syndrome is difficult to define. The Conciliation Commission of American Physicians defines sepsis as a very severe form of a systemic response to inflammation syndrome in patients with a primary focus of infection confirmed by blood cultures, with signs of CNS depression and multiple organ failure.
We should not forget about the possibility of developing sepsis even in the absence of a primary focus of infection. In such cases, microorganisms and endotoxins may appear in the blood due to translocation intestinal bacteria and endotoxins in the blood.
Then the intestine becomes a source of infection, which was not taken into account when searching for the causes of bacteremia. Translocation of bacteria and endotoxins from the intestine into the bloodstream becomes possible when the barrier function of the intestinal mucosa is impaired due to ischemia of the walls during
- peritonitis,
- acute intestinal obstruction,
- and other factors.
Under these conditions, the intestine in the systemic inflammatory response syndrome becomes similar to an "undrained purulent cavity".
Complications of systemic inflammatory response syndrome
A collaborative study covering several medical centers in the United States showed that of the total number of patients with systemic inflammatory response syndrome, only 26% developed sepsis and 4% - septic shock. Mortality increased depending on the severity of the syndrome. It was 7% in severe systemic inflammatory response syndrome, 16% in sepsis, and 46% in septic shock.
Features of the treatment of systemic response syndrome to inflammation
Knowledge of the pathogenesis of the syndrome allows the development of anticytokine therapy, prevention and treatment of complications. For these purposes, in the treatment of the disease, they use:
monoclonal antibodies against cytokines,
antibodies against the most active pro-inflammatory cytokines (IL-1, IL-6, tumor necrosis factor).
There are reports on the good efficiency of plasma filtration through special columns that allow the removal of excess cytokines from the blood. To inhibit the cytokine-producing function of leukocytes and reduce the concentration of cytokines in the blood in the treatment of systemic inflammatory response syndrome, they are used (though not always successfully) large doses steroid hormones. The most important role in the treatment of patients with symptoms of the syndrome belongs to the timely and adequate treatment of the underlying disease, comprehensive prevention and treatment of dysfunction of vital organs.
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abstract
FROMsystemic inflammatory response.Sepsis
Introduction
The term "sepsis" in a meaning close to the current understanding was first used by Hippoktas more than two thousand years ago. This term originally meant the process of tissue breakdown, inevitably accompanied by decay, disease and death.
The discoveries of Louis Pasteur, one of the founders of microbiology and immunology, played a decisive role in the transition from empirical experience to a scientific approach in the study of surgical infections. Since that time, the problem of the etiology and pathogenesis of surgical infections and sepsis has been considered from the point of view of the relationship between macro- and microorganisms.
In the works of the outstanding Russian pathologist I.V. Davydovsky, the idea of the leading role of macroorganism reactivity in the pathogenesis of sepsis was clearly formulated. It was certainly a progressive step, orienting clinicians to rational therapy, aimed, on the one hand, at the eradication of the pathogen, and on the other hand, at correcting the dysfunction of organs and systems of the macroorganism.
1. ModernThese ideas about inflammation
Inflammation should be understood as a universal, phylogenetically determined reaction of the body to damage.
Inflammation has an adaptive nature, due to the reaction of the body's defense mechanisms to local damage. The classic signs of local inflammation - hyperemia, local fever, swelling, pain - are associated with:
morphological and functional rearrangement of endotheliocytes of postcapillary venules,
coagulation of blood in postcapillary venules,
adhesion and transendothelial migration of leukocytes,
complement activation,
kininogenesis,
expansion of arterioles
Degranulation of mast cells.
The cytokine network occupies a special place among inflammatory mediators.
Controlling the processes of implementation of immune and inflammatory reactivity
The main producers of cytokines are T-cells and activated macrophages, as well as, to varying degrees, other types of leukocytes, endotheliocytes of postcapillary venules, platelets and various types of stromal cells. Cytokines act primarily in the focus of inflammation and in the reacting lymphoid organs, ultimately performing a number of protective functions.
Mediators in small amounts are able to activate macrophages and platelets, stimulate the release of adhesion molecules from the endothelium and the production of growth hormone.
The developing acute phase reaction is controlled by pro-inflammatory mediators interleukins IL-1, IL-6, IL-8, TNF, as well as their endogenous antagonists, such as IL-4, IL-10, IL-13, soluble TNF receptors, called anti-inflammatory mediators. . Under normal conditions, by maintaining a balance of relationships between pro- and anti-inflammatory mediators, prerequisites are created for wound healing, the destruction of pathogenic microorganisms, and the maintenance of homeostasis. Systemic adaptive changes in acute inflammation include:
stress reactivity of the neuroendocrine system,
a fever
The release of neutrophils into the circulatory bed from the vascular and bone marrow
increased leukocytopoiesis in the bone marrow,
hyperproduction of acute phase proteins in the liver,
development of generalized forms of the immune response.
When the regulatory systems are unable to maintain homeostasis, the destructive effects of cytokines and other mediators begin to dominate, which leads to impaired capillary permeability and endothelial function, the triggering of DIC, the formation of distant foci of systemic inflammation, and the development of organ dysfunction. The cumulative effects of mediators form the systemic inflammatory response syndrome (SIR).
As criteria for a systemic inflammatory reaction that characterizes the body's response to local tissue destruction, the following are used: ESR, C-reactive protein, systemic temperature, leukocyte index of intoxication, and other indicators that have different sensitivity and specificity.
At the Consensus Conference of the American College of Pulmonologists and the Society for Critical Care Medicine, held in 1991 in Chicago, under the leadership of Roger Bone, it was proposed to consider at least three of the four unified signs as criteria for a systemic inflammatory response of the body:
* heart rate over 90 per minute;
* the frequency of respiratory movements is more than 20 in 1 minute;
* body temperature more than 38°C or less than 36°C;
* the number of leukocytes in peripheral blood more than 12x106 or less
4x106 or the number of immature forms is more than 10%.
The approach proposed by R. Bon to determine the systemic inflammatory response caused ambiguous responses among clinicians - from complete approval to categorical denial. The years that have passed since the publication of the decisions of the Conciliation Conference have shown that, despite numerous criticisms of this approach to the concept of systemic inflammation, it remains today the only one generally recognized and commonly used.
2. Furanism and structure of inflammation
sepsis pasteur inflammatory surgical
Inflammation can be imagined by taking a basic model in which five main links involved in the development of the inflammatory response can be distinguished:
· Clotting system activation- according to some opinions, the leading link in inflammation. With it, local hemostasis is achieved, and the Hegeman factor activated in its process (factor 12) becomes the central link in the subsequent development of the inflammatory response.
· Platelet link of hemostasis- performs the same biological function as clotting factors - stops bleeding. However, products released during platelet activation, such as thromboxane A2, prostaglandins, due to their vasoactive properties, play a crucial role in the subsequent development of inflammation.
· mast cells activated by factor XII and platelet activation products stimulate the release of histamine and other vasoactive elements. Histamine, acting directly on smooth muscles, relaxes the latter and provides vasodilation of the microvascular bed, which leads to an increase in the permeability of the vascular wall, an increase in total blood flow through this zone, while reducing blood flow velocity.
· Activation of kallikrein-kinin The system also becomes possible due to factor XII, which ensures the conversion of prekallikrein to kallikrenin, a catalyst for the synthesis of bradykinin, the action of which is also accompanied by vasodilation and an increase in the permeability of the vascular wall.
· Activation of the complement system proceeds both along the classical and alternative paths. This leads to the creation of conditions for the lysis of the cellular structures of microorganisms, in addition, activated complement elements have important vasoactive and chemoattractant properties.
The most important common property of these five different inducers of the inflammatory response - their interactivity and mutual reinforcement of the effect. This means that when any of them appear in the damage zone, all the others are activated.
Phases of inflammation.
The first phase of inflammation is the induction phase. The biological meaning of the action of inflammation activators at this stage is to prepare the transition to the second phase of inflammation - the phase of active phagocytosis. For this purpose, leukocytes, monocytes, and macrophages accumulate in the intercellular space of the lesion. The most important role in this process is played by endothelial cells.
When the endothelium is damaged, the activation of endothelial cells and the maximum synthesis of NO-synthetase occur, which as a result leads to the production of nitric oxide and the maximum dilatation of intact vessels, and the rapid movement of leukocytes and platelets to the damaged area.
The second phase of inflammation (the phase of phagocytosis) begins from the moment when the concentration of chemokines reaches a critical level necessary to create an appropriate concentration of leukocytes. when the concentration of chemokines (a protein that promotes the selective accumulation of leukocytes in the focus) reaches a critical level necessary to create an appropriate concentration of leukocytes.
The essence of this phase is the migration of leukocytes to the site of injury, as well as monocytes. monocytes reach the site of injury, where they differentiate into two distinct subpopulations, one dedicated to killing microorganisms and the other to phagocytosis of necrotic tissue. Tissue macrophages process antigens and deliver them to T and B cells, which are involved in the destruction of microorganisms.
Along with this, anti-inflammatory mechanisms are launched simultaneously with the onset of the act of inflammation. They include cytokines with a direct anti-inflammatory effect: IL-4, IL-10 and IL-13. There is also expression of receptor antagonists, such as the IL-1 receptor antagonist. However, the mechanisms of termination of the inflammatory response are still not fully understood. There is an opinion that it is most likely that a decrease in the activity of the processes that caused it plays a key role in stopping the inflammatory reaction.
3. Systemic inflammatory response syndrome (SIRS)
After the introduction into clinical practice of the terms and concepts proposed at the Conciliation Conference by R. Bonom and co-authors in 1991, a new stage began in the study of sepsis, its pathogenesis, principles of diagnosis and treatment. A single set of terms and concepts focused on Clinical signs. Based on them, at present, there are quite definite ideas about the pathogenesis of generalized inflammatory reactions. The leading concepts were "inflammation", "infection", "sepsis".
The development of the systemic inflammatory response syndrome is associated with a violation (breakthrough) of the restrictive function of local inflammation and the ingress of pro-inflammatory cytokines and inflammatory mediators into the systemic circulation.
To date, quite numerous groups of mediators are known that act as stimulators of the inflammatory process and anti-inflammatory protection. The table shows some of them.
The hypothesis of R. Bon et al. (1997) on the patterns of development of the septic process, which is currently accepted as the leading one, is based on the results of studies confirming that the activation of chemoattractants and pro-inflammatory cytokines as inducers of inflammation stimulates the release of contractors - anti-inflammatory cytokines, the main function of which is to reduce the severity of the inflammatory response.
This process, which immediately follows the activation of inflammatory inducers, is called the "anti-inflammatory compensatory response", in the original transcription - "compensatory anti-inflammatory response syndrome (CARS)". In terms of severity, the anti-inflammatory compensatory reaction can not only reach the degree of the pro-inflammatory reaction, but also exceed it.
It is known that when determining freely circulating cytokines, the probability of error is so significant (without taking into account cytokines on the cell surface-2) that this criterion cannot be used as a diagnostic criterion.
°~ for the syndrome of anti-inflammatory compensatory reaction.
Assessing the options for the clinical course of the septic process, four groups of patients can be distinguished:
1. Patients with severe injuries, burns, purulent diseases, who do not have clinical signs of systemic inflammatory response syndrome and the severity of the underlying pathology determines the course of the disease and prognosis.
2. Patients with sepsis or severe illness (trauma) who develop a moderate systemic inflammatory response syndrome, dysfunction of one or two organs occurs, which recovers quickly enough with adequate therapy.
3. Patients who rapidly develop a severe form of systemic inflammatory response syndrome, which is severe sepsis or septic shock. Mortality in this group of patients is maximum.
4. Patients in whom the inflammatory response to the primary injury is not so pronounced, but already a few days after the onset of signs of the infectious process, organ failure progresses (such dynamics of the inflammatory process, which has the form of two peaks, is called the "double-humped curve"). Mortality in this group of patients is also quite high.
However, can such significant differences in the variants of the clinical course of sepsis be explained by the activity of pro-inflammatory mediators? The answer to this question is given by the hypothesis of the pathogenesis of the septic process, proposed by R. Bon et al. In accordance with it, five phases of sepsis are distinguished:
1. Local reaction to injury or infection. Primary mechanical damage leads to the activation of pro-inflammatory mediators, which are characterized by multiple overlapping effects of interaction with each other. The main biological meaning of such a response is to objectively determine the volume of the lesion, its local limitation, and create conditions for a subsequent favorable outcome. The composition of anti-inflammatory mediators includes: IL-4,10,11,13, IL-1 receptor antagonist.
They reduce the expression of the monocytic histocompatibility complex and reduce the ability of cells to produce anti-inflammatory cytokines.
2. Primary systemic reaction. With a severe degree of primary damage, pro-inflammatory, and later anti-inflammatory mediators enter the systemic circulation. The organ disorders that occurred during this period due to the entry of pro-inflammatory mediators into the systemic circulation, as a rule, are transient and are quickly leveled.
3. Massive systemic inflammation. A decrease in the effectiveness of the regulation of the pro-inflammatory response leads to a pronounced systemic reaction, clinically manifested by signs of a systemic inflammatory response syndrome. The basis of these manifestations may be the following pathophysiological changes:
* progressive dysfunction of the endothelium, leading to an increase in microvascular permeability;
* stasis and platelet aggregation, leading to blockage of the microvasculature, redistribution of blood flow and, following ischemia, postperfusion disorders;
* activation of the coagulation system;
* deep vasodilation, extravasation of fluid into the intercellular space, accompanied by a redistribution of blood flow and the development of shock. The initial consequence of this is organ dysfunction, which develops into organ failure.
4. Excessive immunosuppression. Overactivation of the anti-inflammatory system is not uncommon. In domestic publications, it is known as hypoergy or anergy. In foreign literature, this condition is called immunoparalysis or “window to immunodeficiency”. R. Bon with co-authors proposed to call this condition the syndrome of anti-inflammatory compensatory reaction, investing in its meaning a broader meaning than immunoparalysis. The predominance of anti-inflammatory cytokines does not allow the development of excessive, pathological inflammation, as well as the normal inflammatory process that is necessary to complete the wound process. It is this reaction of the body that is the cause of long-term non-healing wounds with a large number of pathological granulations. In this case, it seems that the process of reparative regeneration has stopped.
5. Immunological dissonance. The final stage of multiple organ failure is called the “phase of immunological dissonance”. During this period, both progressive inflammation and its opposite state, a deep syndrome of anti-inflammatory compensatory reaction, can occur. The lack of a stable balance is the most feature this phase.
According to acad. RAS and RAMS V.S. Saveliev and Corresponding Member. RAMS A.I. Kiriyenko's hypothesis above, the balance between pro-inflammatory and anti-inflammatory systems can be disturbed in one of three cases:
*when infection, severe injury, bleeding, etc. so strong that this is quite enough for a massive generalization of the process, systemic inflammatory response syndrome, multiple organ failure;
* when, due to a previous serious illness or injury, patients are already “prepared” for the development of a systemic inflammatory response syndrome and multiple organ failure;
* when the pre-existing (background) state of the patient is closely related precisely to the pathological level of cytokines.
According to the concept of acad. RAS and RAMS V.S. Saveliev and Corresponding Member. RAMS A.I. Kirienko, the pathogenesis of clinical manifestations depends on the ratio of the cascade of pro-inflammatory (for a systemic inflammatory response) and anti-inflammatory mediators (for an anti-inflammatory compensatory response). The form of clinical manifestation of this multifactorial interaction is the severity of multiple organ failure, determined on the basis of one of the international agreed scales (APACHE, SOFA, etc.). In accordance with this, three gradations of severity of sepsis are distinguished: sepsis, severe sepsis, septic shock.
Diagnostics
According to the decisions of the Conciliation Conference, the severity of systemic violations is determined based on the following settings.
The diagnosis of "sepsis" is proposed to be established in the presence of two or more symptoms of a systemic inflammatory reaction with a proven infectious process (this includes verified bacteremia).
The diagnosis of "severe sepsis" is proposed to be established in the presence of organ failure in a patient with sepsis.
The diagnosis of organ failure is made on the basis of agreed criteria that formed the basis of the SOFA scale (Sepsis oriented failure assessment)
Treatment
A decisive shift in treatment methodology occurred after the agreed definitions of sepsis, severe sepsis, and septic shock were adopted.
This allowed different researchers to speak the same language using the same concepts and terms. The second most important factor was the introduction of the principles of evidence-based medicine into clinical practice. These two circumstances led to the development of evidence-based recommendations for the treatment of sepsis, published in 2003 and called the "Barcelona Declaration". It announced the creation of an international program known as the "Movement for effective treatment of sepsis" (Surviving sepsis campaign).
Primary intensive care measures. Aimed at achieving in the first 6 hours of intensive care (activities begin immediately after diagnosis) the following parameter values:
* CVP 8-12 mm Hg. Art.;
* Mean BP >65 mmHg Art.;
* the amount of urine excreted> 0.5 mlDkghh);
* saturation of mixed venous blood >70%.
If the transfusion of various infusion media fails to achieve an increase in CVP and the level of saturation of mixed venous blood to the indicated figures, then it is recommended:
* transfusion of erythromass to achieve a hematocrit level of 30%;
* infusion of dobutamine at a dose of 20 mcg/kg per minute.
Carrying out the specified complex of measures allows to reduce mortality from 49.2 to 33.3%.
Antibiotic therapy
* All samples for microbiological studies are taken immediately upon admission of the patient, before the start of antibiotic therapy.
*Treatment with broad-spectrum antibiotics begins within the first hour of diagnosis.
* Depending on the results of microbiological studies, after 48-72 hours, the scheme of antibacterial drugs used is reviewed to select a narrower and targeted therapy.
Control of the source of the infectious process. Each patient with signs of severe sepsis should be carefully examined to identify the source of the infectious process and carry out appropriate source control measures, which include three groups of surgical interventions:
1. Drainage of the abscess cavity. An abscess is formed as a result of triggering an inflammatory cascade and the formation of a fibrin capsule surrounding a fluid substrate consisting of necrotic tissue, polymorphonuclear leukocytes and microorganisms and well known to clinicians as pus.
Drainage of an abscess is a mandatory procedure.
2. Secondary surgical treatment (necrectomy). Removal of necrotic tissues involved in the infectious process is one of the main tasks in achieving source control.
3. Removal of foreign bodies that support (initiate) the infectious process.
The main areas of therapy for severe sepsis and septic shock, which have received an evidence base and are reflected in the documents of the "Movement for the effective treatment of sepsis", include:
Infusion therapy algorithm;
The use of vasopressors;
Inotropic therapy algorithm;
Use of low doses of steroids;
Use of recombinant activated protein C;
Transfusion therapy algorithm;
ALV algorithm for acute lung injury syndrome / respiratory - adult distress syndrome (ADS / ARDS);
Protocol for sedation and analgesia in patients with severe sepsis;
Glycemic control protocol;
Protocol for the treatment of acute renal failure;
Bicarbonate protocol;
Prevention of deep vein thrombosis;
Prevention of stress ulcers.
Conclusion
Inflammation is a necessary component of reparative regeneration, without which the healing process is impossible. However, according to all the canons of the modern interpretation of sepsis, it must be considered as a pathological process that must be fought. This conflict is well understood by all leading experts in sepsis, so in 2001 an attempt was made to develop a new approach to sepsis, essentially continuing and developing the theory of R. Bohn. This approach is called the PIRO concept (PIRO - predisposition infection response outcome). The letter P stands for predisposition ( genetic factors, previous chronic diseases, etc.), I - infection (type of microorganisms, localization of the process, etc.), P - result (outcome of the process) and O - response (the nature of the response of various body systems to infection). Such an interpretation seems to be very promising, however, the complexity, heterogeneity of the process and the extreme breadth of clinical manifestations have not made it possible to unify and formalize these signs so far. Understanding the limitations of the interpretation proposed by R. Bon, it is widely used on the basis of two ideas.
First, there is no doubt that severe sepsis is the result of the interaction of microorganisms and a macroorganism, which entailed a violation of the functions of one or several leading life support systems, which is recognized by all scientists involved in this problem.
Secondly, the simplicity and convenience of the approach used in the diagnosis of severe sepsis (criteria for a systemic inflammatory response, infectious process, criteria for diagnosing organ disorders) make it possible to single out more or less homogeneous groups of patients. The use of this approach has made it possible today to get rid of such ambiguously defined concepts as "septicemia", "septicopyemia", "chroniosepsis", "refractory septic shock".
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