Systemic manifestations of inflammation. bacteremia and sepsis

The term "sepsis" comes from Greek sep-ein, which means putrid decay. Previously, it was used as a synonym for infection, later "septic" was called the physiological reaction of the body of a patient experiencing the effects of a gram-negative infection. In the 1970s, it was established that death caused by severe infection was preceded by a progressive deterioration in function. internal organs. However, not all patients with the corresponding signs were found to have foci of infection, but all had a risk of multiple organ failure and lethal outcome. Furthermore, specific treatment infectious foci did not guarantee recovery. Agreed definitions related to the inflammatory response were developed in 1991 (box 18-1).

Systemic inflammatory response syndrome(SIRS) - a widespread initial non-specific reaction (see box 18-1) to a variety of acute conditions(block 18-2). Obviously, SIRS is observed in almost all patients in critical condition. In the United States, approximately 70% of patients receiving highly specialized medical care, meet SIRS, and sepsis develops in 30% of cases. The latter is defined as SIRS in the presence of a focus of infection. Septic shock is classified as severe sepsis. To clarify the definitions of block 18-1, it is worth adding that hypoperfusion refers to acidosis, ol and houria and severe violations consciousness.

The appearance of SIRS does not necessarily predetermine the development of sepsis or multiple organ failure syndrome (MOS), but progression from SIRS to severe sepsis itself increases the risk of developing multiple organ failure. Concerning timely diagnosis SIRS alerts the clinician to a possible worsening of the condition at a time when it is still possible to perform an emergency intervention and prevent an extremely Negative consequences. The development of shock increases the lethality attributed to SIRS: from probability

Block 18-1. Definition of systemic inflammatory response syndrome and its consequences

Systemic inflammatory response syndrome

The diagnosis of SIRS is made when two or more of the following are present:

Body temperature >38°C or<36 °С

Pulse >90/min

Respiratory rate >20/min or paCO2<4,3 кПа (44 см вод.ст.)

White blood cell count >12x109/l (>12,000/ml) or<4хЮ9/л (<4 000/мл) или >10% immature cell forms

Infection

Inflammatory reaction to microorganisms or their invasion into initially sterile tissues of the human body

SIBO + confirmed infectious process severe sepsis

SIRS + organ dysfunction, hypoperfusion and arterial

hypotension

Septic shock

Sepsis with hypotension and hypoperfusion despite adequate fluid replacement Multiple organ failure syndrome

Organ dysfunction in an acute illness in which homeostasis cannot be maintained without outside intervention

Block 18-2. Factors that increase systemic inflammatory response syndrome

Infection Endotoxins

Hypovolemia, including bleeding Ischemia

Reperfusion injury Major trauma Pancreatitis

Inflammatory bowel disease less than 10% to 50% or more, with approximately 30% of patients with sepsis observed dysfunction of at least one organ. The incidence of death from MODS varies between 20% and 80% and generally increases as more organ systems are involved and also depending on the severity of physiological disturbances at the onset of the disease. The respiratory system often suffers first of all, however, the sequence of development of organ dysfunction also depends on the localization of the primary damage and on concomitant diseases.

The development of SIRS is accompanied by activation of the components of humoral and cellular immunity (block 18-3). These mediators regulate the processes responsible for the severity of the immune response and control the corresponding mechanisms. Mediators limit their own release, stimulate the release of antagonists, and inhibit their own functions depending on local concentration and interactions. It can be assumed that the inflammatory response is aimed at protecting the body from damage. If specific components of the immune system are absent, repeated infections pose a constant threat to life. However, uncontrolled activity of pro-inflammatory mediators is detrimental, and the individual's relative well-being, in terms of health and pathology, depends on the reactivity and endogenous modulation of the inflammatory response.

Macrophages are key cells in the development of the inflammatory process. They secrete mediators, mainly tumor necrosis factor (TNF) a, IL-1 and IL-6, which trigger a cascade of reactions and activate neutrophils, as well as vascular endothelial cells and platelets.

The activation of vascular endothelial cells is accompanied by the expression of leukocyte adhesion molecules.

Endotheliocytes produce a variety of inflammatory mediators, including cytokine and nitric oxide. As a result of stimulation of the endothelium, vasodilatation occurs, and capillary permeability increases, which leads to the formation of an inflammatory exudate. Antithrombotic properties of endothslial cells replace prothrombotic ones: tissue factor and plasminogen inhibitor are released. In the microvascular bed, blood coagulation occurs, which probably serves to delimit the pathological process and the agent that causes it. In addition to thrombogenic properties, thrombin has a pro-inflammatory effect that enhances the systemic response.

Local hypoxia or damage caused by ischemia and reperfusion also directly stimulates endotheliocytes. The release of chemotaxis factors attracts neutrophils, which sequentially attach to the endothelium and penetrate through it into the intercellular space. Both neutrophils and macrophages are involved in the destruction and phagocytosis of infectious agents. After the elimination of local causes that provoke inflammation, the activity of limiting regulatory mechanisms increases. Macrophages, in cooperation with other cells, regulate tissue repair, enhancing fibrosis and angiogenesis, and remove apoptotic neutrophils by phagocytosis.

These processes are accompanied by hyperthermia, neuroendocrine activity contributes to an increase in heart rate and stroke volume. Oxygen consumption by tissues increases, and, despite its delivery in the same amount, anaerobic metabolism develops. Such physiological events are observed in patients and healthy volunteers receiving sepsis inducers in the form of infusion in the experiment.

The development of SIRS has three phases. Initially, the initiating agent causes only local activation of pro-inflammatory mediators. At the second stage, the mediators go beyond the damage site, enter the general circulation and stimulate the synthesis of acute phase proteins in the liver. Anti-inflammatory mechanisms are also involved in the reactions. At the third stage, the regulatory systems are depleted, and a vicious circle of uncontrolled increase in the effects of pro-inflammatory mediators occurs. Pathological physiological reactions develop, including a decrease in myocardial contractility and total peripheral vascular resistance (OPVR), accumulation of fluid and proteins in the interstitium (“sequestration in the third space”). This may be followed by arterial hypotension with tissue hypoperfusion and hypoxia, which leads to a gradual disruption of organ functions. The two-hit hypothesis implies that additional damage is required to progress from SIRS to MODS. The first stimulus triggers an inflammatory response, while the second one shifts the balance towards the predominance of pro-inflammatory activation and organ damage. Studies confirm that in order to stimulate the cells of the inflammation zone, after primary activation by large doses of mediators, only a minimal stimulus is needed.

The development of SIRS is accompanied by increased metabolism. Catabolism accelerates, basal metabolic rate and oxygen consumption increase. The respiratory quotient increases, which confirms the oxidation of mixed substrates, and most of the energy is released from amino acids and lipids, with body weight minus adipose tissue rapidly and consistently decreasing. Much of the increased basal metabolic rate is due to the freedom of metabolic mediators. The changes presented cannot be mitigated by nutrition until the root cause is eliminated. Sepsis is accompanied by insulin resistance, which, along with increased levels of catecholamines, growth hormone and cortisol, leads to hyperglycemia.

In sepsis, hypoalbuminemia is often detected, but it does not indicate a violation of the nutritional status. The concentration of albumin is influenced not only by the total content of protein in the body, but, more importantly, by plasma volume and capillary permeability. Accordingly, hypoalbuminemia rather reflects plasma dilution and capillary leakage. This indicator indicates an unfavorable outcome, hypoalbuminemia and malnutrition can occur simultaneously. Artificial nutrition may be appropriate for other reasons, but albumin levels are unlikely to return to normal before sepsis resolves. Cytokine activation accompanies acute phase reactions, and measurements of plasma albumin and C-reactive protein provide the clinician with valuable information about the progression of the patient's condition.

Hyperglycemia predisposes to sepsis, myopathy, and neuropathy, all of which delay recovery.

A recent study examined the benefits of tight glycemic control in adult patients on controlled breathing. The patients were divided into two groups: one received intensive insulin therapy, with which the glucose level was maintained between 4.1 and 6.1 mmol/l; in the other group, insulin was administered to patients only when the glucose level exceeded 11.9 mmol/l, the indicator was maintained within the range of 10-11.1 mmol/l. Active insulin therapy was associated with a significant reduction in mortality among patients who were in the intensive care unit for more than 5 days. The maximum effect was observed in relation to the reduction in the frequency of deaths caused by multiple organ failure against the background of sepsis. Intensive insulin therapy, in addition, was accompanied by a shorter duration of artificial ventilation, a shorter period of stay in this department and a decrease in the need for hemofiltration.

The term “multiple organ failure syndrome” is preferable to “multiple organ dysfunction syndrome” because it more accurately reflects the progression of organ dysfunction than pathological decline in function on an all-or-nothing basis. MODS suggests the existence of a potentially reversible situation in which an organ that functions normally in a state of health cannot maintain homeostasis when exposed to a serious disease. It follows from this that the concomitant disease is predisposed. believes to SPON (block 18-4). Manifestations of organ dysfunction in severe illness are presented in block 18-5. Special conditions such as adult respiratory distress syndrome (ARDS), SR have generally accepted definitions, but no agreed names have been developed for states of multiorgan system dysfunction, although a number of options have been proposed. Primary SPON - direct track. the effect of specific damage, which led to an early dysfunction of the involved op. ganov. In secondary MODS, organ dysfunction

Block 18-4. Comorbid conditions that predispose to the development of a systemic inflammatory response and its consequences

Early and old age Eating disorders

Associated malignancies and precancerous conditions

Intercurrent diseases

Liver problems or jaundice

Kidney disorders

Respiratory disorders

Diabetes

Conditions accompanied by immunosuppression Condition after slenectomy Organ transplant recipient HIV infection Primary immunodeficiencies Immunosuppressive therapy Glucocorticoids and azathioprine Cytotoxic chemotherapy Radiation therapy

Block 18-5. Clinical manifestations of multiple organ failure

Pulmonary

hypoxia

Hypercapnia

Acid-base balance disorders

Cardiovascular

Arterial hypotension

Fluid overload Metabolic acidosis

Loss of concentration Oliguria

Liquid overload

Electrolyte and acid-base disorders

Hepatic

coagulopathy

hypoglycemia

metabolic acidosis

encephalopathy

Gastrointestinal

Intestinal obstruction

pancreatitis

Cholecystitis

Gastrointestinal bleeding

Malabsorption

metabolic

hyperglycemia

Hematological

coagulopathy

Leukopenia

neurological

Change in the level of consciousness

Seizures

neuropathy

- generalized activation of the basic mechanisms, which in classical inflammation are localized in the focus of inflammation;

- the leading role of the reaction of microvessels in all vital organs and tissues;

- lack of biological expediency for the organism as a whole;

- Systemic inflammation has self-development mechanisms and is the main driving force behind the pathogenesis of critical complications, namely, shock states of various genesis and multiple organ failure syndrome, which are the main causes of death.

XVIII. PATHOPHYSIOLOGY OF TUMOR GROWTH

In every science there is a small number of such tasks and problems that can potentially be solved, but this solution has either not been found or, due to a fatal set of circumstances, has been lost. For many centuries, these problems have attracted the interest of scientists. When trying to solve them, outstanding discoveries are made, new sciences are born, old ideas are revised, new theories appear and die. Examples of such tasks and problems are: in mathematics - the famous Fermat's theorem, in physics - the problem of finding the elementary structure of matter, in medicine - the problem of tumor growth. This section is devoted to this problem.

It would be more correct to speak not about the problem of tumor growth, but about the problems of tumor growth, since here we are faced with several problems.

First, the tumor is a biological problem, since it is the only disease known to us that is so widespread in nature and occurs in almost the same form in all species of animals, birds, and insects, regardless of their level of organization and habitat. Tumors (osteomas) have already been found in fossil dinosaurs that lived 50 million years ago. Neoplasms are also found in plants - in the form of crown galls in trees, potato "cancer", etc. But there is another side: the tumor consists of the cells of the body itself, therefore, having understood the laws of the emergence and development of the tumor, we will be able to understand many biological laws growth, division, reproduction and differentiation of cells. Finally, there is a third side: the tumor

is an autonomous proliferation of cells, therefore, in the study of the occurrence of tumors, it is impossible to bypass the laws of biological integration of cells.

Secondly, the tumor is a social problem, if only because it is a disease of mature and old age: malignant tumors occur most often at the age of 45–55 years. In other words, highly qualified workers who are still in the period of active creative activity die from malignant neoplasms.

Thirdly, the tumor is an economic problem, since the death of oncological patients is usually preceded by a long and painful illness, therefore, there is a need for specialized medical institutions for a large number of patients, the training of specialized medical personnel, the creation of complex and expensive equipment, the maintenance of research institutions, maintenance of intractable patients.

Fourthly, the tumor is a psychological problem: the appearance of a cancer patient significantly changes the psychological climate in the family and in the team where he works.

The tumor, finally, is also a political problem, since all people on earth, regardless of their race, skin color, social and political structure in their countries. It is not for nothing that almost all countries, establishing political and scientific contacts among themselves, always create bilateral and multilateral programs to combat cancer.

For any tumor, one of the following Greek or Latin terms is used: tumor, blastoma, neoplasm, oncos. When it is necessary to emphasize that we are talking about a malignant growth of a tumor, then the word malignus is added to one of the listed terms, with benign growth - the word benignus.

In 1853, R. Virchow's first work was published, outlining his views on the etiology and pathogenesis of tumors. Since that moment, the cellular direction in oncology has taken a dominant position. "Omnis cellula ex cellula". A tumor cell, like any cell in the body, is formed only from cells. With his statement, R. Virchow put an end to all theories about the emergence of tumors from fluids, lymph, blood, blasts, all kinds of

sty humoral theories. Now the focus is on the tumor cell, and the main task is to study the causes that cause the transformation of a normal cell into a tumor cell, and the ways in which this transformation occurs.

The second major event in oncology was the publication in 1877 of M.A. Novinsky for a master's degree in veterinary sciences with a description of his experiments on transplanting three microsarcomas of dogs into other dogs. The author used young animals for these experiments and grafted into them small pieces not from decaying (as was usually done before), but from living parts of canine tumors. This work marked, on the one hand, the emergence of experimental oncology, and, on the other hand, the emergence of the method of tumor transplantation, i.e. transplantation of spontaneously occurring and induced tumors. The improvement of this method made it possible to determine the main conditions for successful vaccination.

1. For vaccination, live cells must be taken.

2. The number of cells may vary. There are reports of successful inoculation of even a single cell, but still, the more cells are injected, the greater the likelihood of successful tumor inoculation.

3. Repeated vaccinations succeed sooner, and tumors reach large sizes, i.e. if you grow a tumor on an animal, take cells from it and inoculate them in another animal of the same species, then they take root better than in the first animal (the first owner).

4. Autologous transplantation is best performed, i.e. tumor transplantation to the same host, but to a new location. Syngeneic transplantation is also effective; grafting of the tumor onto animals of the same inbred line as the original animal. Tumors take root worse in animals of the same species, but of a different line (allogeneic transplantation), and tumor cells take root very poorly when transplanted into an animal of another species (xenogenic transplantation).

Along with tumor transplantation, the method of explantation is also of great importance for understanding the characteristics of malignant growth; cultivation of tumor cells outside the body. Back in 1907, R.G. Harrison showed the possibility of growing cells on artificial nutrient media, and soon, in 1910, A. Carrel and M. Burrows published data on the possibility of in vitro cultivation of malignant tissues. This method made it possible to study tumor cells of various animals.

and even a person. The latter include the Hela strain (from epic

dermoid cervical cancer), Hep-1 (also obtained from the cervix), Hep-2 (laryngeal cancer), etc.

Both methods are not without drawbacks, among which the most significant are the following:

with repeated vaccinations and crops in culture, the properties of the cells change;

the ratio and interaction of tumor cells with stromal and vascular elements, which are also part of the tumor growing in the body, are disturbed;

the regulatory influence of the organism on the tumor is removed (when the tumor tissue is cultivated in vitro).

With the help of the described methods, we can still study the properties of tumor cells, the peculiarities of their metabolism, and the effect of various chemical and medicinal substances on them.

The occurrence of tumors is associated with the action on the body of various factors.

1. Ionizing radiation. In 1902, A. Frieben in Hamburg described skin cancer on the back of the hand in an employee in a factory manufacturing X-ray tubes. This worker spent four years checking the quality of the pipes by looking through his own hand.

2. Viruses. In the experiments of Ellerman and Bang (C. Ellerman, O. Bang)

in 1908 and P. Rous in 1911 established the viral etiology of leukemia and sarcoma. However, at that time, leukemia was not considered a neoplastic disease. And although these scientists created a new, very promising direction in the study of cancer, their work was ignored for a long time and did not receive high praise. Only in 1966, 50 years after the discovery, P. Raus was awarded the Nobel Prize.

Along with numerous viruses that cause tumors in animals, viruses that act as an etiological factor for the induction of tumors in humans have been isolated. Of the RNA-containing retroviruses, these include the HTLV-I virus (eng. hu man T-cell lymphotropic virus type I), which causes the development of 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 human papillomavirus (cervical cancer), hepatitis B and C viruses (liver cancer), Epstein-Barr virus (in addition to infectious mononucleosis, is an etiological factor for lymphoma Burkitt and nasopharyngeal carcinoma).

3. Chemicals. In 1915, the work of Yamagiwa and Ichikawa (K. Yamagiwa and K. Ichikawa) “Experimental study of atypical epithelial proliferation” was published, which described the development of a malignant tumor in rabbits under the influence of long-term lubrication of the skin of the inner surface of the ear with coal tar. Later, a similar effect was obtained by smearing the backs of mice with this resin. Undoubtedly, this observation was a revolution in experimental oncology, since the tumor was induced in the body of an experimental animal. This is how the method of tumor induction appeared. But at the same time, the question arose: what is the active principle, which of the many substances that make up the resin serves as a carcinogen?

The subsequent years of development of experimental and clinical oncology are characterized by the accumulation of factual data, which since the beginning of the 60s. 20th century began to be generalized into more or less coherent theories. Nevertheless, even today we can say that we know quite a lot about tumor growth, but we still do not understand everything about it and are still far from the final solution of oncological problems. But what do we know today?

Tumor, neoplasm– pathological cell proliferation uncontrolled by the body with relative autonomy of metabolism and significant differences in structure and properties.

A tumor is a clone of cells that originated from the same parent cell and have the same or similar properties. Academician R.E. Kavetsky proposed to distinguish three stages in tumor development: initiation, stimulation and progression.

Initiation stage

The transformation of a normal cell into a tumor cell is characterized by the fact that it acquires new properties. These "new" properties of a tumor cell should be correlated with changes in the genetic apparatus of the cell, which are triggers for carcinogenesis.

Physical carcinogenesis. Changes in the DNA structure leading to the development of a tumor can be caused by various physical factors, and ionizing radiation should be put in the first place here. Under the influence of radioactive substances, gene mutations occur, some of which can lead to the development of a tumor. As for other physical factors, such as mechanical irritation, thermal effects (chronic burns), polymeric substances (metal foil, synthetic foil),

they stimulate (or activate) the growth of the already induced, i.e. an already existing tumor.

chemical carcinogenesis. Changes in the structure of DNA can also be caused by various chemicals, which served as the basis for the creation of theories of chemical carcinogenesis. For the first time, the possible role of chemicals in the induction of a tumor was indicated in 1775 by the English physician Percivall 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 this assumption was experimentally confirmed in the works of Japanese researchers Yamagiwa and Ichikawa (K. Yamagiwa and K. Ichikawa), who caused a malignant tumor in rabbits with coal tar.

At the request of the English researcher J.W. Cook, in 1930, 2 tons of resin were subjected to fractional distillation at a gas plant. After repeated distillation, crystallization, and preparation of characteristic derivatives, 50 g of some unknown compound was isolated. It was 3,4-benzpyrene, which, as was established by biological tests, turned out to be quite suitable for research as a carcinogen. But 3,4-benzpyrene is not among the very first pure carcinogens. Even earlier (1929), Cooke had already synthesized 1,2,5,6-dibenzathracene, which also turned out to be an active carcinogen. Both compounds, 3,4-benzpyrene and 1,2,5,6 dibenzoatracene, belong to the class of polycyclic hydrocarbons. Representatives of this class contain benzene rings as the main building block, which can be combined into numerous ring systems in various combinations. Later, other groups of 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 vital activity of plants and fungi (cicasine, safrole, ragwort alkaloids, etc.); heterocyclic aromatic hydrocarbons (1,2,5,6-dibenzacridine, 1,2,5,6 and 3,4,5,6-dibenzcarbazole, etc.). Consequently, carcinogens differ from each other in chemical structure, but nevertheless they all have a number of common properties.

1. From the moment of action of a carcinogenic substance to the appearance of a tumor, a certain latent period passes.

2. The action of a chemical carcinogen is characterized by a summation effect.

3. The influence of carcinogens on the cell is irreversible.

4. There are no subthreshold doses for carcinogens, i.e. any, even a very small dose of a carcinogen causes a tumor. However, at very low doses of a carcinogen, the latent period can exceed the lifespan of a person or animal, and the organism dies from a cause other than a tumor. This can also explain the high frequency of tumor diseases in the elderly (a person is exposed to low concentrations of carcinogens, therefore, the latent period is long and the tumor develops only in old age).

5. Carcinogenesis is an accelerated process, i.e., having begun under the influence of a carcinogen, it will not stop, and the cessation of the action of a carcinogen on the body does not stop the development of a tumor.

6. Essentially, all carcinogens are toxic; able to kill the cell. This means that at particularly high daily doses of carcinogens, cells die. In other words, the carcinogen interferes with itself: at high daily doses, a larger amount of the substance is required to produce a tumor than at low ones.

7. The toxic effect of a carcinogen is directed primarily against normal cells, as a result of which “resistant” tumor cells gain advantages in selection when exposed to a carcinogen.

8. Carcinogenic substances can replace each other (the phenomenon of syncarcinogenesis).

There are two options for the appearance of carcinogens in the body: intake from outside (exogenous carcinogens) and formation in the body itself (endogenous carcinogens).

Exogenous carcinogens. Only a few of the known exogenous carcinogens are capable of causing tumor formation without changing their chemical structure, 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 residues, exhaust fumes, street dust, fresh earth in the field, cigarette smoke and even smoked products contain in some cases a significant amount of this carcinogenic hydrocarbon. Aromatic amines themselves are not carcinogenic at all, which has been proven by direct experiments (Georgiana

Bonser). Consequently, the bulk of carcinogenic substances should be formed in the body of an animal and a person from substances coming from outside. There are several mechanisms for the formation of carcinogens in the body.

Firstly, substances that are inactive in terms of carcinogenicity can be activated in the body during chemical transformations. At the same time, some cells are capable of activating carcinogenic substances, while others are not. Carcinogens, which can do without activation and which do not have to pass through metabolic processes in the cell in order to manifest their destructive properties, should be considered as an exception. Sometimes activating reactions are referred to as a process of toxication, since the formation of genuine toxins occurs in the body.

Secondly, a violation of detoxification reactions, during which toxins are neutralized, including carcinogens, will also contribute to carcinogenesis. But even if not disturbed, these reactions can contribute to carcinogenesis. For example, carcinogens (particularly aromatic amines) are converted into esters (glycosides) of glucuronic acid and then excreted by the kidneys through the ureter into the bladder. And urine contains glucuronidase, which, by destroying glucuronic acid, promotes the release of carcinogens. Apparently, this mechanism plays an important role in the occurrence of bladder cancer under the influence of aromatic amines. Glucuronidase has been found in human and dog urine, but is absent in mice and rats, and as a consequence, humans and dogs are prone to bladder cancer, while mice and rats

Endogenous carcinogens. In the human and animal body, there are a lot of various "raw materials" for the emergence of substances that may have carcinogenic activity - these are bile acids, and vitamin D, and cholesterol, and a number of steroid hormones, in particular sex hormones. All these are ordinary components of the animal organism in which they are synthesized, undergo significant chemical changes, and are utilized by tissues, which is accompanied by a change in their chemical structure and the elimination of the remains of their metabolism from the body. At the same time, as a result of this or that metabolic disorder, instead of a normal, physiological product, say, a steroid structure, some very close, but still different product arises, with a different effect on tissues - this is how endogenous carcinogenic substances arise. As you know, people get cancer most often in 40-60 years. This age has

biological features - this is the age of menopause in the broadest sense of the term. During this period, there is not so much a cessation of the function of the gonads as their dysfunction, leading to the development of hormone-dependent tumors. Therapeutic measures with the use of hormones deserve special attention. Cases of the development of malignant tumors of the mammary gland with the immoderate administration of natural and synthetic estrogens are described not only in women (with infantilism), but also in men. It does not at all follow from this that estrogens should not be prescribed at all, however, the indications for their use in necessary cases and especially the doses of administered drugs should be well thought out.

The mechanism of action of carcinogens . It has now been established that at around 37°C (i.e. body temperature) DNA breaks are constantly occurring. These processes proceed at a fairly high rate. Consequently, the existence of a cell, even under favorable conditions, is possible only because the DNA repair (repair) system usually has time to eliminate such damage. However, under certain conditions of the cell, and primarily during its aging, the balance between the processes of DNA damage and repair is disturbed, which is the molecular genetic basis for the increase in the frequency of tumor diseases with age. Chemical carcinogens can accelerate the development of the process of spontaneous (spontaneous) DNA damage due to an increase in the rate of formation of DNA breaks, suppress the activity of mechanisms that restore the normal structure of DNA, and also change the secondary structure of DNA and the nature of its packaging in the nucleus.

There are two mechanisms of viral carcinogenesis.

The first is induced viral carcinogenesis. The essence of this mechanism is that the virus that existed outside the body enters the cell and causes tumor transformation.

The second is "natural" viral carcinogenesis. The virus that causes tumor transformation enters the cell not from the outside, but is a product of the cell itself.

induced viral carcinogenesis. Currently, more than 150 oncogenic viruses are known, which are divided into two large groups: DNA and RNA-containing. Their main common property is the ability to transform normal cells into tumor cells. RNA-containing oncoviruses (oncornaviruses) represent a larger unique group.

When a virus enters a cell, different variants of their interaction and relationships between them are possible.

1. Complete destruction of the virus in the cell - in this case, there will be no infection.

2. Complete reproduction of viral particles in the cell, i.e. replication of the virus in the cell. This phenomenon is called a productive infection and is most often encountered by infectious disease specialists. An animal species in which the virus circulates under normal conditions, being transmitted from one animal to another, is called a natural host. Natural host cells infected with a virus and productively synthesizing viruses are called permissive cells.

3. As a result of the action of protective cellular mechanisms on the virus, it is not completely reproduced; the cell is not able to completely destroy the virus, and the virus cannot fully ensure the reproduction of viral particles and destroy the cell. This often occurs when the virus enters the cells of a non-natural host, but of an animal of another species. Such cells are called nonpermissive. Consequently, the cell genome and part of the viral genome simultaneously exist and interact in the cell, which leads to a change in the properties of the cell and can lead to its tumor transformation. It has been established that productive infection and cell transformation under the action of DNA-containing oncoviruses are usually mutually exclusive: cells of the natural host are mainly infected productively (permissive cells), while cells of another species are more often transformed (non-permissive cells).

AT it is now generally accepted that abortive infection, i.e. interruption of the full cycle of oncovirus reproduction at any stage is an obligatory factor causing the tumor

cell transformation. Such interruption of the cycle can occur when a full infectious virus infects genetically resistant cells, when a defective virus infects permissive cells, and, finally, when a full virus infects susceptible cells under unusual (non-permissive) conditions, for example, at high temperature (42°C).

Cells transformed with DNA-containing oncoviruses, as a rule, do not replicate (do not reproduce) the infectious virus, but in such neoplastically altered cells, a certain function of the viral genome is constantly realized. It turned out that it is precisely this abortive form of the relationship between the virus and the cell that creates favorable conditions for embedding, incorporating the viral genome into the cellular one. To resolve the issue of the nature of the incorporation of the virus genome into the DNA of a cell, it is necessary to answer the following questions: when, where, and how does this integration take place?

The first question is when? – refers to the phase of the cell cycle during which the process of integration is possible. This is possible in the S phase of the cell cycle, because during this period individual DNA fragments are synthesized, which are then combined into a single strand using the DNA ligase enzyme. If among such fragments of cellular DNA there are also fragments of a DNA containing oncovirus, then they can also be included in the newly synthesized DNA molecule and it will have new properties that change the properties of the cell and lead to its tumor transformation. It is possible that the DNA of an oncovirus, having penetrated into a normal cell not in the S-phase, is first in a state of "rest" in anticipation of the S-phase, when it mixes with fragments of the synthesized cellular DNA, in order to then be included in the cellular DNA with the help of DNA- ligases.

The second question is where? – refers to the place where the DNA of the oncogene virus is incorporated into the cell genome. Experiments have shown that it occurs in regulatory genes. The inclusion of the oncovirus genome in the structural genes is unlikely.

The third question is how is the integration going?

follows logically from the previous one. The minimal structural unit of DNA from which information is read out, the transcripton, is represented by the regulatory and structural zones. The reading of information by DNA-dependent RNA polymerase starts from the regulatory zone and proceeds towards the structural zone. The point from which the process begins is called the promoter. If a DNA virus is included in a transcripton, it contains two

motors are cellular and viral, and information reading starts from the viral promoter.

AT case of integration of oncovirus DNA between the regulatory

and structural zones RNA polymerase starts transcription from the viral promoter, bypassing the cellular promoter. As a result, a heterogeneous chimeric messenger RNA is formed, part of which corresponds to the virus genes (starting from the viral promoter), and the other part corresponds to the structural gene of the cell. Consequently, the structural gene of the cell is completely out of control of its regulatory genes; regulation is lost. If an oncogenic DNA virus is included in the regulatory zone, then part of the regulatory zone will still be translated, and then the loss of regulation will be partial. But in any case, the formation of chimeric RNA, which serves as the basis for enzyme protein synthesis, leads to a change in cell properties. According to available data, up to 6–7 viral genomes can integrate with cellular DNA. All of the above referred to DNA-containing oncogenic viruses, the genes of which are directly incorporated into the DNA of the cell. But they cause a small number of tumors. Much more tumors are caused by RNA-containing viruses, and their number is greater than that of DNA-containing ones. At the same time, it is well known that RNA cannot be incorporated into DNA by itself; therefore, carcinogenesis caused by RNA-containing viruses must have a number of features. Proceeding from the chemical impossibility of incorporating the viral RNA of oncornaviruses into cellular DNA, the American researcher H.M. Temin, Nobel Prize in 1975, based on his experimental data, suggested that oncornaviruses synthesize their own viral DNA, which is included in the cellular DNA in the same way as in the case of DNA-containing viruses. Temin called this form of DNA synthesized from viral RNA a provirus. It is probably appropriate to recall here that Temin's proviral hypothesis appeared in 1964, when the central position of molecular biology that the transfer of genetic

information goes according to the scheme DNA RNA protein. Temin's hypothesis introduced a fundamentally new stage into this scheme - DNA RNA. This theory, met by the majority of researchers with obvious mistrust and irony, nevertheless, was in good agreement with the main position of the virogenetic theory on the integration of the cellular and viral genomes, and, most importantly, explained it.

It took six years for Temin's hypothesis to receive experimental confirmation, thanks to the discovery of

ment, carrying out the synthesis of DNA on RNA, - reverse transcriptase. This enzyme has been found in many cells and has also been found in RNA viruses. It was found that the reverse transcriptase of RNA containing tumor viruses differs from conventional DNA polymerases; information about its synthesis is encoded in the viral genome; it is present only in virus-infected cells; reverse transcriptase has been found in human tumor cells; it is necessary only for tumor transformation of the cell and is not required to maintain tumor growth. When the virus enters the cell, its reverse transcriptase begins to work and the synthesis of a complete copy of the viral genome occurs - a DNA copy, which is a provirus. The synthesized provirus is then incorporated into the genome of the host cell, and then the process develops in the same way as in the case of DNA-containing viruses. In this case, the provirus can be included entirely in one DNA site, or, having decomposed into several fragments, it can be included in different regions of cellular DNA. Now, when the synthesis of cellular DNA is activated, the synthesis of viruses will always be activated.

In the body of the natural host, the complete copying of the viral genome and the synthesis of the complete virus occur from the provirus. In a non-natural organism, the provirus is partially lost and only 30–50% of the complete viral genome is transcribed, which contributes to tumor cell transformation. Consequently, in the case of RNA-containing viruses, tumor transformation is associated with abortive (interrupted) infection.

Until now, we have considered viral carcinogenesis from the standpoint of classical virology, i.e. proceeded from the fact that the virus is not a normal component of the cell, but enters it from the outside and causes its tumor transformation, i.e. induces tumor formation; therefore, such carcinogenesis is called induced viral carcinogenesis.

products of a normal cell (or, as they are called, endogenous viruses). These viral particles have all the features characteristic of oncornaviruses. At the same time, these endogenous viruses are, as a rule, apathogenic for the organism, and often they are not even infectious at all (i.e., they are not transmitted to other animals), only some of them have weak oncogenic properties.

To date, endogenous viruses have been isolated from normal cells of almost all bird species and all mouse strains, as well as rats, hamsters, guinea pigs, cats, pigs, and monkeys. It has been established that any cell can practically be a virus producer; such a cell contains the necessary information for the synthesis of an endogenous virus. The part of the normal cellular genome encoding the structural components of the virus is called the virogen (virogens).

Two main properties of virogens are inherent in all endogenous viruses: 1) ubiquitous distribution - moreover, one normal cell may contain information for the production of two or more endogenous viruses that differ from each other; 2) vertical hereditary transmission, i.e. from mother to offspring. The virogen can be included in the cellular genome not only as a single block, but also individual genes or their groups that make up the virogen as a whole can be included in different chromosomes. It is not difficult to imagine (since there is no single functioning structure) that in most cases normal cells containing a virogen in their composition do not form a complete endogenous virus, although they can synthesize its individual components in various quantities. All the functions of endogenous viruses under physiological conditions have not yet been fully elucidated, but it is known that they are used to transfer information from a cell to a cell.

The participation of endogenous viruses in carcinogenesis is mediated by various mechanisms. In accordance with the concept of R.J. Huebner and Y.J. Todaro (Hubner - Todaro) virogen contains a gene (or genes) responsible for the tumor transformation of the cell. This gene is called an oncogene. Under normal conditions, the oncogene is in an inactive (repressed) state, since its activity is blocked by repressor proteins. Carcinogenic agents (chemical compounds, radiation, etc.) lead to derepression (activation) of the corresponding genetic information, resulting in the formation of virions from the virus precursor contained in the chromosome, which can cause the transformation of a normal cell into a tumor cell. H.M. Temin based on detailed tumor studies

The study of cell transformation by the Rous sarcoma virus postulated that the virogen does not contain oncogenes; genes that determine the transformation of a normal cell into a tumor cell. These genes arise as a result of mutations in certain regions of cellular DNA (protoviruses) and the subsequent transfer of genetic information along a pathway that includes reverse transcription (DNA RNA DNA). Based on modern concepts of the molecular mechanisms of carcinogenesis, it can be argued that the mutation of a prooncogene is not the only way of its transformation into an oncogene. The inclusion (insertion) of a promoter (the DNA region that RNA polymerase binds to initiate gene transcription) near the protooncogene can lead to the same effect. In this case, the role of a promoter is played either by DNA copies of certain sections of oncornoviruses, or by mobile genetic structures or “jumping” genes, i.e. DNA segments that can move and integrate into different parts of the cell genome. The transformation of a proto-oncogene into an oncogene may also be due to amplification (lat.amplificatio - distribution, increase

- this is an increase in the number of protooncogenes that normally have a small trace activity, as a result of which the total activity of protooncogenes increases significantly) or translocation (movement) of a protooncogene to a locus with a functioning promoter. For the study of these mechanisms, the Nobel Prize in 1989.

received J.M. Bishop and H.E. Varmus.

Thus, the theory of natural oncogenesis considers viral oncogenes as genes of a normal cell. In this sense, Darlington's catchy aphorism (C.D. Darlington) "A virus is a freaked out gene" most accurately reflects the essence of natural oncogenesis.

It turned out that viral oncogenes, the existence of which was pointed out by L.A. Silber, encode proteins that are regulators of the cell cycle, processes of cell proliferation and differentiation, and apoptosis. Currently, more than a hundred oncogenes are known that encode components of intracellular signaling pathways: tyrosine and serine/threonine protein kinases, GTP-binding proteins of the Ras-MAPK signaling pathway, nuclear transcription regulatory proteins, as well as growth factors and their receptors.

The protein product of the v-src gene of the Rous sarcoma virus functions as a tyrosine protein kinase, the enzymatic activity of which determines the oncogenic properties of v-src. The protein products of five other viral oncogenes (fes/fpc ,yes ,ros ,abl ,fgr ) also turned out to be tyrosine new protein kinases. Tyrosine protein kinases are enzymes that phosphorylate various proteins (enzymes, regulatory

chromosome proteins, membrane proteins, etc.) by tyrosine residues. Tyrosine protein kinases are currently considered as the most important molecules that provide the transduction (transmission) of an external regulatory signal to intracellular metabolism; in particular, the important role of these enzymes in the activation and further triggering of the proliferation and differentiation of T- and B-lymphocytes through their antigen-recognizing receptors has been proven. One gets the impression that these enzymes and the signaling cascades triggered by them are intimately involved in the regulation of the cell cycle, the processes of proliferation and differentiation of any cells.

It turned out that normal, non-retrovirus-infected cells contain normal cell genes related to viral oncogenes. This relationship was originally established as a result of the discovery of homology in the nucleotide sequences of the transforming Rous sarcoma virus oncogene v-src (viral src ) and the normal chicken c-src gene (cellular src ). Apparently, the Rous sarcoma virus was the result of recombinations between c-src and the ancient standard avian retrovirus. This mechanism, recombination between the viral gene and the host gene, is an obvious explanation for the formation of transforming viruses. For this reason, the functions of normal genes and their role in nonviral neoplasms are of great interest to researchers. In nature, the normal forms of oncogenes are very conservative. For each of them there are human homologues, some of them are present in all eukaryotic organisms up to and including invertebrates and yeasts. Such conservatism indicates that these genes perform vital functions in normal cells, and the oncogenic potential is acquired by genes only after functionally significant changes (such as those that occur upon recombination with a retrovirus). These genes are referred to as proto-oncogenes.

Some of these genes, grouped into the ras family of cellular oncogenes, were discovered by cell transfection with DNA taken from human tumor cells. Activation of ras genes is common in some chemically induced rodent epithelial carcinomas, suggesting activation of these genes by chemical carcinogens. The important role of ras genes in the regulation of activation, proliferation, and differentiation of normal, non-tumor cells, in particular, T-lymphocytes, has been proven. Other human protooncogenes have also been identified that perform the most important functions in normal nontumor cells. Study of the proteins encoded by the virus

oncogenes and their normal cellular homologues, clarifies the mechanisms of functioning of these genes. Proteins encoded by the ras protooncogene are associated with the inner surface of the cell membrane. Their functional activity, which consists in GTP binding, is a manifestation of the functional activity of GTP-binding or G-proteins. The ras genes are phylogenetically ancient; they are present not only in the cells of mammals and other animals, but also in yeast. The main function of their products is to trigger a mitogen-activated signaling pathway that is directly involved in the regulation of cell proliferation and includes sequential cascade activation of MAPKKK (a kinase that phosphorylates MAPKK; in vertebrates, serine-threonine protein kinase Raf), MAPKK (a kinase that phosphorylates MAPK; in in vertebrates - protein kinase MEK; from English mitogen-activated and extracellularly activated kinase) and MAPK (from English mitogen-activated protein kinase; in vertebrates - protein kinase ERK; from English extracellular signal-regulated kinase) protein kinases. Therefore, it may turn out that transforming Ras proteins belong to the class of altered G proteins that transmit a constitutive growth signal.

Proteins encoded by three other oncogenes - myb, myc, fos - are located in the cell nucleus. In some, but not all cells, the normal myb homologue is expressed during the Gl phase of the cell cycle. The functioning of the other two genes seems to be closely related to the mechanisms of action of the growth factor. When stunted fibroblasts are exposed to platelet-derived growth factor, expression of a specific set of genes (estimated at 10 to 30), including the c-fos and c-myc proto-oncogenes, begins to be expressed, and cellular mRNA levels of these genes increase. Expression of c-myc is also stimulated in resting T- and B-lymphocytes after exposure to the corresponding mitogens. After the cell enters the growth cycle, c-myc expression remains almost constant. After the cell loses the ability to divide (for example, in the case of postmitotic differentiated cells), c-myc expression ceases.

An example of protooncogenes that function as growth factor receptors are genes encoding epidermal growth factor receptors. In humans, these receptors are represented by 4 proteins, designated as HER1, HER2, HER3 and HER4 (from the English human epidermal growth factor receptor). All receptor variants have a similar structure and consist of three domains: extracellular ligand-binding, transmembrane lipophilic, and intracellular

th, which has the activity of tyrosine protein kinase and is involved in signal transduction into the cell. A sharply increased expression of HER2 was found in breast cancer. Epidermal growth factors stimulate proliferation, prevent the development of apoptosis, and stimulate angiogenesis and tumor metastasis. The high therapeutic efficacy of monoclonal antibodies against the extracellular domain of HER2 (drug trastuzumab, which has passed clinical trials in the USA) in the treatment of breast cancer has been proven.

Therefore, protooncogenes can normally function as regulators of the "activation" of cell growth and differentiation and serve as nuclear targets for signals generated by growth factors. When altered or deregulated, they can provide a defining stimulus for unregulated cell growth and abnormal differentiation, which is characteristic of neoplastic conditions. The data discussed above indicate the most important role of protooncogenes in the functioning of normal cells and in the regulation of their proliferation and differentiation. "Breakdown" of these mechanisms of intracellular regulation (as a result of the action of retroviruses, chemical carcinogens, radiation, etc.) can lead to malignant transformation of the cell.

In addition to proto-oncogenes that control cell proliferation, damage to growth-inhibiting tumor suppressor genes plays an important role in tumor transformation.

(eng. growth-inhibiting cancer-suppressor genes), performing the function of anti-oncogenes. In particular, many tumors have mutations in the gene encoding the synthesis of the p53 protein (p53 tumor suppressor protein), which triggers signaling pathways in normal cells that are involved in the regulation of the cell cycle (stopping the transition from the G1 phase to the S phase of the cell cycle) , induction of apoptosis processes, inhibition of angiogenesis. In tumor cells of retinoblastoma, osteosarcomas, and small cell lung cancer, there is no synthesis of the retinoblastoma protein (pRB protein) due to a mutation of the RB gene encoding this protein. This protein is involved in the regulation of the G1 phase of the cell cycle. An important role in the development of tumors is also played by the mutation of the bcl-2 genes (English anti-apoptotic protein B-cell lymphoma 2),

leading to inhibition of apoptosis.

For the occurrence of a tumor, no less important than the factors that cause it is the selective sensitivity of cells to these factors. It has been established that an indispensable prerequisite for the appearance of a tumor is the presence in the initial tissue of a population of dividing

moving cells. This is probably why mature brain neurons of an adult organism, which have completely lost the ability to divide, never form a tumor, in contrast to the glial elements of the brain. Therefore, it is clear that all factors that promote tissue proliferation also contribute to the emergence of neoplasms. The first generation of dividing cells of highly differentiated tissues is not an exact copy of parental, highly specialized cells, but turns out to be like a “step back” in the sense that it is characterized by a lower level of differentiation and some embryonic features. Later, in the process of division, they differentiate in a strictly determined direction, “ripening” to the phenotype inherent in the given tissue. These cells have a less rigid program of behavior than cells with a complete phenotype; in addition, they may be incompetent to some regulatory influences. Naturally, the genetic apparatus of these cells more easily switches to the path of tumor transformation,

and they serve as direct targets for oncogenic factors. Having turned into neoplasm elements, they retain some features that characterize the stage of ontogenetic development at which they were caught by the transition to a new state. From these positions, the increased sensitivity to oncogenic factors of embryonic tissue becomes clear, consisting entirely of immature, dividing

and differentiating elements. It also largely determines the phenomenontransplacental blastomogenesis: doses of blastomogenic chemical compounds, harmless to the pregnant female, act on the embryo, which leads to the appearance of tumors in the cub after birth.

Stage of stimulation of tumor growth

The stage of initiation is followed by the stage of stimulation of tumor growth. At the initiation stage, one cell degenerates into a tumor cell, but a whole series of cell divisions is still needed to continue tumor growth. During these repeated divisions, cells with different abilities for autonomous growth are formed. Cells that obey the regulatory influences of the body are destroyed, and cells that are most prone to autonomous growth acquire growth advantages. There is a selection, or selection of the most autonomous cells, and hence the most malignant. The growth and development of these cells is influenced by various factors – some of them accelerate the process, while others, on the contrary, inhibit it, thereby preventing the development of a tumor. Factors that in themselves

are not capable of initiating a tumor, are not able to cause tumor transformation, but stimulate the growth of tumor cells that have already arisen, are called cocarcinogens. These primarily include factors that cause proliferation, regeneration or inflammation. These are phenol, carbolic ether, hormones, turpentine, healing wounds, mechanical factors, mitogens, cell regeneration, etc. These factors cause tumor growth only after or in combination with a carcinogen, for example, cancer of the lip mucosa in pipe smokers (cocarcinogenic mechanical factor), cancer of the esophagus and stomach (mechanical and thermal factors), bladder cancer (the result of infection and irritation), primary liver carcinoma (most often based on liver cirrhosis), lung cancer (in cigarette smoke, except for carcinogens - benzpyrene and nitrosamine, contain phenols acting as cocarcinogens). concept co carcinogenesis should not be confused with the concept syncarcinogenesis, which we talked about earlier. Synergistic action of carcinogens is understood as syncarcinogenesis, i.e. substances that can cause, induce a tumor. These substances are capable of replacing each other in tumor induction. Cocarcinogenesis refers to factors that contribute to carcinogenesis, but are not carcinogenic in and of themselves.

Tumor progression stage

Following initiation and stimulation, the stage of tumor progression begins. Progression is a steady increase in the malignant properties of a tumor during its growth in the host organism. Since a tumor is a clone of cells originating from a single parent cell, therefore, both the growth and progression of the tumor obey the general biological laws of clonal growth. First of all, several cell pools, or several groups of cells, can be distinguished in a tumor: a pool of stem cells, a pool of proliferating cells, a pool of non-proliferating cells, and a pool of lost cells.

Stem cell pool. This population of tumor cells has three properties: 1) the ability to self-maintenance, i.e. the ability to persist indefinitely in the absence of cell supply: 2) the ability to produce differentiated cells; 3) the ability to restore the normal number of cells after damage. Only stem cells have an unlimited proliferative potential, while non-stem proliferating cells inevitably die after a series of divisions. Sle

Consequently, stem cells in tumors can be defined as cells capable of unlimited proliferation and resumption of tumor growth after injury, metastasis, and inoculation into other animals.

Pool of proliferating cells. The proliferative pool (or growth fraction) is the proportion of cells currently participating in proliferation, i.e. in the mitotic cycle. The concept of a proliferative pool in tumors has become widespread in recent years. It is of great importance in connection with the problem of treating tumors. This is due to the fact that many active antitumor agents act mainly on dividing cells, and the size of the proliferative pool may be one of the factors determining the development of tumor treatment regimens. When studying the proliferative activity of tumor cells, it turned out that the duration of the cycle in such cells is shorter, and the proliferative pool of cells is larger than in normal tissue, but at the same time, both of these indicators never reach the values ​​characteristic of regenerating or stimulated normal tissue. We have no right to speak about a sharp increase in the proliferative activity of tumor cells, since normal tissue can proliferate and proliferate during regeneration more intensively than the tumor grows.

Pool of non-proliferating cells . Represented by two types of cells. On the one hand, these are cells that are capable of dividing, but have exited the cell cycle and entered the G stage. 0 , or a phase in which. The main factor determining the appearance of these cells in tumors is insufficient blood supply, leading to hypoxia. The stroma of tumors grows more slowly than the parenchyma. As tumors grow, they outgrow their own blood supply, which leads to a decrease in the proliferative pool. On the other hand, the pool of non-proliferating cells is represented by maturing cells; some of the tumor cells are capable of maturation and maturation to mature cell forms. However, during normal proliferation in an adult organism in the absence of regeneration, there is an equilibrium between dividing and maturing cells. In this state, 50% of the cells formed during division are differentiated, which means that they lose the ability to reproduce. In tumors, the pool of maturing cells decreases; less than 50% of cells differentiate, which is a prerequisite for progressive growth. The mechanism of this disruption remains unclear.

The pool of lost cells. The phenomenon of cell loss in tumors has been known for a long time, it is determined by three different processes: cell death, metastasis, maturation and sloughing of cells (more typical for tumors of the gastrointestinal tract and skin). Obviously, for most tumors, the main mechanism of cell loss is cell death. In tumors, it can proceed in two ways: 1) in the presence of a zone of necrosis, cells continuously die at the border of this zone, which leads to an increase in the amount of necrotic material; 2) death of isolated cells away from the necrosis zone. Four main mechanisms can lead to cell death:

1) internal defects of tumor cells, i.e. cell DNA defects;

2) maturation of cells as a result of the preservation in tumors of a process characteristic of normal tissues; 3) insufficiency of blood supply resulting from the lag of vascular growth from tumor growth (the most important mechanism of cell death in tumors); 4) immune destruction of tumor cells.

The state of the above pools of cells that make up the tumor determines the tumor progression. The laws of this tumor progression were formulated in 1949 by L. Foulds as six rules for the development of irreversible qualitative changes in a tumor, leading to the accumulation of malignancy (malignancy).

Rule 1. Tumors arise independently of each other (the processes of malignancy proceed independently of each other in different tumors in the same animal).

Rule 2. Progression in this tumor does not depend on the dynamics of the process in other tumors of the same organism.

Rule 3. The processes of malignancy do not depend on tumor growth.

Notes:

a) during the primary manifestation, the tumor may be at a different stage of malignancy; b) irreversible qualitative changes that occur in

tumors are independent of tumor size.

Rule 4. The progression of the tumor can be carried out either gradually or abruptly, suddenly.

Rule 5. The progression of the tumor (or the change in the properties of the tumor) goes in one (alternative) direction.

Rule 6. Tumor progression does not always reach its end point of development during the life of the host.

From the foregoing, it follows that tumor progression is associated with the continuous division of tumor cells, in the process of

After that, cells appear that differ in their properties from the original tumor cells. First of all, this concerns biochemical shifts in the tumor cell: not so much new biochemical reactions or processes arise in the tumor, but there is a change in the ratio between the processes occurring in the cells of normal, unaltered tissue.

In tumor cells, a decrease in respiration processes is observed (according to Otto Warburg, 1955, respiratory failure is the basis of tumor cell transformation). The lack of energy resulting from a decrease in respiration forces the cell to somehow make up for energy losses. This leads to the activation of aerobic and anaerobic glycolysis. The reasons for the increase in the intensity of glycolysis are an increase in the activity of hexokinase and the absence of cytoplasmic glycerophosphate dehydrogenase. It is believed that about 50% of the energy needs of tumor cells are covered by glycolysis. The formation of glycolysis products (lactic acid) in the tumor tissue causes acidosis. The breakdown of glucose in the cell also proceeds along the pentose phosphate pathway. Of the oxidative reactions in the cell, the breakdown of fatty acids and amino acids is carried out. In the tumor, the activity of anabolic enzymes of nucleic acid metabolism is sharply increased, which indicates an increase in their synthesis.

Most tumor cells proliferate. Due to increased cell proliferation, protein synthesis is enhanced. However, in the tumor cell, in addition to the usual cellular proteins, new proteins begin to be synthesized that are absent in the normal original tissue, this is a consequence of dedifferentiation tumor cells, in their properties they begin to approach embryonic cells and progenitor cells. Tumor-specific proteins are similar to embryonic proteins. Their determination is important for the early diagnosis of malignant neoplasms. As an example, Yu.S. Tatarinov and G.I. Abelev is a fetoprotein that is not detected in the blood serum of healthy adults, but is found with great constancy in some forms of liver cancer, as well as in excessive liver regeneration under conditions of damage. The effectiveness of their proposed reaction was confirmed by the WHO verification. Another protein isolated by Yu.S. Tatarinov, is a trophoblastic 1-glycoprotein, an increase in the synthesis of which is observed in tumors and pregnancy. An important diagnostic value is the determination of carcinoembryonic proteins.

kov with different molecular weight, cancer embryonic antigen, etc.

At the same time, damage to the DNA structure leads to the fact that the cell loses the ability to synthesize some proteins that it synthesized under normal conditions. And since enzymes are proteins, the cell loses a number of specific enzymes and, as a result, a number of specific functions. In turn, this leads to alignment or leveling of the enzymatic spectrum of various cells that make up the tumor. Tumor cells have a relatively uniform enzyme spectrum, which reflects their dedifferentiation.

A number of properties specific to tumors and their constituent cells can be identified.

1. Uncontrolled cell proliferation. This property is an essential feature of any tumor. The tumor develops at the expense of the body's resources and with the direct participation of humoral factors. host organism, but this growth is not caused or conditioned by his needs; on the contrary, the development of a tumor not only does not maintain the body's homeostasis, but also has a constant tendency to disturb it. This means that by uncontrolled growth they mean growth that is not due to the needs of the body. At the same time, local and systemic limiting factors can affect the tumor as a whole, slow down the growth rate, and determine the number of cells proliferating in it. Slowdown of tumor growth can also proceed along the path of increased destruction of tumor cells (as, for example, in mouse and rat hepatomas, which lose up to 90% of divided cells during each mitotic cycle). Today we no longer have the right to speak, as our predecessors did 10–20 years ago, that tumor cells are generally not sensitive to regulatory stimuli and influences. Thus, until recently it was believed that tumor cells completely lose their ability to contact inhibition; are not amenable to the inhibiting division of the influence of neighboring cells (a dividing cell, upon contact with a neighboring cell, under normal conditions, stops dividing). It turned out that the tumor cell still retains the ability to contact inhibition, only the effect occurs at a higher concentration of cells than normal and upon contact of the tumor cell with normal cells.

The tumor cell also obeys the proliferation 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, while cAMP inhibits it. In the tumor, the balance is shifted towards cGMP. Prostaglandins affect the proliferation of tumor cells through a change in the concentration of cyclic nucleotides in the cell. Finally, growth in the tumor can be influenced by serum growth factors, which are called poetins, various metabolites delivered to the tumor by the blood.

The cells and intercellular substance, which form the basis of the tumor microenvironment, have a great influence on the proliferation of tumor cells. So a tumor that grows slowly in one place of the body, being transplanted to another place, begins to grow rapidly. For example, benign Shoup rabbit papilloma, being transplanted into the same animal, but into other parts of the body (muscles, liver, spleen, stomach, under the skin), turns into a highly malignant tumor, which, infiltrating and destroying adjacent tissues, quickly leads to death of the organism.

In human pathology, there are stages when the cells of the mucous membrane enter the esophagus and take root in it. Such "dystopic" tissue tends to form tumors.

Tumor cells, however, lose the upper "limit" on the number of their divisions (the so-called Hayflick limit). Normal cells divide up to a certain maximum limit (in mammals under cell culture conditions, up to 30–50 divisions), after which they die. Tumor cells acquire the ability to endless division. The result of this phenomenon is the immortalization (“immortality”) of a given cell clone (with a limited life span of each individual cell, its component).

Therefore, unregulated growth should be considered a fundamental feature of any tumor, while all the following features, which will be discussed, are secondary - the result of tumor progression.

2. Anaplasia (from Greek ana - opposite, opposite and plasis - formation), cataplasia. Many authors believe that anaplasia, or a decrease in the level of tissue differentiation (morphological and biochemical characteristics) after its neoplastic transformation, is a characteristic feature of a malignant tumor. Tumor cells lose the ability, which is 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 traits corresponding to the stage of cell ontogeny at which it was overtaken by nonplastic transformation. This process involves tumor

cells are not to the same extent, which often leads to the formation of cells that have no analogues in normal tissue. In such cells, there is a mosaic of preserved and lost features of cells of a given level of maturity.

3. Atypism. Anaplasia is associated with atypism (from Greek a – negation and typicos – exemplary, typical) of tumor cells. There are several types of atypia.

Atypism of reproduction, due to the unregulated growth of cells mentioned earlier and the loss of the upper limit or "limit" of the number of their divisions.

Atypism of differentiation, manifested in partial or complete inhibition of cell maturation.

Morphological atypism, which is divided into cellular and tissue. In malignant cells, there is a significant variability in the size and shape of cells, the size and number of individual cell organelles, the content of DNA in cells, the shape

and number of chromosomes. In malignant tumors, along with cell atypism, there is tissue atypism, which is expressed in the fact that, compared with normal tissues, malignant tumors have a different shape and size of tissue structures. For example, the size and shape of glandular cells in tumors of glandular adenocarcinomas differ sharply from the original normal tissues. Tissue atypism without cellular atypism is typical only for benign tumors.

Metabolic and energy atypism, which includes: intensive synthesis of oncoproteins (“tumor” or “tumor” proteins); decrease in the synthesis and content of histones (transcription suppressor proteins); education not characteristic of mature

cells of embryonic proteins (including -fetoprotein); change in the method of ATP resynthesis; the appearance of substrate “traps”, which are manifested by increased uptake and consumption of glucose for energy production, amino acids for building the cytoplasm, cholesterol for building cell membranes, as well as α-tocopherol and other antioxidants for protection against free radicals and stabilization of membranes; a decrease in the concentration of the intracellular messenger cAMP in the cell.

Physicochemical atypism, which is reduced to an increase in the content of water and potassium ions in tumor cells against the background of a decrease in the concentration of calcium and magnesium ions. At the same time, an increase in the water content facilitates the diffusion of metabolic substrates

inside the cells and its products out; a decrease in the content of Ca2+ reduces intercellular adhesion, and an increase in the concentration of K+ prevents the development of intracellular acidosis caused by increased glycolysis and accumulation of lactic acid in the growing peripheral zone of the tumor, since there is an intensive exit from the decaying structures of K+ and protein.

Functional atypism, characterized by a complete or partial loss of the ability of tumor cells to produce specific products (hormones, secretions, fibers); or inadequate, inappropriate enhancement of this production (for example, an increase in insulin synthesis by insuloma, a tumor from the cells of the pancreatic islets of Langerhans); or "perversion" of the noted function (synthesis by tumor cells in breast cancer of the thyroid hormone - calciotonin or synthesis by tumor cells of lung cancer of the hormones of the anterior pituitary gland - adrenocorticotropic hormone, antidiuretic hormone, etc.). Functional atypism is usually associated with biochemical atypism.

Antigenic atypism, which manifests itself in antigenic simplification or, conversely, in the appearance of new antigens. In the first case, the tumor cells lose the antigens that were present in the original normal cells (for example, the loss of the organ-specific liver h-antigen by tumor hepatocytes), and in

the second is the emergence of new antigens (for example, -fetoprotein).

Atypism of the "interaction" of tumor cells with the body, which consists in the fact that the cells do not participate in the coordinated interconnected activity of the organs and tissues of the body, but, on the contrary, violate this harmony. For example, a combination of immunosuppression, a decrease in antitumor resistance, and potentiation of tumor growth by the immune system leads to the escape of tumor cells from the immune surveillance system. Secretion of hormones and other biologically active substances by tumor cells, deprivation of the body of essential amino acids and antioxidants, tumor stress effect, etc. aggravate the situation.

4. Invasiveness and destructive growth. The ability of tumor cells to grow (invasiveness) into the surrounding healthy tissues (destructive growth) and destroy them are characteristic features of all tumors. The tumor induces the growth of connective tissue, and this leads to the formation of the underlying tumor stroma, as it were, a "matrix", without which tumor development is impossible. Neoplasm cells

The connective tissue bath, in turn, stimulates the reproduction of tumor cells that grow into it, releasing some biologically active substances. The properties of invasiveness are, strictly speaking, nonspecific for malignant tumors. Similar processes can be observed in ordinary inflammatory reactions.

Infiltrating tumor growth leads to destruction of normal tissues adjacent to the tumor. Its mechanism is associated with the release of proteolytic enzymes (collagenase, cathepsin B, etc.), release of toxic substances, competition with normal cells for energy and plastic material (in particular, for glucose).

5. Chromosomal abnormalities. They are often found in tumor cells and may be one of the mechanisms of tumor progression.

6. Metastasis(from Greek meta - middle, statis - position). The spread of tumor cells by separation from the main focus is the main sign of malignant tumors. Usually, the activity of a tumor cell does not end in the primary tumor, sooner or later the tumor cells migrate from the compact mass of the primary tumor, are carried by the blood or lymph, and settle somewhere in the lymph node or in another tissue. There are a number of reasons for migrating.

An important reason for settling is a simple lack of space (overpopulation leads to migration): the internal pressure in the primary tumor continues to increase until cells start to be pushed out of it.

Cells entering mitosis become rounded and largely lose their connections with surrounding cells, partly due to disruption of the normal expression of cell adhesion molecules. Since a significant number of cells are dividing in the tumor at the same time, their contacts in this small area are weakened, and such cells can more easily fall out of the total mass than normal ones.

In the course of progression, tumor cells increasingly acquire the ability to grow autonomously, as a result of which they break away from the tumor.

There are the following ways of metastasis: lymphogenous, hematogenous, hematolymphogenic, "cavitary" (transfer of tumor cells by fluids in body cavities, for example, cerebrospinal fluid), implantation (direct transition of tumor cells from the tumor surface to the surface of a tissue or organ).

Whether a tumor will metastasize, and if so, when, is determined by the properties of the tumor cells and their immediate environment. However, where the released cell will migrate, where it will settle, and when a mature tumor is formed from it, a significant role belongs to the host organism. Clinicians and experimenters have long noted that metastases in the body spread unevenly, apparently giving preference to certain tissues. Thus, the spleen almost always escapes this fate, while the liver, lungs, and lymph nodes are favorite sites for metastasizing cells to settle. The addiction of some tumor cells to certain organs sometimes reaches extreme expression. For example, mouse melanoma has been described with a particular affinity for lung tissue. During transplantation of such mouse melanoma, in the paw of which the lung tissue was previously implanted, the melanoma grew only in the lung tissue, both in the implanted area and in the normal lung of the animal.

In some cases, tumor metastasis begins so early and with such a primary tumor that it overtakes its growth and all the symptoms of the disease are due to metastases. Even at autopsy, it is sometimes impossible to find the primary source of metastasis among the many tumor foci.

The very fact of the presence of tumor cells in the lymphatic and blood vessels does not predetermine the development of metastases. Numerous cases are known when at a certain stage of the course of the disease, most often under the influence of treatment, they disappear from the blood and metastases do not develop. Most of the tumor cells circulating in the vascular bed die after a certain period of time. Another part of the cells die under the action of antibodies, lymphocytes, and macrophages. And only the most insignificant part of them finds favorable conditions for their existence and reproduction.

Distinguish intraorganic, regional and distant metastases. Intraorganic metastases are detached tumor cells that are fixed in the tissues of the same organ in which the tumor has grown, and have given secondary growth. Most often, such metastasis occurs by the lymphogenous route. Regional metastases are called, which are located in the lymph nodes adjacent to the organ in which the tumor has grown. At the initial stages of tumor growth, the lymph nodes react with increasing hyperplasia of the lymphoid tissue and reticular cellular elements. As the tumor progresses, sensitized lymphoid cells migrate from the regional lymph node to more distant ones.

With the development of metastases in the lymph nodes, the proliferative and hyperplastic processes in them decrease, dystrophy of the cellular elements of the lymph node and the reproduction of tumor cells occur. The lymph nodes are enlarged. Distant metastases mark the dissemination or generalization of the tumor process and are beyond the scope of radical therapeutic action.

7. Recurrence(from lat. recedivas - return; re-development of the disease). It is based on: a) incomplete removal of tumor cells during treatment, b) implantation of tumor cells into the surrounding normal tissue, c) transfer of oncogenes into normal cells.

The listed properties of tumors determine the features of tumor growth, the features of the course of a tumor disease. In the clinic, it is customary to distinguish two types of tumor growth: benign and malignant, which have the following properties.

For benign growth typical, as a rule, is slow tumor growth with tissue expansion, absence of metastases, preservation of the structure of the original tissue, low mitotic activity of cells, and prevalence of tissue atypism.

For malignant growth usually characterized by rapid growth with destruction of the original tissue and deep penetration into the surrounding tissues, frequent metastasis, significant loss of the structure of the original tissue, high mitotic and amitotic activity of cells, the predominance of cellular atypia.

A simple enumeration of the features of benign and malignant growth indicates the conventionality of such a division of tumors. A tumor characterized by benign growth, localized in vital organs, poses no less, if not greater danger for the body than a malignant tumor localized far from vital organs. Moreover, benign tumors, especially those of epithelial origin, can become malignant. It is often possible to trace the malignancy of benign growths in humans.

From the point of view of the mechanisms of tumor progression, benign growth (i.e., a benign tumor) is a stage in this progression. It cannot be argued that a benign tumor in all cases serves as an obligatory stage in the development of a malignant tumor, but the undoubted fact that this is often the case justifies the idea of ​​a benign tumor as one of the initial phases of progression. Tumors are known to

throughout the life of the organism do not become malignant. These are, as a rule, very slowly growing tumors, and it is possible that their malignancy takes time longer than the life span of the organism.

Principles of classification of tumors

According to the clinical course, all tumors are divided into benign and malignant.

According to the histogenetic principle, which is based on determining whether a tumor belongs to a specific tissue source of development, tumors are distinguished:

epithelial tissue;

connective tissue;

muscle tissue;

melanin-forming tissue;

nervous system and membranes of the brain;

blood systems;

teratoma.

According to the histological principle, which is based on the severity of atypia, mature tumors (with a predominance of tissue atypism) and immature ones (with a predominance of cellular atypism) are distinguished.

According to the oncological principle, tumors are characterized according to the International Classification of Diseases.

According to the prevalence of the process, the characteristics of the primary focus, metastases to the lymph nodes and distant metastases are taken into account. The international TNM system is used, where T (tumor)

– characteristics of the tumor, N (nodus) – the presence of metastases in the lymph nodes, M (metastasis) – the presence of distant metastases.

The immune system and tumor growth

Tumor cells change their antigenic composition, which has been repeatedly shown (in particular, in the works of Academician L.A. Zilber, who founded the first scientific laboratory of tumor immunology in our country in the 1950s). Consequently, the process must inevitably include the immune system, one of the most important functions of which is censorship, i.e. detection and destruction of the “foreign” in the body. Tumor cells that have changed their antigenic composition represent this “foreign” subject to destruction.

niyu. Tumor transformation occurs constantly and relatively often during life, but immune mechanisms eliminate or suppress the reproduction of tumor cells.

Immunohistochemical analysis of tissue sections of various human and animal tumors shows that they are often infiltrated with cells of the immune system. It has been established that in the presence of T-lymphocytes, NK-cells or myeloid dendritic cells in the tumor, the prognosis is much better. For example, the frequency of five-year survival in patients with ovarian cancer in the case of detection of T lymphocytes in a tumor removed during surgery is 38%, and in the absence of T-lymphocyte infiltration of the tumor, only 4.5%. In patients with gastric cancer, the same indicator with tumor infiltration by NK cells or dendritic cells is 75% and 78%, respectively, and with low infiltration by these cells, 50% and 43%, respectively.

Conventionally, two groups of mechanisms of antitumor immunity are distinguished: natural resistance and the development of an immune response.

The leading role in the mechanisms of natural resistance belongs to NK cells, as well as activated macrophages and granulocytes. These cells have natural and antibody dependent cellular cytotoxicity towards tumor cells. Due to the fact that the manifestation of this action does not require long-term differentiation and antigen-dependent proliferation of the corresponding cells, the mechanisms of natural resistance form the first echelon of the antitumor defense of the body, since they are always included in it immediately.

The main role in the elimination of tumor cells during the development of the immune response is played by effector T-lymphocytes, which form the second defense echelon. It should be emphasized that the development of an immune response ending in an increase in the number of cytotoxic T-lymphocytes (synonym: T-killers) and T-effectors of delayed-type hypersensitivity (synonym: activated pro-inflammatory Th1-lymphocytes) requires from 4 to 12 days. This is due to the processes of activation, proliferation and differentiation of cells of the corresponding clones of T-lymphocytes. Despite the duration of the development of the immune response, it is he who provides the second echelon of the body's defense. The latter, due to the high specificity of antigen-recognizing receptors of T-lymphocytes, a significant increase (by thousands or hundreds of thousands of times) in the number of cells of the corresponding clones as a result of proliferation and differentiation

predecessors, is much more selective and effective. By analogy with the current weapons systems of the armies of various countries, the mechanisms of natural resistance can be compared with tank armies, and effector T-lymphocytes with high-precision space-based weapons.

Along with an increase in the number of effector T lymphocytes and their activation, the development of an immune response to tumor antigens as a result of the interaction of T and B lymphocytes leads to clonal activation, proliferation, and differentiation of B lymphocytes into plasma cells producing antibodies. The latter, in most cases, do not inhibit the growth of tumors; on the contrary, they can enhance their growth (the phenomenon of immunological enhancement associated with the “shielding” of tumor antigens). At the same time, antibodies can participate in antibody dependent cellular cytotoxicity. Tumor cells with fixed IgG antibodies are recognized by NK cells through the receptor for the IgG Fc fragment (Fc RIII, CD16). In the absence of a signal from the killer inhibitory receptor (in the case of a simultaneous decrease in the expression of class I histocompatibility molecules by tumor cells as a result of their transformation), NK cells lyse the target cell coated with antibodies. Antibody dependent cellular cytotoxicity can also involve natural antibodies that are present in the body in low titer before contact with the corresponding antigen, i.e. before the development of an immune response. The formation of natural antibodies is a consequence of the spontaneous differentiation of the corresponding clones of B-lymphocytes.

The development of a cell-mediated immune response requires a complete presentation of antigenic peptides in combination with molecules of the major histocompatibility complex I (for cytotoxic T-lymphocytes) and class II (for Th1-lymphocytes) and additional costimulatory signals (in particular, signals involving CD80/CD86) . T-lymphocytes receive this set of signals when interacting with professional antigen-presenting cells (dendritic cells and macrophages). Therefore, the development of an immune response requires infiltration of the tumor not only by T lymphocytes, but also by dendritic and NK cells. Activated NK cells lyse tumor cells that express ligands for killer-activating receptors and have reduced expression of class I major histocompatibility complex molecules (the latter act as a ligand for killer-inhibitory receptors). Activation of NK cells also leads to the secretion of IFN-, TNF-,

granulocyte-monocyte colony stimulating factor (GM-CSF), chemokines. In turn, these cytokines activate dendritic cells, which migrate to regional lymph nodes and trigger the development of an immune response.

With the normal functioning of the immune system, the probability of survival of single transformed cells in the body is very low. It increases in some congenital immunodeficiency diseases associated with impaired function of natural resistance effectors, exposure to immunosuppressive agents, and aging. Influences that suppress the immune system contribute to the occurrence of tumors, and vice versa. The tumor itself has a pronounced immunosuppressive effect, sharply inhibits immunogenesis. This action is realized through the synthesis of cytokines (IL-10, transforming growth factor-), low molecular weight mediators (prostaglandins), activation of CD4+ CD25+ FOXP3+ regulatory T-lymphocytes. The possibility of a direct cytotoxic effect of tumor cells on cells of the immune system has been experimentally proven. In view of the foregoing, the normalization of the functions of the immune system in tumors is a necessary component in the complex pathogenetic treatment.

Treatment, depending on the type of tumor, its size, spread, presence or absence of metastases, includes surgery, chemotherapy and radiation therapy, which themselves can have an immunosuppressive effect. Correction of the functions of the immune system with immunomodulators should be carried out only after the end of radiation therapy and / or chemotherapy (the risk of developing drug-induced immunological tolerance to tumor antigens as a result of the destruction of antitumor clones of T-lymphocytes when their proliferation is activated before the appointment of cytostatics). In the absence of subsequent chemotherapy or radiation therapy, the use of immunomodulators in the early postoperative period (for example, myelopid lymphotropic, imunofan, polyoxidonium) can significantly reduce the number of postoperative complications.

Currently, approaches to immunotherapy of neoplasms are being intensively developed. Methods of active specific immunotherapy are being tested (introduction of vaccines from tumor cells, their extracts, purified or recombinant tumor antigens); active non-specific immunotherapy (administration of BCG vaccine, vaccines based on Corynebacterium parvum and other microorganisms to obtain an adjuvant effect and switch

Ministry of Education of the Russian Federation

Penza State University

Medical Institute

Department of Surgery

Head department of d.m.s.

"Syndrome of systemic inflammatory response»

Completed: 5th year student

Checked by: Ph.D., Associate Professor

Penza

Plan

1. The system of functional computer monitoring in the diagnosis of conditions "threatening" the development of the systemic inflammatory response syndrome

2. Conclusions and analysis

Literature

1. The system of functional computer monitoring in the diagnosis of conditions "threatening" the development of the systemic inflammatory response syndrome

Successful treatment of systemic inflammatory response syndrome and sepsis as one of its forms should be based primarily on early diagnosis. As a rule, the treatment of neglected conditions that manifested themselves in a complete clinical picture, unfortunately, is ineffective and leads mainly to unfavorable results. This provision has long been well known to practitioners, but the methods of early diagnosis of “threatening” conditions and their prevention still have no practical implementation. The strategy and tactics of early preventive therapy, that is, which patients, which drugs, at what dose and for what period should be prescribed - this is decided in its own way in each medical institution, and most often each more or less experienced doctor. Thus, the determination of early, rather even threatening signs of the development of complications, is a very important task in practical terms.

Using the criteria of the functional computer monitoring system allows us to identify a number of points in the dynamics of the clinical course, which can be decisive in determining the main trends in the development of events in the post-traumatic period. As already emphasized in the fourth chapter, in the course of the pathophysiological characterization of the identified clusters, it was possible to identify a cluster of “metabolic imbalance”, in which there is still no visible decompensation of vital functions, however, apparently, all the prerequisites for this are already being created.

The main one is the progression of the anaerobic nature of energy synthesis in the body, which is extremely unfavorable energetically (compared to aerobic) and leads to the accumulation of unoxidized products. At the heart of this phenomenon, as already noted, there are several mechanisms. The most probable is the blocking (by endotoxins) of the intracellular mechanisms of oxygen-dependent energy synthesis - the tricarboxylic acid cycle. The use of a functional monitoring system makes it possible to diagnose the signs of this pathophysiological profile at the earliest possible date.

A study using the criteria of functional computer monitoring of observations with developed systemic inflammatory response syndrome and sepsis made it possible to determine that out of 53 observations with SIRS, 43 (corresponding to 81%) were located in the zone of the “metabolic imbalance” profile - cluster B (that is, the distance from the center of a particular observation to the center of cluster B was minimal at that moment). Thus, the zone in which the distance to cluster B will be minimal, even in the absence of clinical signs of SIRS, can be considered a kind of “risk zone” for the development of this syndrome. It can probably be assumed that the development of clinical signs of the systemic inflammatory response syndrome occurs against the background of metabolic disorders characteristic of the pathophysiological profile of “metabolic imbalance”. The condition of patients, as clinical analysis shows, is characterized by instability of the main pathophysiological criteria, accompanied by rapid dynamics of the studied parameters.

In such a situation, a functional computer monitoring system becomes especially necessary. The effectiveness of its use is clearly demonstrated using the following clinical example.

Wounded S., aged 17, on March 23, 1991, was admitted to the emergency department of the military field surgery clinic 1 hour after receiving several gunshot wounds. On the way, the ambulance team injected intravenously: polyglucin - 400 ml of disol - 400 ml. atropine sulfate - 0.7 ml, prednisolone 90 mg. calypsola - 100 mg.

A preliminary examination revealed a penetrating wound with damage to the abdominal organs, ongoing intra-abdominal bleeding. During an emergency laparotomy, up to 500 ml of blood with a large amount of fecal content was found in the abdominal cavity, the intestinal loops were hyperemic. During the revision of the abdominal organs, a penetrating wound of the sigmoid colon, transverse colon, multiple penetrating wounds of the jejunum (five wounds in a 10 cm area), a penetrating wound of the antrum of the stomach, a penetrating wound of the right lobe of the liver, a penetrating wound of the gallbladder and domes of the diaphragm.

Wounds of the transverse colon and stomach were sutured, a portion of the jejunum was resected with end-to-end anastomosis, cholecystostomy was performed, and wounds of the liver and diaphragm were sutured. A section of the sigmoid colon with bullet holes was brought out in the left iliac region in the form of a double-barreled unnatural anus. A cecostomy was applied to decompress the transverse colon. Produced intubation of the small intestine nasogastrointestinal probe.

The postoperative diagnosis was formulated as follows: “Multiple combined blind bullet wounds of the pelvis, abdomen, chest, left upper limb. Through bullet wound of the left forearm, blind bullet thoracoabdominal wound with damage to the liver, gallbladder, stomach, jejunum, transverse colon and sigmoid colon, dome of the diaphragm. Ongoing intra-abdominal bleeding, diffuse fecal peritonitis, reactive phase. Alcohol intoxication. Traumatic shock 1 degree.”

Already after the completion of the operation, which lasted six hours, due to the unstable condition of the victim, esophagoscopy, thoracoscopy and pericardiocentesis were performed during the surgical intervention. The bullet was removed from the pericardial cavity. In total, the patient was under anesthesia in the operating room for 12 hours. In order to prevent wound infection, the wounded person was injected with a solution of 100 ml of metragil 2 times a day, sodium salt of ampicillin, 1 million units. 4 times a day intravenously. Given such a severe injury - ISS=36. artificial ventilation of the lungs was carried out using the “Phase-5” apparatus, intensive therapy continued, including infusion, blood transfusion, symptomatic, - cardiac glycosides, camphor preparations, corticosteroids.

25.03.91 g a day after transfer to the intensive care unit, the patient underwent studies of the criteria for SFCM, which were subsequently performed daily until the end of the acute period. The numbers indicate the sequence of the studies, and in parentheses are those clusters, the distance to which at the time of the study was minimal. At three points - 3. 4, 5 - the days of the study and the time are affixed.

2. Conclusions and analysis

The analysis of the presented trajectory shows that at the time of the first study, the wounded man was in a state as close as possible to the profile of the control values ​​- the distance is up to R=3.95.

Assessment of hemodynamic parameters: stable blood pressure within 120/60 - 120/80 mm Hg. Art. pulse rate was 114 beats/min, respiratory rate - 25-30 per 1 min. General clinical blood test: Hb - 130 g/l. erythrocytes - 4.7- 10 12 c / l. hematocrit - 0.46 l/l. leukocytes - 7.2-10 4 c / l. stab - 30%. leukocyte index of intoxication - 7.3. body temperature during the entire observation period remained within 36.2-36.7 "C.

By the way, in accordance with the decisions of the “conciliation conference”, in this situation it was possible to make a diagnosis of a systemic inflammatory reaction, however, we believe that in cases of combined trauma, a combination of all four criteria is necessary for such a diagnosis. This approach is due to the fact that in the case of severe injuries, a systemic inflammatory response is necessarily present as a component of the normal response of the body. However, with the appearance of its entire detailed picture, this process is likely to pass from the physiological to the pathological.

The analysis of biochemical parameters indicated that almost all indicators remained within normal limits (the activity of alanine aminotransferase and aspartate aminotransferase was slightly increased). The total infusion was 4.320 ml. Daily diuresis - 2.2 liters without the use of diuretics. From the first day after the injury, in order to prevent the development of disseminated intravascular coagulation, the patient began to receive anticoagulant therapy - heparin and trental. To treat peritonitis and prevent its progression, the lymphatic duct was drained in the first interdigital space on the rear of the foot, and antegrade endolymphatic therapy was started, which included heparin, metrogil, and ampicillin.

The minimum distance to the R profile (the profile of normal values) during this period can be interpreted as the result of the complex efforts of surgeons and resuscitators to stabilize the condition of this wounded man, which did not allow the full development of pathological processes that appeared at the time of injury - peritonitis, acute respiratory and cardiac failure. At the same time, it is probably too early to consider that all the difficulties of the post-traumatic period are over, as evidenced by the high score of ARACNE II - 10.

On the second day after the injury, a sharp increase in cardiac activity is determined, with an increase in one-time (SRLZh_I=98.85 g/m 2) and minute (CI=6.15 d/(min-m 2)) productivity, which is so characteristic of the hyperdynamic stress response pattern. Based on these data, it can be stated that on the second day there was a development of the very stress reaction that should accompany the injury. According to the results of the analyzes, there is a slight decrease in the severity of the shift of the leukocyte formula to the left - the number of stab leukocytes decreased to 209 g. the level of the leukocyte index of intoxication decreased to 5.2. there is a decrease in the integral indicator for assessing the severity of the condition - according to the APACNE II scale, it is equal to 1 point. Volume infusion therapy was planned in the amount of 2800 ml. However, at 15:00, against the background of infusion therapy, a rise in body temperature to 38.8 ° C was recorded. In connection with this (hyperthermia was regarded as a reaction to the transfusion of the infusion medium), it was decided to refuse further therapy. The patient was diagnosed with “the presence of fluid in the left pleural cavity.” Against this background, from 7 am on March 27, the patient had an increase in blood pressure from 130 to 160 mm Hg. profile (in the system of FKM criteria) of the wounded person at that moment of time shifted relative to 10.00 on March 26, 1991 due to a sharp increase in metabolic disorders in the zone closest to the “metabolic imbalance” profile. decreased cardiac output and carbon dioxide tension in venous blood decreased arteriovenous oxygen gradient.

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abstract

FROMsystemic inflammatory response.Sepsis

Introduction

The term "sepsis" in a meaning close to the current understanding was first used by Hippoktas more than two thousand years ago. This term originally meant the process of tissue breakdown, inevitably accompanied by decay, disease and death.

The discoveries of Louis Pasteur, one of the founders of microbiology and immunology, played a decisive role in the transition from empirical experience to a scientific approach in the study of surgical infections. Since that time, the problem of the etiology and pathogenesis of surgical infections and sepsis has been considered from the point of view of the relationship between macro- and microorganisms.

In the works of the outstanding Russian pathologist I.V. Davydovsky, the idea of ​​the leading role of macroorganism reactivity in the pathogenesis of sepsis was clearly formulated. It was certainly a progressive step, orienting clinicians to rational therapy, aimed, on the one hand, at the eradication of the pathogen, and on the other hand, at correcting the dysfunction of organs and systems of the macroorganism.

1. ModernThese ideas about inflammation

Inflammation should be understood as a universal, phylogenetically determined reaction of the body to damage.

Inflammation has an adaptive nature, due to the reaction of the body's defense mechanisms to local damage. The classic signs of local inflammation - hyperemia, local fever, swelling, pain - are associated with:

morphological and functional rearrangement of endotheliocytes of postcapillary venules,

coagulation of blood in postcapillary venules,

adhesion and transendothelial migration of leukocytes,

complement activation,

kininogenesis,

expansion of arterioles

Degranulation of mast cells.

The cytokine network occupies a special place among inflammatory mediators.

Controlling the processes of implementation of immune and inflammatory reactivity

The main producers of cytokines are T-cells and activated macrophages, as well as, to varying degrees, other types of leukocytes, endotheliocytes of postcapillary venules, platelets and various types of stromal cells. Cytokines act primarily in the focus of inflammation and in the reacting lymphoid organs, ultimately performing a number of protective functions.

Mediators in small amounts are able to activate macrophages and platelets, stimulate the release of adhesion molecules from the endothelium and the production of growth hormone.

The developing acute phase reaction is controlled by pro-inflammatory mediators interleukins IL-1, IL-6, IL-8, TNF, as well as their endogenous antagonists, such as IL-4, IL-10, IL-13, soluble TNF receptors, called anti-inflammatory mediators. . Under normal conditions, by maintaining a balance of relationships between pro- and anti-inflammatory mediators, prerequisites are created for wound healing, the destruction of pathogenic microorganisms, and the maintenance of homeostasis. Systemic adaptive changes in acute inflammation include:

stress reactivity of the neuroendocrine system,

a fever

The release of neutrophils into the circulatory bed from the vascular and bone marrow

increased leukocytopoiesis in the bone marrow,

hyperproduction of acute phase proteins in the liver,

development of generalized forms of the immune response.

When the regulatory systems are unable to maintain homeostasis, the destructive effects of cytokines and other mediators begin to dominate, which leads to impaired capillary permeability and endothelial function, the triggering of DIC, the formation of distant foci of systemic inflammation, and the development of organ dysfunction. The cumulative effects of mediators form the systemic inflammatory response syndrome (SIR).

As criteria for a systemic inflammatory reaction that characterizes the body's response to local tissue destruction, the following are used: ESR, C-reactive protein, systemic temperature, leukocyte index of intoxication, and other indicators that have different sensitivity and specificity.

At the Consensus Conference of the American College of Pulmonologists and the Society for Critical Care Medicine, held in 1991 in Chicago, under the leadership of Roger Bone, it was proposed to consider at least three of the four unified signs as criteria for a systemic inflammatory response of the body:

* heart rate over 90 per minute;

* the frequency of respiratory movements is more than 20 in 1 minute;

* body temperature more than 38°C or less than 36°C;

* the number of leukocytes in the peripheral blood is more than 12x106 or less

4x106 or the number of immature forms is more than 10%.

The approach proposed by R. Bon to determine the systemic inflammatory response caused ambiguous responses among clinicians - from complete approval to categorical denial. The years that have passed since the publication of the decisions of the Conciliation Conference have shown that, despite numerous criticisms of this approach to the concept of systemic inflammation, it remains today the only one generally recognized and commonly used.

2. Furanism and structure of inflammation

sepsis pasteur inflammatory surgical

Inflammation can be imagined by taking a basic model in which five main links involved in the development of the inflammatory response can be distinguished:

· Clotting system activation- according to some opinions, the leading link in inflammation. With it, local hemostasis is achieved, and the Hegeman factor activated in its process (factor 12) becomes the central link in the subsequent development of the inflammatory response.

· Platelet link of hemostasis- performs the same biological function as clotting factors - stops bleeding. However, products released during platelet activation, such as thromboxane A2, prostaglandins, due to their vasoactive properties, play a crucial role in the subsequent development of inflammation.

· mast cells activated by factor XII and platelet activation products stimulate the release of histamine and other vasoactive elements. Histamine, acting directly on smooth muscles, relaxes the latter and provides vasodilation of the microvascular bed, which leads to an increase in the permeability of the vascular wall, an increase in total blood flow through this zone, while reducing blood flow velocity.

· Activation of kallikrein-kinin The system also becomes possible due to factor XII, which ensures the conversion of prekallikrein to kallikrenin, a catalyst for the synthesis of bradykinin, the action of which is also accompanied by vasodilation and an increase in the permeability of the vascular wall.

· Activation of the complement system proceeds both along the classical and alternative paths. This leads to the creation of conditions for the lysis of the cellular structures of microorganisms, in addition, activated complement elements have important vasoactive and chemoattractant properties.

The most important common property of these five different inducers of the inflammatory response is their interactivity and mutual reinforcement of the effect. This means that when any of them appear in the damage zone, all the others are activated.

Phases of inflammation.

The first phase of inflammation is the induction phase. The biological meaning of the action of inflammation activators at this stage is to prepare the transition to the second phase of inflammation - the phase of active phagocytosis. For this purpose, leukocytes, monocytes, and macrophages accumulate in the intercellular space of the lesion. The most important role in this process is played by endothelial cells.

When the endothelium is damaged, the activation of endothelial cells and the maximum synthesis of NO-synthetase occur, which as a result leads to the production of nitric oxide and the maximum dilatation of intact vessels, and the rapid movement of leukocytes and platelets to the damaged area.

The second phase of inflammation (the phase of phagocytosis) begins from the moment when the concentration of chemokines reaches a critical level necessary to create an appropriate concentration of leukocytes. when the concentration of chemokines (a protein that promotes the selective accumulation of leukocytes in the focus) reaches a critical level necessary to create an appropriate concentration of leukocytes.

The essence of this phase is the migration of leukocytes to the site of injury, as well as monocytes. monocytes reach the site of injury, where they differentiate into two distinct subpopulations, one dedicated to killing microorganisms and the other to phagocytosis of necrotic tissue. Tissue macrophages process antigens and deliver them to T- and B-cells, which are involved in the destruction of microorganisms.

Along with this, anti-inflammatory mechanisms are launched simultaneously with the onset of the act of inflammation. They include cytokines with a direct anti-inflammatory effect: IL-4, IL-10 and IL-13. There is also expression of receptor antagonists, such as the IL-1 receptor antagonist. However, the mechanisms of termination of the inflammatory response are still not fully understood. There is an opinion that it is most likely that a decrease in the activity of the processes that caused it plays a key role in stopping the inflammatory reaction.

3. Systemic inflammatory response syndrome (SIRS)

After the introduction into clinical practice of the terms and concepts proposed at the Conciliation Conference by R. Bonom and co-authors in 1991, a new stage began in the study of sepsis, its pathogenesis, principles of diagnosis and treatment. A single set of terms and concepts focused on clinical signs was defined. Based on them, at present, there are quite definite ideas about the pathogenesis of generalized inflammatory reactions. The leading concepts were "inflammation", "infection", "sepsis".

The development of the systemic inflammatory response syndrome is associated with a violation (breakthrough) of the restrictive function of local inflammation and the ingress of pro-inflammatory cytokines and inflammatory mediators into the systemic circulation.

To date, quite numerous groups of mediators are known that act as stimulators of the inflammatory process and anti-inflammatory protection. The table shows some of them.

The hypothesis of R. Bon et al. (1997) on the patterns of development of the septic process, which is currently accepted as the leading one, is based on the results of studies confirming that the activation of chemoattractants and pro-inflammatory cytokines as inducers of inflammation stimulates the release of contractors - anti-inflammatory cytokines, the main function of which is to reduce the severity of the inflammatory response.

This process, which immediately follows the activation of inflammatory inducers, is called the "anti-inflammatory compensatory response", in the original transcription - "compensatory anti-inflammatory response syndrome (CARS)". In terms of severity, the anti-inflammatory compensatory reaction can not only reach the degree of the pro-inflammatory reaction, but also exceed it.

It is known that when determining freely circulating cytokines, the probability of error is so significant (without taking into account cytokines on the cell surface-2) that this criterion cannot be used as a diagnostic criterion.

°~ for the syndrome of anti-inflammatory compensatory reaction.

Assessing the options for the clinical course of the septic process, four groups of patients can be distinguished:

1. Patients with severe injuries, burns, purulent diseases, who do not have clinical signs of systemic inflammatory response syndrome and the severity of the underlying pathology determines the course of the disease and prognosis.

2. Patients with sepsis or severe illness (trauma) who develop a moderate systemic inflammatory response syndrome, dysfunction of one or two organs occurs, which recovers quickly enough with adequate therapy.

3. Patients who rapidly develop a severe form of systemic inflammatory response syndrome, which is severe sepsis or septic shock. Mortality in this group of patients is maximum.

4. Patients in whom the inflammatory response to the primary injury is not so pronounced, but already a few days after the onset of signs of the infectious process, organ failure progresses (such dynamics of the inflammatory process, which has the form of two peaks, is called the "double-humped curve"). Mortality in this group of patients is also quite high.

However, can such significant differences in the variants of the clinical course of sepsis be explained by the activity of pro-inflammatory mediators? The answer to this question is given by the hypothesis of the pathogenesis of the septic process, proposed by R. Bon et al. In accordance with it, five phases of sepsis are distinguished:

1. Local reaction to injury or infection. Primary mechanical damage leads to the activation of pro-inflammatory mediators, which are characterized by multiple overlapping effects of interaction with each other. The main biological meaning of such a response is to objectively determine the volume of the lesion, its local limitation, and create conditions for a subsequent favorable outcome. The composition of anti-inflammatory mediators includes: IL-4,10,11,13, IL-1 receptor antagonist.

They reduce the expression of the monocytic histocompatibility complex and reduce the ability of cells to produce anti-inflammatory cytokines.

2. Primary systemic reaction. With a severe degree of primary damage, pro-inflammatory, and later anti-inflammatory mediators enter the systemic circulation. The organ disorders that occurred during this period due to the entry of pro-inflammatory mediators into the systemic circulation, as a rule, are transient and are quickly leveled.

3. Massive systemic inflammation. A decrease in the effectiveness of the regulation of the pro-inflammatory response leads to a pronounced systemic reaction, clinically manifested by signs of a systemic inflammatory response syndrome. The basis of these manifestations may be the following pathophysiological changes:

* progressive dysfunction of the endothelium, leading to an increase in microvascular permeability;

* stasis and platelet aggregation, leading to blockage of the microvasculature, redistribution of blood flow and, following ischemia, postperfusion disorders;

* activation of the coagulation system;

* deep vasodilation, extravasation of fluid into the intercellular space, accompanied by a redistribution of blood flow and the development of shock. The initial consequence of this is organ dysfunction, which develops into organ failure.

4. Excessive immunosuppression. Overactivation of the anti-inflammatory system is not uncommon. In domestic publications, it is known as hypoergy or anergy. In foreign literature, this condition is called immunoparalysis or “window to immunodeficiency”. R. Bon with co-authors proposed to call this condition the syndrome of anti-inflammatory compensatory reaction, investing in its meaning a broader meaning than immunoparalysis. The predominance of anti-inflammatory cytokines does not allow the development of excessive, pathological inflammation, as well as the normal inflammatory process that is necessary to complete the wound process. It is this reaction of the body that is the cause of long-term non-healing wounds with a large number of pathological granulations. In this case, it seems that the process of reparative regeneration has stopped.

5. Immunological dissonance. The final stage of multiple organ failure is called the “phase of immunological dissonance”. During this period, both progressive inflammation and its opposite state, a deep syndrome of anti-inflammatory compensatory reaction, can occur. The lack of a stable balance is the most characteristic feature of this phase.

According to acad. RAS and RAMS V.S. Saveliev and Corresponding Member. RAMS A.I. Kiriyenko's hypothesis above, the balance between pro-inflammatory and anti-inflammatory systems can be disturbed in one of three cases:

*when infection, severe injury, bleeding, etc. so strong that this is quite enough for a massive generalization of the process, systemic inflammatory response syndrome, multiple organ failure;

* when, due to a previous serious illness or injury, patients are already “prepared” for the development of a systemic inflammatory response syndrome and multiple organ failure;

* when the pre-existing (background) state of the patient is closely related precisely to the pathological level of cytokines.

According to the concept of acad. RAS and RAMS V.S. Saveliev and Corresponding Member. RAMS A.I. Kirienko, pathogenesis clinical manifestations depends on the ratio of the cascade of pro-inflammatory (for a systemic inflammatory response) and anti-inflammatory mediators (for an anti-inflammatory compensatory response). The form of clinical manifestation of this multifactorial interaction is the severity of multiple organ failure, determined on the basis of one of the international agreed scales (APACHE, SOFA, etc.). In accordance with this, three gradations of severity of sepsis are distinguished: sepsis, severe sepsis, septic shock.

Diagnostics

According to the decisions of the Conciliation Conference, the severity of systemic violations is determined based on the following settings.

The diagnosis of "sepsis" is proposed to be established in the presence of two or more symptoms of a systemic inflammatory reaction with a proven infectious process (this includes verified bacteremia).

The diagnosis of "severe sepsis" is proposed to be established in the presence of organ failure in a patient with sepsis.

The diagnosis of organ failure is made on the basis of agreed criteria that formed the basis of the SOFA scale (Sepsis oriented failure assessment)

Treatment

A decisive shift in treatment methodology occurred after the agreed definitions of sepsis, severe sepsis and septic shock.

This allowed different researchers to speak the same language using the same concepts and terms. The second most important factor was the introduction of the principles of evidence-based medicine into clinical practice. These two circumstances led to the development of evidence-based recommendations for the treatment of sepsis, published in 2003 and called the "Barcelona Declaration". It announced the creation of an international program known as the "Movement for effective treatment sepsis” (Surviving sepsis campaign).

Primary intensive care measures. Aimed at achieving in the first 6 hours of intensive care (activities begin immediately after diagnosis) the following parameter values:

* CVP 8-12 mm Hg. Art.;

* Mean BP >65 mmHg Art.;

* the amount of urine excreted> 0.5 mlDkghh);

* saturation of mixed venous blood >70%.

If the transfusion of various infusion media fails to achieve an increase in CVP and the level of saturation of mixed venous blood to the indicated figures, then it is recommended:

* transfusion of erythromass to achieve a hematocrit level of 30%;

* infusion of dobutamine at a dose of 20 mcg/kg per minute.

Carrying out the specified complex of measures allows to reduce mortality from 49.2 to 33.3%.

Antibiotic therapy

* All samples for microbiological studies are taken immediately upon admission of the patient, before the start of antibiotic therapy.

*Treatment with antibiotics a wide range actions begin within the first hour after diagnosis.

*Depending on the results obtained microbiological research after 48-72 h regimen used antibacterial drugs 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 source control measures, which include three groups of surgical interventions:

1. Drainage of the abscess cavity. An abscess is formed as a result of triggering an inflammatory cascade and the formation of a fibrin capsule surrounding a fluid substrate consisting of necrotic tissue, polymorphonuclear leukocytes and microorganisms and well known to clinicians as pus.

Drainage of an abscess is a mandatory procedure.

2. Secondary debridement(necrectomy). Removal of necrotic tissues involved in the infectious process is one of the main tasks in achieving source control.

3. Removal foreign bodies supporting (initiating) the infectious process.

To the main directions of treatment of severe sepsis and septic shock, received evidence base and reflected in the documents of the "Movement for effective treatment of sepsis", include:

Infusion therapy algorithm;

The use of vasopressors;

Inotropic therapy algorithm;

Use of low doses of steroids;

Use of recombinant activated protein C;

Transfusion therapy algorithm;

Algorithm of mechanical ventilation in the syndrome acute injury lungs / respiratory - adult distress syndrome (ADS / ARDS);

Protocol for sedation and analgesia in patients with severe sepsis;

Glycemic control protocol;

Protocol for the treatment of acute renal failure;

Bicarbonate protocol;

Prevention of deep vein thrombosis;

Prevention of stress ulcers.

Conclusion

Inflammation is a necessary component of reparative regeneration, without which the healing process is impossible. However, according to all the canons of the modern interpretation of sepsis, it must be considered as pathological process that needs to be fought. This conflict is well understood by all leading experts in sepsis, so in 2001 an attempt was made to develop a new approach to sepsis, essentially continuing and developing R. Bohn's theory. This approach is called the PIRO concept (PIRO - predisposition infection response outcome). The letter P stands for predisposition ( genetic factors, preceding chronic diseases etc.), I - infection (type of microorganisms, localization of the process, etc.), P - result (outcome of the process) and O - response (nature of the response various systems body for infection). Such an interpretation seems to be very promising, however, the complexity, heterogeneity of the process and the extreme breadth of clinical manifestations have not made it possible to unify and formalize these signs so far. Understanding the limitations of the interpretation proposed by R. Bon, it is widely used on the basis of two ideas.

First, there is no doubt that severe sepsis is the result of the interaction of microorganisms and a macroorganism, which entailed a violation of the functions of one or several leading life support systems, which is recognized by all scientists involved in this problem.

Secondly, the simplicity and convenience of the approach used in the diagnosis of severe sepsis (criteria for a systemic inflammatory response, infectious process, criteria for diagnosing organ disorders) make it possible to single out more or less homogeneous groups of patients. The use of this approach has made it possible today to get rid of such ambiguously defined concepts as "septicemia", "septicopyemia", "chroniosepsis", "refractory septic shock".

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History of occurrenceSIRS, concept, criteriaSIRS, modern provisions diagnosis of sepsis; modern provisionsSIRS.

Systemic Inflammatory Response Syndrome (SIRS) = Systemic Inflammatory Response Syndrome (SIRS).

In 1991, at the conciliation conference of the American Society of Thoracic Surgeons and Emergency Physicians, dedicated to the definition of sepsis, a new concept was introduced - Systemic Inflammatory Response Syndrome (SIRS) or SIRS. The terms SIRS (systemic inflammatory response syndrome) and SIRS (systemic inflammatory response) are used in the literature of the CIS countries and are similar to the term SIRS. SIRS, SIRS and SIRS are the same concept, which are clinical and laboratory manifestations of a generalized form of an inflammatory reaction. At the conciliation conference (1991), a number of SIRS provisions were developed:

Tachycardia > 90 beats per minute;

Tachypnea > 20 in 1 min. or Pa CO 2 - 32 mm Hg. Art. against the background of IVL;

Temperature > 38.0 deg. C or< 36,0 град. С;

The number of leukocytes in peripheral blood > 12 × 10 9 / l or< 4 × 10 9 / л либо число незрелых форм > 10%;

The diagnosis of SIRS is stated only in those cases when a focus of infection and two or more of the above two criteria (signs) are identified;

The difference between SIRS and sepsis was determined - at the initial stages of the inflammatory process in SIRS, the infectious component may be absent, and in sepsis, a generalized intravascular infection, which is characterized by bacteremia, must be present.

In the initial stages of a generalized form of inflammation, SIRS is formed by excessive activation of polypeptide and other mediators, as well as their cells, which form a cytokine network.

In the future, generalized inflammation progresses, the protective function of the local inflammatory focus is lost, and the mechanisms of systemic alteration come into play at the same time.

A cytokine network is a complex of functionally related cells, consisting of polymorphonuclear leukocytes, monocytes, macrophages and lymphocytes that secrete cytokines and other inflammatory mediators (tissue inflammatory mediators, immune systemokine lymphokines, and other biologically active substances), as well as from cells (in this group includes endotheliocytes) of any functional specialization that respond to the actions of activating agents.

In connection with the emergence scientific works in 1991-2001 devoted to the problem of SIRS, the recommendations of the conciliation conference in Chicago (1991) were found to be too broad and not specific enough. At the last conference in 2001 (Washington), devoted to the development of a new approach to the definition of sepsis, it was recognized that there is no complete identity between SIRS and sepsis. And also, for practical medicine, it was proposed to use additional (in relation to SIRS) extended criteria for the diagnosis of sepsis; the latter consist of key and inflammatory changes, changes in hemodynamics, manifestations of organ dysfunction, and indicators of tissue hypoperfusion. Before the advent of extended criteria for the diagnosis of sepsis (until 2001), the diagnosis of "sepsis" was eligible in the presence of a focus of infection and two criteria. By the decision of the conference from 2001 (Washington) and at the present time, the diagnosis of "sepsis" is made in the presence of a focus of infection and in the presence of signs of organ dysfunction taking place in at least one organ system in combination with a decrease in tissue perfusion.