The concept of systemic inflammatory response syndrome. View of modern medicine
GBOU VPO Krasnoyarsk State Medical University named after. prof. V.F. Voino-Yasenetsky Ministry of Health of Russia
Department of Pathophysiology with a 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”
Topic index: O.O.00.
Head of the Department________________ Doctor of Medical Sciences Ruksha T.G.
Compiled by:
Doctor of Medical Sciences, Associate Professor Artemyev S.A.
Krasnoyarsk
Purpose of the lecture:
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 site 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 sequential stages:
alteration
microcirculation disorders
exudation
emigration
phagocytosis
proliferation
Systemic manifestations of inflammation include fever, reactions of hematopoietic tissue 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 the Latin phlogosis - inflammation, synonymous with 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)
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 and are characterized by metabolic disturbances in the tissue, changes in its structure and function. There are primary and secondary alterations.
Primary alteration is the result of the damaging effects of the inflammatory agent itself, therefore its severity, other things being equal (body reactivity, localization) depends on the properties of the phlogogen.
Secondary alteration is a consequence of the effect on connective tissue, microvessels and blood of lysosomal enzymes and active oxygen metabolites released into the extracellular space. 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 anabolic reactions. On the carbohydrate metabolism side, there is an increase in glycolysis and glycogenolysis, which ensures increased 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 an intensification of lipid peroxidation. 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-mentioned features of the course of metabolic reactions at 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 acidic products of catabolism: lactic, pyruvic acids, amino acids, IVF 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, and hydrolysis of salts. Hyperosmia leads to overhydration of the inflammation site, stimulation of leukocyte emigration, changes in the tone of the vascular walls, as well as the formation of a feeling of pain.
Hyperonkia – increased oncotic pressure in tissue
Caused by an increase in protein concentration in the site of inflammation due to increased enzymatic and non-enzymatic hydrolysis of proteins and the release of proteins from the blood into the site of inflammation due to increased permeability of the vascular wall. The consequence of hyperonkia is the development of edema at the site of inflammation.
Change in cell surface charge
Caused by a violation of the water-electrolyte balance in the inflamed tissue due to disturbances in transmembrane ion transport and the development of electrolyte imbalance. A change in the surface charge of cells causes a change in the threshold of excitability, induces the migration of phagocytes and cellular cooperation due to a change in the value of their surface charge.
Changes in the colloidal state of the intercellular substance and hyaloplasm of cells at the site of inflammation.
It is caused by enzymatic and non-enzymatic hydrolysis of macromolecules and phase changes in microfilaments, leading to an increase in phase permeability.
Reducing the surface tension of cell membranes
Caused by the effect of surfactants on cell membranes (phospholipids, IVFA, K +, Ca ++). Leads to facilitation of cell motility and potentiation of 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 implemented 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 biological effects, H 3 - for inhibitory effects. During inflammation, the predominant effects are those exerted through the H1 receptors of endothelial cells. The effect of histamine is manifested in dilating blood vessels and increasing their permeability. By acting on nerve endings, histamine causes pain. Histamine also promotes the emigration of leukocytes by increasing the adhesiveness of endothelial cells and stimulates phagocytosis.
Serotonin in moderate concentrations causes dilation of arterioles, narrowing of venules and promotes the development of venous stagnation. In high concentrations it promotes spasm of arterioles.
Towards education kinins leads to activation of serum and tissue factors, carried out through a cascade mechanism. Kinins dilate arterioles and venules at the site 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 break down the fibrin clot and promote the formation of vasoactive peptides.
Complement system. Complement system includes a group of serum proteins that sequentially activate each other according to a 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 manifests itself at several stages of its development: during the formation of the vascular reaction, the implementation of phagocytosis and the lysis of pathogenic microorganisms. The result of activation of the complement system is the formation of a lytic complex that disrupts the integrity of the membrane of cells, primarily bacterial ones.
Eicosanoids belong to inflammatory mediators that play an important role in the development of the 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 enzyme phospholipase A2.
Leukotrienes appear at the site of inflammation after 5-10 minutes. Mainly released by mast cells and basophils, constrict small vessels, increase their permeability, enhance the adhesion of leukocytes to the endothelium, and 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 blood vessels, causes pain, and regulates the production of other mediators.
Thromboxane TXA2 causes narrowing of venules, platelet aggregation, secretion of active products by platelets, and is a source of pain.
Acute phase proteins are about 30 plasma proteins involved in the body's inflammatory response to various damages. Acute phase proteins are synthesized in the liver, their concentrations depend I t on the stage of the disease and/or the extent of the damage (hence the value of tests for OF 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 connection between changes in the level of CRP and the severity and dynamics clinical manifestations inflammation. A higher concentration of CRP means a higher 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 measurement of CRP concentration is widely used to monitor and control the effectiveness of therapy for bacterial and viral infections, chronic inflammatory diseases, cancer, complications in surgery and gynecology, etc. However, different causes of inflammatory processes increase CRP levels in different ways.
For bacterial infections, during exacerbation of certain chronic inflammatory diseases (for example, rheumatoid arthritis) and with tissue damage (surgery, 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 the serum, platelet aggregation is inhibited.
Fibrinogen not only the most important of the blood clotting proteins, but also the source of the formation of fibrinopeptides, which have anti-inflammatory activity.
Ceruloplasmin- a polyvalent oxidizer (oxidase), it inactivates superoxide anion radicals formed during inflammation, and thereby protects biological membranes.
Haptoglobin not only is it capable of binding hemoglobin to form a complex with peroxidase activity, but it also quite 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. This proteinase inhibitor (α -antitrypsin), antichymotrypsin, α-macroglobulin. Their role is to inhibit the activity of elastase-like and chymotrypsin-like proteinases coming from granulocytes into inflammatory exudates and causing 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 during septic shock or acute pancreatitis, this is a very poor prognostic sign.
Bacterial infection . This is where the highest levels are observed. SRB (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 issue of choosing another antibacterial treatment is decided.
Sepsis in newborns . If sepsis is suspected in newborns, the CRP concentration is more than 12 mg/l is an indication for immediate initiation of antimicrobial therapy. But it should be taken into account 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 may increase only slightly ( less than 20 mg/l), which is used to differentiate a viral infection from a bacterial one. In children with meningitis SRP concentration above 20 mg/l- this is an absolute basis for starting antibiotic therapy.
Neutropenia . In case of neutropenia in an adult patient, the level of CRP more than 10 mg/l may be the only objective indication of the presence of a bacterial infection and the need for antibiotics.
Postoperative complications . If CRP continues to remain high (or increases) within 4-5 days after surgery, this indicates the development of complications (pneumonia, thrombophlebitis, wound abscess).
I– infection - infection
R– response – the patient’s response
O– organ dysfunction – dysfunction of organs
Some authors believe that in polytrauma SIRS and MODS are phenomena of the same order - SIRS represents 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 Small vessel thrombosis Increased fibrinogen levels Impaired tissue perfusion Thrombin Prothrombin Factor VIIa Factor X Factor X Factor Va |
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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 breathing movements more than 20 per minute or arterial hypocapnia less than 32 mm Hg. st;
- leukocytosis more than 12,000 mm3 or leukopenia less than 4,000 mm3, 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 occurs.
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 proinflammatory mediators and their endogenous antagonists, such as interleukin-1 antagonists, 10, 13; tumor necrosis factor. Due to the balance between cytokines, neurotransmitter receptor antagonists and antibodies in normal conditions prerequisites are created for wound healing, destruction of pathogenic microorganisms, and maintenance of homeostasis.
Third stage characterized by generalization of the inflammatory reaction. In the event that regulatory systems are unable to maintain homeostasis, the destructive effects of cytokines and other mediators begin to dominate, which leads to:
disruption of the permeability and function of the capillary endothelium,
increased 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 disturbances of blood flow.
In Western literature, the term SIRS is used to define a clinical syndrome that was previously referred to as “sepsis,” and the diagnosis of “sepsis” is used only for 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 severe wounds suddenly died within 24-48 hours from acute respiratory failure.
Causes development ARDS:
Lung infections
Aspiration of fluid
Conditions after heart and lung transplantation
Inhalation of toxic gases
Pulmonary edema
Shock conditions
Autoimmune diseases
Pathogenesis of acute respiratory distress syndrome (ARDS)
Starting torque ARDS most often is embolization of the microvessels of the lungs with aggregates of blood cells, drops of neutral fat, particles of damaged tissue, microclots of donor blood against the background of the toxic effects of biologically active substances formed in the tissues (including lung tissue) - prostaglandins, kinins, etc. The key cytokine in development of ARDS is IL-1β, which even in small doses can cause inflammation in the lungs. Locally produced under the influence of IL-1β and tumor necrosis factor-α, the chemokine CXCL8 causes migration of neutrophils into the lungs, which produce cytotoxic substances that cause damage to the alveolar epithelium, alveolar-capillary membranes and increased permeability of the walls of the capillaries of the lungs, which ultimately leads to the development of hypoxemia .
Manifestations of ARDS:
Shortness of breath: distress syndrome is characterized by tachypnea
Increase MOD
Decrease in lung volumes (total lung capacity, residual volume lungs, vital capacity, functional residual capacity of the lungs)
Hypoxemia, acute respiratory alkalosis
Increased cardiac output (in the terminal stage of the syndrome - decrease)
Multiple organ dysfunction/multiple organ dysfunction syndrome (MODS, MOF)
Term MODS(multiple organ dysfunction syndrome) replaced MOF(multiple organ failure), since it focuses attention on the course of the dysfunction process, and not on its outcome.
In development MODS There are 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 of the type of compensatory anti-inflammatory response syndrome
5. immunological disorders.
Pathogenesis of multiple organ dysfunction syndrome (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, adhesion molecules - selectins, ICAM-1, VCAM-1), which leads to activation and migration of leukocytes, which produce cytotoxic enzymes, reactive metabolites of oxygen and nitrogen, causing damage to organs and tissues.
Conclusions:
IN inflammation is characterized by the following sequential 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
Voinov V.A. Atlas of pathophysiology: Textbook. – M.: Medical Information Agency, 2004. – 218 p.
3. Dolgikh V.T. General pathophysiology: a 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: Electronic course on pathophysiology: textbook. - M.: MIA, 2006.
2.Electronic catalog of KrasSMU
Also known as SIRS, systemic inflammatory response syndrome is a pathological condition associated with increased dangers severe consequences for the patient's body. SIRS is possible due to surgical interventions, which are currently extremely widespread, in particular if we're talking about about malignant pathologies. There is no other way to cure the patient except surgery, but the intervention can provoke SIRS.
Features of the question
Since systemic inflammatory response syndrome in surgery more often occurs in patients who were prescribed treatment against a background of general weakness, illness, the likelihood severe course is caused by side effects of other therapeutic methods used in a particular case. Regardless of where exactly the injury caused by surgery is located, an early rehabilitation period is associated with an increased risk of secondary injury.
As is known from pathological anatomy, 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 and a number of auxiliary phenomena. The more unfavorable the background of the operation, the more severe the course of VSSO will be.
What and how?
Systemic inflammatory response syndrome is a pathological condition indicated by tachypnea, fever, and heart rhythm disturbances. Tests show leukocytosis. In many ways, this response of the body is due to the peculiarity of the activity of cytokines. Pro-inflammatory cellular structures, which 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 harm is caused to the tissues and organs of one’s own body.
The problem of determining and predicting the likelihood of the occurrence of systemic inflammatory response syndrome, encrypted in ICD-10 with code R65, in the absence suitable method assessment of the patient's initial condition. There are several options and gradations to determine how bad the patient’s health is, but none of them are 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 and prolonged, the likelihood of complications, pneumonia, increases.
About terms and theory
Systemic inflammatory response syndrome, coded as R65 in ICD-10, was discussed in 1991 at a conference that brought together leading experts in the field of 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 proliferation of cytokines, and it is not possible to bring this process under control by the body. Inflammatory mediators are generated at the primary site infectious infection, from where they move into the tissue around, thus ending up in circulatory system. The processes occur with the involvement of macrophages and activators. Other tissues of the body, distant from the primary focus, become areas of generation of similar substances.
According to the pathophysiology of the systemic inflammatory response syndrome, histamine is most often used. Factors that activate platelets and those associated with necrotic tumor processes have similar effects. The participation of adhesive molecular structures of the cell, parts of complement, and nitrogen oxides is possible. SIRS may be explained by the activity of toxic products of oxygen transformation and fat peroxidation.
Pathogenesis
Systemic inflammatory response syndrome, recorded by code R65 in ICD-10, is observed when a person’s immune system 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 the capillaries becomes more permeable; toxic components from the bed penetrate through the cracks of this tissue into the surrounding vessels of the cell. Over time, inflamed foci appear remote from the primary area, and gradually progressive failure of various internal structures is observed. The result of this process is DIC syndrome, paralysis of the immune system, and failure to function in multiple organ forms.
As numerous studies have shown on the occurrence of systemic inflammatory response syndrome in obstetrics, surgery, and 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 by a person's injury. In some cases, the root cause is an allergic reaction to the medication, ischemia of certain areas 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
While studying systemic inflammatory response syndrome in obstetrics, surgery, and other branches of medicine, scientists paid special attention to the rules for defining such a condition, as well as the intricacies of using various terminology. In particular, it makes sense to talk about sepsis if the cause of inflammation in a systemic form is an infectious focus. In addition, sepsis occurs if the functioning of certain parts of the body is impaired. Sepsis can be diagnosed only with the mandatory identification of both signs: SIRS, 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 version of sepsis is identified. When choosing treatment, it is important to remember the possibility of transistor bacteremia, which does not lead to generalization of the infectious process. If this has become the cause of SIRS or organ dysfunction, it is necessary to choose a therapeutic course indicated for sepsis.
Categories and severity
Based on the diagnostic criteria for systemic inflammatory response syndrome, it is customary to distinguish four forms of the condition. Key signs that allow us to talk about SIRS:
- fever above 38 degrees or temperature below 36 degrees;
- the heart contracts at a rate of more than 90 beats per minute;
- breathing frequency exceeds 20 acts per minute;
- with mechanical ventilation, PCO2 is less than 32 units;
- leukocytes during analysis are defined as 12*10^9 units;
- leukopenia 4*10^9 units;
- new leukocyte forms more than 10% of the total.
To diagnose SIRS, the patient must have two or more of these symptoms.
About the options
If a patient has two or more signs of the above-mentioned manifestations of 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 failure developing according to a multi-organ scenario, with acute disruptions in the patient’s mental status, lactic acidosis, oliguria, or 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 severe form, low blood pressure is persistent, perfusion failures are stable and cannot be controlled by classical methods. In SIRS, hypotension is considered a condition in which the pressure is less than 90 units or less than 40 units relative to the patient’s initial condition, when there are no other factors that can provoke a decrease in the parameter. It is taken into account that taking certain medications may be accompanied by manifestations indicating organ dysfunction, a perfusion problem, while the pressure is maintained adequate.
Could it get any worse?
The most severe version 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 severe, while medication and instrumental methods do not allow to control and stabilize homeostasis, with the exception of methods and techniques of intensive treatment.
Development concept
Currently, a two-phase concept is known in medicine that describes the development of SIRS. The basis of the pathological process is a cascade of cytokines. At the same time, cytokines that initiate inflammatory processes are activated, and along 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 a period during which the focus of inflammation is local, due to a normal organic reaction to the influence of some aggressive factor. The second stage is a cascade, during which too many inflammatory mediators are generated in the body and can penetrate the circulatory system. At the third stage, secondary aggression takes place, directed at one’s own cells. This explains the typical course of 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, and the functioning of organs is greatly impaired. The fifth and final stage is terminal.
Can anything help?
If it is necessary to alleviate the course of systemic inflammatory response syndrome, the clinical recommendation is to monitor the patient’s condition by regularly taking vital signs important organs and also use medications. If necessary, the patient is connected to special equipment. Recently, medications created specifically for the relief of SIRS in its various manifestations look particularly promising.
Drugs effective for SIRS are based on diphosphopyridine nucleotide and also include inosine. Some versions contain digoxin and lisinopril. Combined medications, chosen at the discretion of the treating doctor, suppress SIRS, regardless of what caused the pathological process. Manufacturers assure that a pronounced effect can be achieved in the shortest possible time.
Is surgery necessary?
For SIRS, additional surgical intervention 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 details about medications
Revealing medicinal features diphosphopyridine nucleotide combined with inosine gave doctors new options. Such a drug, as practice has shown, is applicable in the work of cardiologists and nephrologists, surgeons and pulmonologists. Drugs with this composition are used by anesthesiologists, gynecologists, and endocrinologists. Currently, drugs are used for surgical operations on the heart and blood vessels, if necessary, provide assistance to the patient in the intensive care unit.
Such a wide area of use is associated with the general symptoms of sepsis, consequences of burns, manifestations of diabetes occurring in a decompensated head start, shock due to trauma, DFS, necrotic processes in the pancreas and many other severe pathological uprisings. The symptom complex characteristic of SIRS, and effectively relieved by diphosphopyridine nucleotide in combination with inosine, includes weakness, pain, and sleep disturbances. The drug alleviates the condition of the patient who has pain and dizziness, symptoms of encephalopathy appear, the skin turns pale or yellow, the rhythm and frequency of heart contractions are disturbed, and blood flow interruptions occur.
Relevance of the issue
As shown statistical research, SIRS is currently one of the most common variants of the development of severe hypoxia, strong destructive activity of cells of individual tissues. In addition, such a syndrome is highly likely to develop against the background of chronic intoxication. The pathogenesis and etiology of the conditions leading to SIRS are very different.
With any shock, SIRS is always observed. The reaction becomes one aspect of sepsis, a pathological condition caused by injury or burn. It cannot be avoided if a person has suffered 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 or 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 reduces its quality. We are talking about heart attack, ischemia, hypertension, gestosis, burns, osteoarthritis.
- generalized involvement of basic mechanisms, which in classical inflammation are localized at the site of inflammation;
- the leading role of the microvascular reaction in all vital organs and tissues;
- lack of biological feasibility 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 multiple organ failure syndrome are the main causes of death.
XVIII. PATHOPHYSIOLOGY OF TUMOR GROWTH
In every science, there are a small number of such tasks and problems that could potentially be solved, but this solution is either not found or, due to a fatal combination of circumstances, is 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 include: in mathematics – the famous Fermat’s theorem, in physics – the problem of searching for the elementary structure of matter, in medicine – the problem of tumor growth. This section is dedicated to this problem.
It is more correct to talk not about the problem of tumor growth, but about the problems of tumor growth, since here we are faced with several problems.
Firstly, a 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 discovered 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: a tumor consists of cells of the body itself, therefore, by understanding the laws of the occurrence and development of a tumor, we can understand many biological laws growth, division, reproduction and differentiation of cells. Finally, there is a third side: tumor
represents the autonomous proliferation of cells; therefore, when studying the occurrence of tumors, it is impossible to ignore the laws of biological integration of cells.
Secondly, a 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 from malignant neoplasms.
Thirdly, a tumor is an economic problem, since the death of cancer 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 institutes, maintenance of intractable patients.
Fourthly, a tumor represents a psychological problem: the appearance of a cancer patient significantly changes the psychological climate in the family and in the team where he works.
A tumor, finally, is also a political problem, since in the victory over oncological diseases, as well as in preserving peace, space exploration, solving the problem of environmental protection and the problem of raw materials, all people on earth are interested, regardless of their race, skin color, social and political system in their countries. It is not surprising that almost all countries, establishing political and scientific contacts with each other, always create bilateral and multilateral programs to combat cancer.
To designate any tumor, one of the following Greek or Latin terms is used: tumor, blastoma, neo plasma, oncos. When it is necessary to emphasize that we are talking about malignant tumor growth, then the word malignus is added to one of the listed terms; for benign growth, the word benignus is added.
In 1853, Virchow's first work (R. Vir chow) was published, outlining his views on the etiology and pathogenesis of tumors. From that moment on, the cellular direction in oncology took 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, blastomas, all varieties
ties of humoral theories. Now the focus is on the tumor cell, and the main task is to study the reasons that cause the transformation of a normal cell into a tumor cell and the pathways along which this transformation occurs.
The second major event in oncology was the publication of M.A.’s dissertation in 1877. Novinsky for a master's degree in veterinary sciences with a description of his experiences in grafting three microsarcomas from dogs onto other dogs. The author used young animals for these experiments and inoculated them with small pieces not from decaying ones (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, the emergence of a method of tumor transplantation, i.e. grafting of spontaneously occurring and induced tumors. Improvement of this method made it possible to determine the main conditions for successful grafting.
1. For vaccination, you need to take living cells.
2. The number of cells may vary. There are reports of successful grafting of even one cell, but still, the more cells we introduce, the more likely successful tumor grafting.
3. Repeated vaccinations are successful more quickly, and tumors reach larger sizes, i.e. If you grow a tumor on an animal, take cells from it and inoculate them into another animal of the same species, then they survive better than in the first animal (first owner).
4. Autologous transplantation is best performed, i.e. transplantation of a tumor to the same host, but to a new location. Syngeneic transplantation is also effective, i.e. grafting of a tumor onto animals of the same inbred line to which the original animal belongs. Tumors are less likely to engraft into animals of the same species, but of a different strain (allogeneic transplantation), and tumor cells engraft very poorly when transplanted into an animal of a different species (xenogeneic transplantation).
Along with tumor transplantation, the explantation method is also of great importance for understanding the characteristics of malignant growth, i.e. culturing tumor cells outside the body. Back in 1907, R. G. Harrison demonstrated the possibility of growing cells on artificial nutrient media, and soon, in 1910, A. Carrel and M. Burrows published data on the possibility of culturing malignant tissues in vitro. This method made it possible to study tumor cells of various animals
And even a person. The latter include the Hela strain (from epi
dermoid cancer of the cervix), Hep-1 (also obtained from the cervix), Hep-2 (larynx cancer), etc.
Both methods are not without drawbacks, among which the most significant are the following:
with repeated vaccinations and seeding in culture, the properties of the cells change;
the relationship and interaction of tumor cells with stromal and vascular elements, which are also part of the tumor growing in the body, is disrupted;
the body's regulatory influence on the tumor is removed (when culturing tumor tissue in vitro).
Using the methods described, we can still study the properties of tumor cells, the characteristics of metabolism in them, and the influence of various chemicals and drugs on them.
The occurrence of tumors is associated with the effect of various factors on the body.
1. Ionizing radiation. In 1902, A. Frieben in Hamburg described skin cancer on the back of the hand in an employee at a factory producing X-ray tubes. This worker spent four years checking the quality of the pipes by X-raying his own hand.
2. Viruses. In the experiments of Ellerman and Bang (C. Ellerman, O. Bang)
V 1908 and P. Rous in 1911, the viral etiology of leukemia and sarcoma was established. However, at that time, leukemia was not classified as a neoplastic disease. And although these scientists created a new, very promising direction in the study of cancer, their work for a long time were ignored and not highly appreciated. Only in 1966, 50 years after the discovery, P. Rous was awarded the Nobel Prize.
Along with numerous viruses that cause tumors in animals, viruses have been isolated that act as an etiological factor for the induction of tumors in humans. Among the RNA containing retroviruses, these include the HTLV-I virus (English: hu man T-cell lymphotropic virus type I), developmental one of the types 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 the human papilloma virus (cervical cancer), hepatitis B and C viruses (liver cancer), Epstein-Barr virus (in addition to infectious mononucleosis, it 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 “ Experimental study atypical epithelial proliferation,” which described the development of a malignant tumor in rabbits under the influence of long-term smearing 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. Of course, 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 is 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. XX 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 a final solution to oncological problems. But what do we know today?
Tumor, neoplasm– pathological proliferation of cells uncontrolled by the body with relative autonomy of metabolism and significant differences in structure and properties.
A tumor is a clone of cells that were formed from one mother 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 the 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 that lead to the development of a tumor can be caused by various physical factors - and ionizing radiation should be put in 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), then
they stimulate (or activate) the growth of an already induced one, i.e. already existing tumor.
Chemical carcinogenesis. Changes in DNA structure can also be caused by various chemicals, which served as the basis for the creation of theories of chemical carcinogenesis. The possible role of chemicals in tumor induction was first pointed out in 1775. English doctor Percival Pott, who described scrotal cancer in chimney sweeps and associated the occurrence of this tumor with exposure to soot from the chimneys of English houses. But only in 1915 did this assumption receive experimental confirmation 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, it was possible to isolate 50 g of some unknown compound. It was 3,4-benzpyrene, which, as was established by biological tests, turned out to be a carcinogen quite suitable for research. But 3,4-benzpyrene is not one of the earliest pure carcinogens. Even earlier (1929), Cook 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 dibenzathracene—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 carcinogenic substances 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 the life activity of plants and fungi (cycasin, safrole, ragwort alkaloids, etc.); heterocyclic aromatic hydrocarbons (1,2,5,6-dibenzacridine, 1,2,5,6 and 3,4,5,6-dibenzcarbazole, etc.). Consequently, carcinogenic substances 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 carcinogenic substance 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 effect of carcinogens on the cell is irreversible.
4. There are no subthreshold doses for carcinogenic substances, i.e. any, even a very small dose of a carcinogen causes a tumor. However, with very small doses of a carcinogen, the latent period can exceed the life expectancy of a person or animal and the organism dies from a cause other than the tumor. This can also explain the high frequency of tumor diseases in older people (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., once it begins under the influence of a carcinogen, it will not stop and the cessation of the effect of the carcinogen on the body does not stop the development of the tumor.
6. Essentially, all carcinogens are toxic, i.e. capable of killing a 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 receive selection advantages when exposed to a carcinogen.
8. Carcinogenic substances can replace each other (the phenomenon of syncarcinogenesis).
There are two possible options for the appearance of carcinogenic substances in the body: entry from the 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 tumor formation, i.e. are initially carcinogenic. Among 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 combustion residues, exhaust gases, dust on the streets, fresh soil in the field, cigarette smoke and even smoked products in some cases contain significant amounts 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 must be formed in the body of animals and humans from substances coming from outside. There are several mechanisms for the formation of carcinogenic substances in the body.
Firstly, substances that are inactive in carcinogenic terms 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 bypass activation and which do not have to pass through metabolic processes in the cell to manifest their destructive properties, should be considered as an exception. Sometimes activating reactions are spoken of as a toxication process, since the formation of genuine toxins occurs in the body.
Secondly, disruption of detoxification reactions, during which toxins are neutralized, including carcinogenic substances, will also contribute to carcinogenesis. But even if not impaired, these reactions can contribute to carcinogenesis. For example, carcinogens (in particular, aromatic amines) are converted into glucuronic acid esters (glycosides) and then excreted by the kidneys through the ureter into the bladder. And urine contains glucuronidase, which, by destroying glucuronic acid, helps release 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 the urine of humans and dogs, but it is not found in mice and rats, and as a consequence, humans and dogs are susceptible to bladder cancer, and mice and rats
Endogenous carcinogens. In the human and animal body there are many different “raw materials” for the formation of substances that may have carcinogenic activity - these are bile acids, vitamin D, 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 removal of the remnants of their metabolism from the body. At the same time, as a result of one or another metabolic disorder, instead of a normal, physiological product, say, a steroid structure, some very similar, but still different product appears, with a different effect on tissues - this is how endogenous carcinogenic substances arise. As you know, people most often get cancer at the age of 40–60 years. This age has
biological features are the age of menopause in the broad sense of this concept. During this period, it is not so much the cessation of the function of the gonads that occurs, but rather their dysfunction, leading to the development of hormone-dependent tumors. Special attention deserve therapeutic measures using hormones. Cases of development have been described malignant tumors mammary gland with excessive administration of natural and synthetic estrogens, not only in women (with infantilism), but also in men. This does not mean that estrogens should not be prescribed at all, but indications for their use in necessary cases and especially the doses of drugs administered must be well thought out.
Mechanism of action of carcinogenic substances . It has now been established that at temperatures around 37° C (i.e. body temperature), DNA breaks constantly occur. These processes occur at a fairly high speed. Consequently, the existence of a cell, even under favorable conditions, is possible only because the DNA repair system usually “manages” 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 incidence of tumor diseases with age. Chemical carcinogens can accelerate the development of the process of spontaneous DNA damage due to an increase in the rate of formation of DNA breaks, 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 a 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 does not enter the cell 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 options for 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. times the virus multiplies in a cell. This phenomenon is called productive infection and is what infectious disease specialists most often encounter. The animal species in which the virus circulates under normal conditions, transmitted from one animal to another, is called the natural host. Cells of a natural host that are infected with a virus and productively synthesize viruses are called permissive cells.
3. As a result of the action of protective cellular mechanisms on the virus, it does not reproduce completely, i.e. the cell is not able to completely destroy the virus, and the virus cannot completely ensure the reproduction of viral particles and destroy the cell. This often occurs when the virus enters the cells of an animal of another species rather than its natural host. 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 influence of DNA-containing oncoviruses are usually mutually exclusive: cells of the natural host are mainly productively infected (permissive cells), while cells of another species are more often transformed (non-permissive cells).
IN It is now generally accepted that abortive infection, i.e. interruption of the full cycle of oncovirus reproduction at any stage is a mandatory factor causing tumor
y transformation of the cell. Such interruption of the cycle can occur during infection of genetically resistant cells with a complete infectious virus, during infection of permissive cells with a defective virus, and, finally, during infection of susceptible cells with a complete virus under unusual (nonpermissive) conditions, for example, at high temperature (42° C).
Cells transformed with DNA containing oncoviruses themselves, 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 the integration and inclusion of the viral genome into the cellular one. To solve the question about the nature of the inclusion of the virus genome in the DNA of the cell, it is necessary to answer the questions: when, where and how does this integration occur?
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 joined into a single strand using the enzyme DNA ligase. 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 oncovirus DNA, having penetrated into a normal cell not in the S-phase, is first in a state of “rest”, waiting for the S-phase, when it mixes with fragments of synthesized cellular DNA, in order to then be incorporated into cellular DNA with the help of DNA- ligases
The second question is where? – concerns the place where the DNA of an oncogenic virus is inserted into the cell genome. As experiments have shown, it occurs in regulatory genes. The inclusion of the oncovirus genome in structural genes is unlikely.
The third question is how does integration occur?
logically follows from the previous one. The minimal structural unit of DNA from which information is read—transcripton—is represented by regulatory and structural zones. Reading of information by DNA-dependent RNA polymerase begins from the regulatory zone and proceeds towards the structural one. The point at which the process begins is called a promoter. If a DNA virus is included in the transcripton, it contains two pro
the motor is cellular and viral, and the reading of information begins from the viral promoter.
IN case of integration of oncoviral DNA between regulatory
And structural zones RNA polymerase begins 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 genes of the virus (starting from the viral promoter), and the other to the structural gene of the cell. Consequently, the structural gene of the cell completely escapes the 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 the properties of cells. According to available data, up to 6–7 viral genomes can be integrated with cellular DNA. All of the above applied 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 itself cannot be incorporated into DNA; therefore, carcinogenesis caused by RNA-containing viruses must have a number of features. Based on the impossibility from a chemical point of view of the inclusion of viral RNA of oncornaviruses into cellular DNA, the American researcher Temin (Nobel Prize 1975), based on his experimental data, suggested that oncornaviruses synthesize their own viral DNA, which is incorporated into cellular DNA in the same way as in the case of DNA-containing viruses. Temin called this form of DNA, synthesized on 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 transmission of genetic
information goes according to the DNA RNA protein scheme. Temin's hypothesis introduced a fundamentally new stage into this scheme - RNA DNA. This theory, greeted by most researchers with obvious distrust and irony, nevertheless agreed well with the main position of the virogenetic theory about the integration of 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 that synthesizes DNA into RNA - reverse transcriptase. This enzyme has been found in many cells, and it has also been found in RNA viruses. It was found that the reverse transcriptase of RNA-containing tumor viruses is different from conventional DNA polymerases; information about its synthesis is encoded in the viral genome; it is present only in virus-infected cells; reverse transcriptase is found in human tumor cells; it is necessary only for tumor transformation of the cell and is not required to maintain tumor growth. When a virus enters a cell, its reverse transcriptase begins to work and a complete copy of the viral genome is synthesized - 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 it can, having broken up into several fragments, be included in various areas cellular DNA. Now, when the synthesis of cellular DNA is activated, the synthesis of viruses will always be activated.
In the body of a natural host, a complete copying of the viral genome and synthesis of the complete virus occurs from the provirus. In an unnatural organism, a partial loss of the provirus occurs and only 30–50% of the complete viral genome is transcribed, which contributes to the tumor transformation of cells. 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. We 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, so this carcinogenesis is called induced viral carcinogenesis.
products of normal cells (or, as they are called, endogenous viruses). These viral particles have all the features characteristic of oncornaviruses. At the same time, these endogenous viruses, as a rule, are apathogenic for the body, and often even non-infectious (i.e., 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 species of birds and all strains of mice, as well as rats, hamsters, guinea pigs, cats, pigs and monkeys. It has been established that any cell can practically be a producer of a virus, i.e. such a cell contains the necessary information for the synthesis of the endogenous virus. The part of the normal cellular genome that encodes the structural components of the virus is called the virogen(s).
Two main properties of virogens are inherent in all endogenous viruses: 1) widespread 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 in the form of a single block, but also individual genes or their groups, which as a whole make up the virogen, 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 do not form a complete endogenous virus, although they can synthesize its individual components in varying quantities. All functions of endogenous viruses under physiological conditions have not yet been fully elucidated, but it is known that they help transmit information from cell to 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 (Hübner - Todaro) virogen contains a gene (or genes) responsible for 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 that can cause the transformation of a normal cell into a tumor cell. H.M. Temin based on detailed tumor studies
how cells are transformed by the Rous sarcoma virus postulated that the virogen does not contain oncogenes, i.e. genes that determine the transformation of a normal cell into a tumor cell. These genes arise as a result of mutations of certain sections of cellular DNA (protoviruses) and the subsequent transfer of genetic information along a path that includes reverse transcription (DNA RNA DNA). Coming from modern ideas about the molecular mechanisms of carcinogenesis, it can be argued that mutation of a prooncogene is not the only way of its transformation into an oncogene. The same effect can be caused by the inclusion (insertion) of a promoter (a region of DNA to which RNA polymerase binds, initiating gene transcription) near the proto-oncogene. In this case, the role of a promoter is performed 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 can also be caused by amplification (Latin amplification - distribution, increase
– this is an increase in the number of proto-oncogenes, which normally have little trace activity, as a result of which the total activity of proto-oncogenes increases significantly) or by translocation (movement) of a proto-oncogene to a locus with a functioning promoter. For the study of these mechanisms he received 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, C.D. Darlington’s catchy aphorism “A virus is a gene gone wild” most accurately reflects the essence of natural oncogenesis.
It turned out that viral oncogenes, the existence of which was pointed out by L.A. Zilber, encode proteins that regulate 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 proteins-transcription regulators, as well as growth factors and their receptors.
The protein product of the v-src gene of the Rous sarcoma virus works 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 protein kinases. Tyrosine protein kinases are enzymes that phosphorylate various proteins (enzymes, regulatory
chromosome proteins, membrane proteins, etc.) based on tyrosine residues. Tyrosine protein kinases are currently considered as the most important molecules that provide 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 proliferation and differentiation of T and B lymphocytes through their antigen recognition receptors has been proven. It seems 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 cells not infected with retroviruses contain normal cell genes related to viral oncogenes. This relationship was initially established as a result of the discovery of homology in the nucleotide sequences of the transforming oncogene of the Rous sarcoma virus v-src (viral src) and the normal chicken gene c-src (cellular src). Apparently, 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—provides 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 increased interest to researchers. In nature normal forms oncogenes are very conserved. For each of them there are human homologs, some of them are present in all eukaryotic organisms, including invertebrates and yeast. This conservatism indicates that these genes perform vital functions in normal cells, and the oncogenic potential of the genes is acquired only after functionally significant changes (such as, for example, those that occur during recombination with a retrovirus). Such genes are referred to as proto-oncogenes.
Some of these genes, grouped into the ras family of cellular oncogenes, were discovered by transfecting cells with DNA taken from human tumor cells. Activation of ras genes is common in some chemically induced epithelial carcinomas in rodents, 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 proto-oncogenes have also been identified that perform essential functions in normal non-tumor cells. Study of proteins encoded by the virus
oncogenes and their normal cellular homologues, clarifies the mechanisms of functioning of these genes. Proteins encoded by the ras proto-oncogene are associated with the inner surface of the cell membrane. Their functional activity, consisting of GTP binding, is a manifestation 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 the mitogen-activated signaling pathway, which is directly involved in the regulation of cell proliferation and includes the sequential cascade activation of MAPKKK (MAPKK phosphorylating kinase; in vertebrates, serine-threonine protein kinase Raf), MAPKK (MAPK phosphorylating kinase; in vertebrates, in vertebrates - protein kinase MEK; from the English mitogen-activated and extracellularly activated kinase) and MAPK (from the English mitogen-activated protein kinase; in vertebrates - protein kinase ERK; from the English extracellular signal-regulated kinase) protein kinases. Therefore, it may turn out that Ras transforming 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 in the Gl phase of the cell cycle. The functioning of the other two genes seems to be closely related to the mechanisms of growth factor action. When growth-arrested fibroblasts are exposed to platelet-derived growth factor, a specific set of genes (estimated at 10 to 30), including the proto-oncogenes c-fos and c-myc, begin 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 appropriate mitogens. After the cell enters the growth cycle, c-myc expression remains almost constant. Once a cell loses its ability to divide (for example, in the case of postmitotic differentiated cells), c-myc expression ceases.
An example of proto-oncogenes that function as growth factor receptors is the genes encoding epidermal growth factor receptors. In humans, these receptors are represented by 4 proteins, designated 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
It has tyrosine protein kinase activity and is involved in signal transmission into the cell. A sharply increased expression of HER2 was detected in breast cancer. Epidermal growth factors stimulate proliferation, prevent the development of apoptosis, stimulate angiogenesis and tumor metastasis. Monoclonal antibodies against the extracellular domain of HER2 (the drug trastuzumab, which has undergone clinical trials in the USA) have been proven to be highly therapeutic in the treatment of breast cancer.
Consequently, proto-oncogenes can function normally 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 the defining stimulus for unregulated cell growth and abnormal differentiation that characterizes neoplastic conditions. The data discussed above indicate the most important role of proto-on cogenes in the functioning of normal cells, regulation of their proliferation and differentiation. “Breakage” of these mechanisms within cellular 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.
(English: growth-inhibiting cancer-suppressor genes), performing the function of antioncogenes. In particular, in many tumors mutations are found in the gene encoding the synthesis of the protein p53 (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, osteosarcoma, and small cell lung cancer, there is no synthesis of the retinoblastoma protein (pRB protein) due to a mutation in the RB gene encoding this protein. This protein is involved in the regulation of the G1 phase of the cell cycle. Mutation of the bcl-2 (anti-apoptotic protein B-cell lymphoma 2) genes also plays an important role in the development of tumors.
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 of a dividing population in the original tissue
moving cells. This is probably why mature neurons of the adult brain, which have completely lost the ability to divide, never form a tumor, unlike the glial elements of the brain. Therefore, it is clear that all factors that promote tissue proliferation also contribute to the formation of neoplasm. The first generation of dividing cells of highly differentiated tissues is not an exact copy of the parental, highly specialized cells, but turns out to be a “step back” in the sense that it is characterized by a lower level of differentiation and some embryonic features. Subsequently, during the process of division, they differentiate in a strictly determined direction, “ripening” to the phenotype inherent in a given tissue. These cells have a less rigid behavioral program than cells with a complete phenotype; in addition, they may be incompetent to certain 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 transformed into elements of neoplasm, they retain some features that characterize the stage of ontogenetic development at which they were caught in the transition to a new state. From these positions it becomes clear increased sensitivity to oncogenic factors of embryonic tissue, entirely consisting of immature, dividing
And differentiating elements. This also largely determines the phenomenontransplacental blastomogenesis: doses of blastomogenic chemical compounds, harmless to a pregnant female, act on the embryo, which leads to the appearance of tumors in the baby after birth.
Tumor growth stimulation stage
After the initiation stage comes the stage of tumor growth stimulation. At the initiation stage, one cell degenerates into a tumor cell, but a whole series of cell divisions is required to continue tumor growth. During these repeated divisions, cells with different abilities for autonomous growth are formed. Cells that obey the body's regulatory influences are destroyed, and cells that are most prone to autonomous growth gain growth advantages. Selection occurs, or selection of the most autonomous cells, and therefore 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 the tumor. Factors that themselves
are not capable of initiating a tumor, are not capable of causing tumor transformation, but stimulate the growth of already existing tumor cells; they 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, cellular 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 that act as cocarcinogens). Concept co carcinogenesis should not be confused with the concept syncarcinogenesis, which we talked about earlier. Syncarcinogenesis is understood as the synergistic effect of carcinogens, i.e. substances capable of causing or inducing tumors. These substances can replace each other in tumor induction. Cocarcinogenesis refers to factors that contribute to carcinogenesis, but are not carcinogenic in themselves.
Stage of tumor progression
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 body. Since a tumor is a clone of cells originating from one mother 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 losing cells.
Stem cell pool. This population of tumor cells has three properties: 1) the ability to self-maintain, 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 unlimited proliferative potential, while non-stem proliferating cells inevitably die after a series of divisions. Next
Consequently, stem cells in tumors can be defined as cells capable of unlimited proliferation and resumption of tumor growth after damage, metastasis and inoculation into other animals.
Pool of proliferating cells. The proliferative pool (or growth fraction) is the proportion of cells currently involved 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 cycle duration of 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 talk about a sharp increase in the proliferative activity of tumor cells, since normal tissue can and does proliferate during regeneration more intensively than the tumor grows.
Pool of non-proliferating cells . Presented by two types of cells. On the one hand, these are cells capable of dividing, but have left the cell cycle and entered the G stage 0 , or the post-natal phase. The main factor determining the appearance of these cells in tumors is insufficient blood supply, leading to hypoxia. The tumor stroma 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, i.e. Some 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 become differentiated, which means they lose the ability to reproduce. In tumors, the pool of maturing cells decreases, i.e. Less than 50% of cells differentiate, which is a prerequisite for progressive growth. The mechanism of this disorder remains unclear.
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 desquamation of cells (more typical for tumors of the gastrointestinal tract and skin). It is clear that for most tumors the main mechanism of cell loss is cell death. In tumors it can go 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 far 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, which occurs as a result of vascular growth lagging behind 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 tumor progression. The laws of this tumor progression were formulated in 1949 by L. Foulds in the form of six rules for the development of irreversible qualitative changes in the tumor, leading to the accumulation of malignancy (malignancy).
Rule 1. Tumors arise independently of each other (malignancy processes occur independently of each other in different tumors in the same animal).
Rule 2. Progression in a given 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 the growth of tumors
Notes:
a) during the initial manifestation, the tumor may be at various stages of malignancy; b) irreversible qualitative changes that occur in
tumors, do not depend on the size of the tumor.
Rule 4. Tumor progression can occur either gradually or intermittently, suddenly.
Rule 5. Tumor progression (or changes in tumor properties) occurs in one (alternative) direction.
Rule 6. Tumor progression does not always reach its end point during the life of the host.
From all of the above, it follows that tumor progression is associated with the continuous division of tumor cells, in the process of
This results in the appearance of cells that differ in their properties from the original tumor cells. First of all, this concerns biochemical changes in the tumor cell: not so much new biochemical reactions or processes arise in the tumor, but rather a change in the ratio between the processes occurring in the cells of normal, unchanged tissue.
In tumor cells, a decrease in respiration processes is observed (according to Otto Warburg, 1955, impaired respiration is the basis for tumor transformation of the cell). The energy deficit resulting from decreased respiration forces the cell to somehow replenish energy losses. This leads to activation of aerobic and anaerobic glycolysis. The reasons for the increase in the intensity of glycolysis are an increase in hexokinase activity and the absence of cytoplasmic glycerophosphate dehydrogenase. It is believed that about 50% of the energy needs of tumor cells are met by glycolysis. The formation of glycolysis products (lactic acid) in tumor tissue causes acidosis. The breakdown of glucose in the cell also occurs along the pentose phosphate pathway. Oxidative reactions in the cell result in the breakdown of fatty acids and amino acids. 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 increases. However, in the tumor cell, in addition to the usual cellular proteins, new proteins that are absent in the normal original tissue begin to be synthesized; this is a consequence dedifferentiation tumor left cells, in their properties they begin to approach embryonic cells and precursor cells. Tumor-specific proteins are similar to embryonic proteins. Their determination is important for the early diagnosis of malignant neoplasms. As an example, we can cite the highlighted 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 consistency in some forms of liver cancer, as well as in excessive liver regeneration in conditions of damage. The effectiveness of their proposed reaction was confirmed by testing by WHO. Another protein isolated by Yu.S. Tatarin, is a trophoblastic 1-glycoprotein, an increase in the synthesis of which is observed in tumors and pregnancy. The determination of carcinoembryonic whites is of great diagnostic importance.
kovs with different molecular weights, carcinoembryonic antigen, etc.
At the same time, a violation of 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 consequence, 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 is a reflection of their dedifferentiation.
It is possible to identify a number of properties specific to tumors and their constituent cells.
1. Uncontrolled cell proliferation. This property is an integral 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 homeostasis of the body, but also has a constant tendency to disrupt it. This means that by uncontrolled growth they mean growth that is not determined by 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. Slowing tumor growth can also occur along the path of increasing 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 not at all sensitive to regulatory stimuli and influences. Thus, until recently it was believed that tumor cells completely lose the ability to undergo contact inhibition, i.e. do not respond to the division-restraining 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 undergo contact inhibition, only the effect occurs when the concentration of cells is higher than normal and when the tumor cell comes into contact with normal cells.
The tumor cell also obeys the proliferation-inhibiting 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, and cAMP inhibits it. In the tumor, the balance is shifted towards cGMP. Prostaglandins influence the proliferation of tumor cells by changing the concentration of cyclic nucleotides in the cell. Finally, growth in a tumor can be influenced by serum growth factors, which are called poetins. various metabolites, delivered to the tumor by blood.
The proliferation of tumor cells is greatly influenced by the cells and intercellular substance that form the basis of the tumor “microenvironment.” Thus, a tumor that grows slowly in one place of the body, when transplanted to another place, begins to grow quickly. For example, a benign Shoup's papilloma of a rabbit, when transplanted to the same animal, but to other parts of the body (muscles, liver, spleen, stomach, under the skin), turns into a highly malignant tumor, which, infiltrating and destroying adjacent tissues, in a short time leads to death of the body.
In human pathology, there are stages when cells of the mucous membrane enter the esophagus and take root in it. Such “dystopian” tissue tends to form tumors.
Tumor cells, however, lose the upper “limit” on the number of their divisions (the so-called Highflick 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 endlessly divide. The result of this phenomenon is the immortalization (“immortality”) of a given cell clone (with a limited lifespan of each individual cell that composes it).
Therefore, unregulated growth should be considered a fundamental feature of any tumor, while all the following features that will be discussed are secondary - the result of tumor progression.
2. Anaplasia (from the Greek ana - reverse, 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 the ability, characteristic of normal cells, to form specific tissue structures and produce specific substances. Cataplasia is a complex phenomenon, and it cannot be explained only by the preservation of immaturity features corresponding to the stage of cell ontogenesis at which it was overtaken by a nonplastic transformation. This process affects tumor
cells not to the same extent, often resulting in cells that have no counterparts in normal tissue. In such cells there is a mosaic of preserved and lost characteristics of cells of a given level of maturity.
3. Atypia. Anaplasia is associated with atypism (from the Greek a - denial and typos - exemplary, typical) of tumor cells. There are several types of atypia.
Atypical reproduction, caused by the previously mentioned unregulated cell growth and the loss of the upper limit or “limit” on the number of their divisions.
Atypia of differentiation, manifested in partial or complete inhibition of cell maturation.
Morphological atypia, which is divided into cellular and tissue. In malignant cells, there is significant variability in the size and shape of cells, the size and number of individual cellular organelles, the DNA content in cells, the shape
And number of chromosomes. In malignant tumors, along with cell atypia, tissue atypism occurs, which is expressed in the fact that, compared to 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 characteristic only of benign tumors.
Metabolic and energy atypia, which includes: intense synthesis of oncoproteins (“tumor-producing” or “tumor” proteins); decreased synthesis and content of histones (transcription suppressor proteins); education not characteristic of mature
cells of embryonic proteins (including fetoprotein); changing 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 the construction of the cytoplasm, cholesterol for the construction of cell membranes, as well as -tocopherol and other antioxidants for protection against free radicals and membrane stabilization; a decrease in the concentration of the intracellular messenger cAMP in the cell.
Physicochemical atypia, which boils down 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 water content facilitates the diffusion of metabolic substrates
inside the cells and its products outside; a decrease in Ca2+ content reduces intercellular adhesion, and an increase in K+ concentration prevents the development of intracellular acidosis, caused by increased glycolysis and the accumulation of lactic acid in the peripheral, growing zone of the tumor, since there is an intensive release of K+ and protein from decaying structures.
Functional atypia, characterized by the complete or partial loss of the ability of tumor cells to produce specific products (hormones, secretions, fibers); or an inadequate, inappropriate increase in this production (for example, an increase in insulin synthesis by insulinoma, a tumor from the cells of the pancreatic islets of Langerhans); or “perversion” of the noted function (synthesis of the hormone by tumor cells in breast cancer thyroid gland– calciotonin or synthesis by tumor cells of lung cancer of 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 emergence of new antigens. In the first case, there is a loss by tumor cells of antigens present in the original normal cells (for example, the loss of organ-specific liver h-antigen by tumor hepatocytes), and in
the second is the appearance of new antigens (for example, -fetoprotein).
Atypical “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 “escaping” 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, antioxidants, stress effect of the tumor, etc. aggravate the situation.
4. Invasiveness and destructive growth. The ability of tumor cells to grow (invasiveness) into surrounding healthy tissues (destructive growth) and destroy them is a characteristic property of all tumors. The tumor induces the growth of connective tissue, and this leads to the formation of the underlying tumor stroma, a kind of “matrix”, without which the development of the tumor is impossible. New cells
bath of connective tissue, in turn, stimulate the proliferation of tumor cells, which grow into it, releasing some biologically active substances. The properties of invasiveness, strictly speaking, are nonspecific for malignant tumors. Similar processes can be observed during normal inflammatory reactions.
Infiltrating tumor growth leads to destruction of normal tissue adjacent to the tumor. Its mechanism is associated with the release of proteolytic enzymes (collagenase, cathepsin B, etc.), we highlight 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 feature of malignant tumors. Typically, the activity of a tumor cell does not end in the primary tumor; sooner or later, tumor cells migrate from the compact mass of the primary tumor, are transported by blood or lymph, and settle somewhere in a lymph node or other tissue. There are a number of reasons for migration.
An important reason for dispersal is a simple lack of space (overcrowding leads to migration): the internal pressure in the primary tumor continues to increase until cells begin to be pushed out of it.
Cells entering mitosis become rounded and largely lose connections with surrounding cells, partly due to disruption of the normal expression of cell adhesion molecules. Since a significant number of cells divide simultaneously in a tumor, their contacts in a given small area weaken, and such cells are able to fall out of the total mass more easily than normal ones.
As tumor cells progress, they increasingly acquire the ability to grow autonomously, causing them to break away from the tumor.
The following pathways of metastasis are distinguished: lymphogenous, hematogenous, hematolymphogenous, “cavitary” (transfer of tumor cells by fluids in body cavities, for example, cerebrospinal fluid), implantation (direct transition of tumor cells from the surface of the tumor to the surface of a tissue or organ).
Whether the tumor will metastasize, and if so, when, is determined by the properties of the tumor cells and their immediate environment. However, the host organism plays a significant role in determining where the released cell will migrate, where it will settle, and when it will form a mature tumor. Clinicians and experimenters have long noted that metastases in the body spread unevenly, apparently giving preference to certain tissues. Thus, the spleen almost always avoids this fate, while the liver, lungs and lymph nodes are favorite places for metastatic cells to settle. The predilection of some tumor cells for certain organs sometimes reaches extreme expression. For example, mouse melanoma has been described with a special affinity for lung tissue. When such a melanoma was transplanted into a mouse, into whose paw 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 caused by metastases. Even at autopsy, it is sometimes impossible to detect the primary source of metastasis among many tumor foci.
The mere fact of the presence of tumor cells in lymphatic and blood vessels does not predetermine the development of metastases. There are numerous cases where at a certain stage of the disease, most often under the influence of treatment, they disappear from the blood and metastases do not develop. Most tumor cells circulating in the vascular bed die after a certain period of time. Another part of the cells dies under the influence of antibodies, lymphocytes, and macrophages. And only the smallest part of them finds favorable conditions for their existence and reproduction.
Metastases are distinguished between intraorgan, regional and distant. Intraorgan metastases are tumor cells that have become detached, established themselves in the tissues of the same organ in which the tumor grew, and given secondary growth. Most often, such metastasis occurs through the lymphogenous route. Regional metastases are those that are located in the lymph nodes close to the organ in which the tumor has grown. At the initial stages of tumor growth, lymph nodes react with increasing hyperplasia of lymphoid tissue and reticular cellular elements. Sensitized lymphoid cells migrate from the regional lymph node to more distant ones as the tumor process develops.
With the development of metastases in the lymph nodes, the proliferative and hyperplastic processes in them decrease, degeneration of the cellular elements of the lymph node and the proliferation of tumor cells occurs. The lymph nodes become enlarged. Distant metastases mark dissemination or generalization of the tumor process and are beyond the scope of radical therapeutic action.
7. Recurrence(from Latin recedivas - return; re-development illnesses). 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 characteristics of tumor growth and the course of 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 Typically characterized by slow tumor growth with tissue expansion, absence of metastases, preservation of the structure of the original tissue, low mitotic activity of cells, and the predominance of tissue atypia.
For malignant growth Typically characterized by rapid growth with destruction of the original tissue and deep penetration into surrounding tissues, frequent metastasis, significant loss of the structure of the original tissue, high mitotic and amitotic activity of cells, and the predominance of cellular atypia.
A simple listing of the features of benign and malignant growth indicates the conventionality of such a division of tumors. Tumor different benign growth, localized in vital organs, poses no less, if not more, danger to 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 malignization of benign growths in humans.
From the perspective of the mechanisms of tumor progression, benign growth (i.e., benign tumor) is a stage of 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 often happens justifies the idea of a benign tumor as one of the initial phases of progression. Tumors are known that
throughout the life of the body do not become malignant. These are, as a rule, very slow-growing tumors, and it is possible that their malignancy requires time exceeding the life expectancy of the organism.
Principles of tumor classification
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 meninges;
blood systems;
teratomas.
According to the histological principle, which is based on the severity of atypia, mature tumors (with a predominance of tissue atypia) and immature (with a predominance of cellular atypia) are distinguished.
Based on the oncologic principle, tumors are characterized according to the International Classification of Diseases.
According to the prevalence of the process, the characteristics of the primary lesion, 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) – presence of metastases in the lymph nodes, M (metastasis) – presence of distant metastases.
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 50s of the 20th century). Consequently, the process must inevitably involve the immune system, one of the most important functions of which is censorship, i.e. identification and destruction of “foreign” in the body. Tumor cells that have changed their antigenic composition represent this “foreign” that must be destroyed
nu. Tumor transformation occurs constantly and relatively frequently throughout life, but immune mechanisms eliminate or suppress the proliferation of tumor cells.
Immunohistochemical analysis of tissue sections of various human and animal tumors shows that they are often infiltrated by 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 significantly better. For example, the five-year survival rate 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 is only 4.5%. In patients with gastric cancer, the same indicator for tumor infiltration by NK cells or dendritic cells is 75% and 78%, respectively, and with low infiltration of these cells, 50% and 43%, respectively.
Conventionally, there are two groups of mechanisms of antitumor immunity: 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 effect 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 body’s antitumor defense, 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 echelon of defense. It should be emphasized that for the development of an immune response, resulting in an increase in the number of cytotoxic T-lymphocytes (synonym: killer T-lymphocytes) and T-effectors of delayed-type hypersensitivity (synonym: activated pro-inflammatory Th1 lymphocytes), it takes from 4 to 12 days. This is due to the processes of activation, proliferation and differentiation of cells of the corresponding T-lymphocyte clones. Despite the duration of development of the immune response, it is precisely this response that provides the second echelon of the body’s defense. The latter, due to the high specificity of antigen recognition receptors of T-lymphocytes, a significant increase (thousands to hundreds of thousands of times) in the number of cells of the corresponding clones as a result of proliferation and differentiation
citations of predecessors, much more selective and effective. By analogy with the currently operating weapons systems of the armies of various countries, the mechanisms of natural resistance can be compared with tank armies, and effector T-lymphocytes can be compared with high-precision space-based weapons.
Along with an increase in the number of effector T lymphocytes and their activation during the development of an immune response to tumor antigens, as a result of the interaction of T and B lymphocytes, clonal activation, proliferation and differentiation of B lymphocytes into plasma cells producing antibodies occurs. 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 IgG antibodies fixed on them are recognized through the receptor for the Fc fragment of IgG (Fc RIII, CD16) by NK cells. 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 spontaneous differentiation of the corresponding clones of B lymphocytes.
For the development of a cell-mediated immune response, a complete presentation of antigenic peptides in complex with molecules of the major histocompatibility complex I is required (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 through interaction with professional antigen-presenting cells (dendritic cells and macrophages). Therefore, for the development of an immune response, tumor infiltration is necessary not only with T lymphocytes, but also with 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 dysfunction of natural resistance effectors, exposure to immunosuppressive drugs, and aging. Exposures that suppress the immune system promote the development of tumors, and vice versa. The tumor itself has a pronounced immunosuppressive effect and sharply inhibits immunogenesis. This action is realized through the synthesis of cytokines (IL-10, transforming growth factor-), low-molecular 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. Taking into account the above, normalization of the functions of the immune system in tumors is a necessary component in complex pathogenetic treatment.
Treatment, depending on the type of tumor, its size, spread, and the 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 danger 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 administration 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 (administration of vaccines from tumor cells, their extracts, purified or recombinant tumor antigens) are being tested; active nonspecific immunotherapy (administration of BCG vaccine, vaccine based on Corynebacterium parvum and other microorganisms to obtain an adjuvant effect and switch
Determining and assessing the severity of treatment for this disease is available to any medical institution. The concept of “systemic inflammatory response syndrome” has been accepted as a term 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 incidence of the disease in patients reaches 50% according to statistics. At the same time, in patients with high temperature bodies (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 exist for a longer time, until the levels of cytokines and nitrogen monoxide (NO) in the blood decrease, until the balance between pro-inflammatory and anti-inflammatory cytokines is restored, and the function of the immune system to control the production of cytokines is restored.
With a decrease in hypercytokinemia, the symptoms of the systemic inflammatory response can 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 severe forms 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 ultimately mutually enhance their pathophysiological effects, creating increasing 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 interplay of cytokines and cytokine-neutralizing molecules in systemic inflammatory response syndrome likely determines the clinical manifestations and course of sepsis. Even severe systemic response to inflammation syndrome cannot be considered sepsis unless the patient has a primary source of infection (portal of entry), bacteremia, confirmed by isolation of bacteria from the blood through multiple cultures.
Sepsis as a sign of systemic response to inflammation syndrome
Sepsis as a clinical symptom of the syndrome is difficult to define. The Consensus Committee of American Physicians defines sepsis as a very severe form of systemic response syndrome to inflammation in patients with a primary site of infection confirmed by blood culture, in the presence of signs of depression of central nervous system function and multiple organ failure.
We should not forget about the possibility of developing sepsis even in the absence of a primary source of infection. In such cases, microorganisms and endotoxins may appear in the blood due to translocation intestinal bacteria and endotoxins into 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 disrupted due to ischemia of the walls during
- peritonitis,
- acute intestinal obstruction,
- and other factors.
Under these conditions, the intestine with systemic inflammatory response syndrome becomes similar to an “undrained purulent cavity.”
Complications of systemic inflammatory response syndrome
A cooperative study involving 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. In severe systemic inflammatory response syndrome it was 7%, in sepsis - 16%, and in septic shock - 46%.
Features of treatment of systemic response syndrome to inflammation
Knowledge of the pathogenesis of the syndrome allows us to develop anti-cytokine therapy, prevention and treatment of complications. For these purposes, the following is used in the treatment of the disease:
monoclonal antibodies against cytokines,
antibodies against the most active proinflammatory cytokines (IL-1, IL-6, tumor necrosis factor).
There are reports of 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 timely and adequate treatment of the underlying disease, comprehensive prevention and treatment of dysfunction of vital organs.
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Essay
WITHsystemic inflammatory response.Sepsis
Introduction
The term "sepsis" in a meaning close to the current understanding was first used by Hippoctus more than two thousand years ago. This term originally meant the process of tissue decay, inevitably accompanied by rotting, 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 etiology and pathogenesis of surgical infections and sepsis began to be considered from the point of view of the relationship between macro- and microorganisms.
In the works of the outstanding Russian pathologist I.V. Davydovsky clearly formulated the idea of the leading role of the reactivity of the macroorganism in the pathogenesis of sepsis. This was, of course, a progressive step, orienting clinicians towards rational therapy aimed, on the one hand, at eradicating the pathogen, and on the other, at correcting dysfunction of organs and systems of the macroorganism.
1. ModernData about inflammation
Inflammation should be understood as a universal, phylogenetically determined response of the body to damage.
Inflammation has an adaptive nature, caused by the reaction of the body's defense mechanisms to local damage. Classic signs of local inflammation - hyperemia, local increase in temperature, swelling, pain - are associated with:
· morpho-functional restructuring of endothelial cells of post-capillary venules,
coagulation of blood in postcapillary venules,
adhesion and transendothelial migration of leukocytes,
activation of complement
· kininogenesis,
dilatation of arterioles,
· degranulation of mast cells.
A special place among mediators of inflammation is occupied by the cytokine network,
Controlling the processes 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, endothelial cells of postcapillary venules, platelets and various types of stromal cells. Cytokines act primarily at the site of inflammation and in the responding lymphoid organs, ultimately performing a number of protective functions.
Mediators in small quantities can 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 receptors for TNF, called anti-inflammatory mediators . Under normal conditions, by maintaining a balance in the relationship between pro- and anti-inflammatory mediators, the prerequisites are created for wound healing, destruction of pathogenic microorganisms, and maintenance of homeostasis. Systemic adaptive changes in acute inflammation include:
· stress reactivity of the neuroendocrine system,
· fever,
release of neutrophils into the circulation 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 immune response.
When regulatory systems are unable to maintain homeostasis, the destructive effects of cytokines and other mediators begin to dominate, which leads to disruption of the permeability and function of the capillary endothelium, the initiation of disseminated intravascular coagulation syndrome, the formation of distant foci of systemic inflammation, and the development of organ dysfunction. The total effects exerted by mediators form the systemic inflammatory response syndrome (SIR).
The criteria for a systemic inflammatory reaction, which characterizes the body’s response to local tissue destruction, are: ESR, C-reactive protein, systemic temperature, leukocyte intoxication index and other indicators that have varying sensitivity and specificity.
At the Consensus Conference of the American College of Chest Physicians and the Society of Critical Care Medicine, held in Chicago in 1991 under the leadership of Roger Bone, it was proposed that the criteria for a systemic inflammatory response of the body should be considered at least three of the four unified signs:
* Heart rate more than 90 per minute;
* respiratory rate more than 20 per minute;
* body temperature more than 38°C or less than 36°C;
* number of leukocytes in peripheral blood more than 12x106 or less
4x106 or the number of immature forms is more than 10%.
The approach to determining the systemic inflammatory response proposed by R. Bohn caused mixed 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 generally accepted and commonly used one.
2. Furanism and the structure of inflammation
sepsis pasteur inflammatory surgical
Inflammation can be imagined using a basic model in which we can distinguish five main links involved in the development of the inflammatory response:
· Activation of the coagulation system- according to some opinions, the leading link of 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 component of hemostasis- performs the same biological function as coagulation factors - stops bleeding. However, products released during platelet activation, such as thromboxaneA2 and prostaglandins, due to their vasoactive properties, play a critical 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, directly acting on smooth muscles, relaxes the latter and ensures vasodilation of the microvascular bed, which leads to an increase in the permeability of the vascular wall, an increase in the total blood flow through this area while simultaneously reducing the speed of blood flow.
· Activation of kallikrein kinin The system also becomes possible thanks to factor XII, which ensures the conversion of prekallikrein into 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 along both the classical and alternative paths. This leads to the creation of conditions for the lysis of cellular structures of microorganisms; in addition, activated complement elements have important vasoactive and chemoattractant properties.
The most important general property these five different inducers of the inflammatory response - their interactivity and mutually reinforcing effect. This means that when any of them appears 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 inflammatory 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. Endothelial cells play a critical role in this process.
When the endothelium is damaged, endothelial cells are activated and NO synthetase is synthesized to the maximum, which consequently leads to the production of nitric oxide and maximum dilatation of intact vessels, and the rapid movement of leukocytes and platelets to the damaged area.
The second phase of inflammation (phagocytosis phase) begins from the moment when the concentration of chemokines reaches the 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 lesion) reaches the critical level necessary to create an appropriate concentration of leukocytes.
The essence of this phase is the migration of leukocytes to the site of damage, as well as monocytes. Monocytes reach the site of injury, where they differentiate into two different subpopulations: one dedicated to the destruction of microorganisms, and the other to phagocytose necrotic tissue. Tissue macrophages process antigens and deliver them to T and B cells, which are involved in the destruction of microorganisms.
At the same time, anti-inflammatory mechanisms are launched simultaneously with the onset of inflammation. They include cytokines that have a direct anti-inflammatory effect: IL-4, IL-10 and IL-13. Expression of receptor antagonists, such as IL-1 receptor antagonist, also occurs. However, the mechanisms of termination of the inflammatory response are still not fully understood. There is an opinion that it is most likely that the key role in stopping the inflammatory reaction is played by reducing the activity of the processes that caused it.
3. Systemic inflammatory response syndrome (SIRS)
After the introduction into clinical practice of the terms and concepts proposed at the Consensus Conference by R. Bon and co-authors in 1991, a new stage began in the study of sepsis, its pathogenesis, principles of diagnosis and treatment. A unified set of terms and concepts focused on Clinical signs. Based on them, fairly definite ideas have now emerged about the pathogenesis of generalized inflammatory reactions. The leading concepts were “inflammation”, “infection”, “sepsis”.
The development of systemic inflammatory response syndrome is associated with a disruption (breakthrough) of the delimiting function of local inflammation and the entry of proinflammatory cytokines and inflammatory mediators into the systemic bloodstream.
To date, quite numerous groups of mediators are known that act as stimulators of the inflammatory process and anti-inflammatory defense. The table shows some of them.
Hypothesis of R. Bon et al. (1997) on the patterns of development of the septic process, currently accepted as the leading one, is based on the results of studies confirming that the activation of chemoattractants and proinflammatory cytokines as inducers of inflammation stimulates the release of counteragents - anti-inflammatory cytokines, the main function of which is to reduce the severity of the inflammatory response.
This process, immediately following the activation of inflammatory inducers, is called the “anti-inflammatory compensatory reaction”, in the original transcription - “compensatory anti-inflammatory response syndrome (CARS)”. In terms of severity, the anti-inflammatory compensatory reaction can not only reach the level 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) that this criterion cannot be used as a diagnostic criterion.
°~ for anti-inflammatory compensatory response syndrome.
Assessing the options for the clinical course of the septic process, we can distinguish four groups of patients:
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 degree of systemic inflammatory response syndrome, dysfunction of one or two organs occurs, which recovers fairly quickly with adequate therapy.
3. Patients who rapidly develop a severe form of systemic inflammatory response syndrome, representing severe sepsis or septic shock. Mortality in this group of patients is maximum.
4. Patients in whom the inflammatory reaction to the primary injury is not so pronounced, but within a few days after the appearance of signs of the infectious process, organ failure progresses (this dynamics of the inflammatory process, which has the shape 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 clinical course of sepsis be explained by the activity of proinflammatory mediators? The answer to this question is given by the hypothesis of the pathogenesis of the septic process, proposed by R. Bohn et al. In accordance with it, there are five phases of sepsis:
1. Local reaction to damage or infection. Primary mechanical damage leads to the activation of pro-inflammatory mediators, which have 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 anti-inflammatory mediators include: IL-4,10,11,13, IL-1 receptor antagonist.
They reduce the expression of the monocyte histocompatibility complex and reduce the ability of cells to produce anti-inflammatory cytokines.
2. Primary systemic reaction. With severe 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 are, as a rule, transient and quickly leveled out.
3. Massive systemic inflammation. A decrease in the efficiency of regulation of the proinflammatory response leads to a pronounced systemic reaction, clinically manifested by signs of systemic inflammatory response syndrome. The basis of these manifestations may be the following pathophysiological changes:
* progressive endothelial dysfunction leading to increased microvascular permeability;
* stasis and aggregation of platelets, leading to blocking of the microcirculation, redistribution of blood flow and, following ischemia, post-perfusion disorders;
* activation of the coagulation system;
* deep vasodilation, transudation of fluid into the intercellular space, accompanied by 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. Excessive activation 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 into immunodeficiency.” R. Bohn and co-authors proposed calling this condition the syndrome of anti-inflammatory compensatory reaction, giving 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, which is necessary to complete the wound process. It is this reaction of the body that causes 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 condition - a deep syndrome of anti-inflammatory compensatory reaction - can occur. The lack of a stable balance is the most characteristic this phase.
According to academician RAS and RAMS V.S. Savelyev and corresponding member. RAMS A.I. Kiriyenko’s hypothesis above, the balance between pro-inflammatory and anti-inflammatory systems can be disrupted in one of three cases:
* when there is an infection, severe injury, bleeding, etc. so strong that this is quite enough for 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 systemic inflammatory response syndrome and multiple organ failure;
* when the patient’s pre-existing (background) condition is closely related to the pathological level of cytokines.
According to the concept of academician RAS and RAMS V.S. Savelyev and corresponding member. RAMS A.I. Kiriyenko, 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 reaction). The form of clinical manifestation of this multifactorial interaction is the severity of multiple organ failure, determined on the basis of one of the internationally agreed scales (APACHE, SOFA, etc.). In accordance with this, three gradations of sepsis severity 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 guidelines.
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 also includes verified bacteremia).
It is proposed to establish the diagnosis of “severe sepsis” in the presence of organ failure in a patient with sepsis.
Diagnosis of organ failure is made on the basis of agreed upon criteria, which formed the basis of the SOFA (Sepsis oriented failure assessment) scale.
Treatment
Crucial shifts in treatment occurred after consensus 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 made it possible to develop 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 Surviving sepsis campaign.
Primary intensive care measures. Aimed at achieving the following parameter values in the first 6 hours of intensive therapy (measures begin immediately after diagnosis):
* CVP 8-12 mm Hg. Art.;
* average blood pressure >65 mm Hg. Art.;
* amount of urine excreted >0.5 mlDkghch);
* mixed venous blood saturation >70%.
If transfusion of various infusion media fails to achieve an increase in central venous pressure and the level of saturation of mixed venous blood to the indicated figures, then it is recommended:
* transfusion of red blood cell mass until a hematocrit level of 30% is achieved;
* dobutamine infusion at a dose of 20 mcg/kg per minute.
Carrying out this set of measures can 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 antibacterial therapy.
*Treatment with broad-spectrum antibiotics begins within the first hour after diagnosis.
*Depending on the results of microbiological studies, after 48-72 hours, the regimen of antibacterial drugs used is reviewed to select a more narrow 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 measures to control the source, which include three groups of surgical interventions:
1. Drainage of the abscess cavity. An abscess forms as a result of the initiation of 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.
Draining an abscess is a mandatory procedure.
2. Secondary surgical treatment (necrectomy). Removal of necrotic tissue 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 treatment 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;
Use of vasopressors;
Algorithm of inotropic therapy;
Use of low doses of steroids;
Use of recombinant activated protein C;
Transfusion therapy algorithm;
Algorithm of mechanical ventilation for acute lung injury syndrome/respiratory distress syndrome in adults (SAPL/ARDS);
Protocol for sedation and analgesia in patients with severe sepsis;
Glycemic control protocol;
Treatment protocol for acute renal failure;
Bicarbonate Use 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 needs to be combated. 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 theories 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). This interpretation seems 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 to date. Understanding the limitations of the interpretation proposed by R. Bon, it is widely used based on two ideas.
Firstly, there is no doubt that severe sepsis is the result of the interaction of microorganisms and a macroorganism, resulting in disruption of the functions of one or more leading life support systems, which is recognized by all scientists dealing with this problem.
Secondly, the simplicity and convenience of the approach used in diagnosing severe sepsis (criteria for a systemic inflammatory response, infectious process, criteria for diagnosing organ disorders) make it possible to identify more or less homogeneous groups of patients. The use of this approach has now made it possible to get rid of such ambiguously defined concepts as “septicemia”, “septicopyemia”, “chroniosepsis”, “refractory septic shock”.
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