Necrosis - It is an irreversible process, which is characterized by the death of individual cells, parts of organs and tissues in a living organism.
Causes of necrosis. Factors causing necrosis:
- physical (gunshot wound, radiation, electricity, low and high temperatures - frostbite and burn),
- toxic (acids, alkalis, salts of heavy metals, enzymes, drugs, ethyl alcohol, etc.),
- biological (bacteria, viruses, protozoa, etc.),
- allergic (endo- and exo-antigens, for example, fibrinoid necrosis in infectious-allergic and autoimmune diseases, the Arthus phenomenon),
- vascular (heart attack - vascular necrosis),
- trophaneurotic (bedsores, non-healing ulcers).
Depending on the mechanism of action pathogenic factor distinguish:
- direct necrosisdue to the direct action of a factor (traumatic, toxic and biological necrosis),
- indirect necrosis, which occurs indirectly through the vascular and neuro-endocrine systems (allergic, vascular and trophaneurotic necrosis).
Etiological types of necrosis:
- traumatic - occurs when physical and chemical factors act
- toxic - occurs when the action of toxins of bacterial and other nature,
- trophaneurotic - associated with impaired microcirculation and innervation of tissues,
- allergic - develops with immunopathological reactions,
- vascular - associated with impaired blood supply to the organ or tissue.
Of all the variety of pathogenetic pathways of necrosis, probably the five most significant can be distinguished:
- binding of cellular proteins to ubiquitin (a small conservative protein that, in eukaryotes, attaches to proteins),
- ATP deficiency,
- generation of reactive oxygen species
- violation of calcium homeostasis,
- loss of cell membranes selective permeability.
The necrotic process goes through a series of morphogenetic stages: paranecrosis, necrobiosis, cell death, autolysis.
Paranecrosis - similar necrotic, but reversible changes.
Necrobiosis - irreversible dystrophic changes, characterized by the predominance of catabolic reactions over anabolic. Anabolism (from the Greek. anabolē - lifting), a set of chemical processes that make up one of the sides of the body's metabolism, aimed at the formation of the constituent parts of cells and tissues. Catabolism (from the Greek. καταβολη, "base, basis") or energy metabolism - the process of metabolic decay, decomposition into simpler substances (differentiation) or oxidation of any substance, usually proceeding with the release of energy in the form of heat and in the form of ATP ..
Autolysis - decomposition of the dead substrate under the action of hydrolytic enzymes of dead cells and cells of the inflammatory infiltrate
Morphological signs of necrosis.
Necrosis is preceded by a period of necrobiosis, the morphological substrate of which is dystrophic changes. (dystrophy → necrosis).
Clinical and morphological forms of necrosis
Necrosis is manifested by various clinical and morphological changes. Differences depend on the structural and functional characteristics of organs and tissues, the speed and type of necrosis, as well as the causes of its occurrence and conditions of development. Among the clinical and morphological forms of necrosis are distinguished coagulation (dry) necrosis and collisional (wet) necrosis.
Coagulation necrosis usually occurs in organs rich in proteins and poor in fluids, for example, in the kidneys, myocardium, adrenal glands, spleen, usually as a result of insufficient blood circulation and anoxia (lack of oxygen), physical, chemical and other damaging factors, for example, coagulative necrosis of liver cells with viral damage or by the action of toxic agents of bacterial and non-bacterial origin.
(The mechanism of coagulation necrosis is not clear enough. Coagulation of cytoplasmic proteins makes them resistant to the action of lysosomal enzymes and, therefore, their liquefaction slows down.)
TO coagulation necrosis include:
1) Heart attack - a type of vascular (ischemic) necrosis of internal organs (except for the brain - stroke). This is the most common type of necrosis.
2) Cheesy (cheesy) necrosis also develops in tuberculosis, syphilis, leprosy, and lymphogranulomatosis. It is also called specific, since it is most often found with specific infectious granulomas. In the internal organs revealed a limited area of tissue dry, crumbling, whitish-yellow. In syphilitic granulomas, very often such areas are not crumbly, but rather pasty, resemble Arabian glue. This is a mixed (that is, extra- and intracellular) type of necrosis, in which both the parenchyma and the stroma (and cells and fibers) simultaneously die. Microscopically, such a piece of tissue is structureless, homogeneous, stained with hematoxylin and eosin in a pink color, clumps of chromatin nuclei (karyorrhexis) are clearly visible.
3) Waxyor Tsenker necrosis (muscle necrosis, usually the anterior abdominal wall and thigh, in severe infections - typhoid and typhus, cholera),
4) Fibrinoid necrosis is a type of connective tissue necrosis, which has already been studied as the outcome of fibrinoid swelling, most often it is observed in allergic and autoimmune diseases (for example, rheumatism, rheumatoid arthritis and systemic lupus erythematosus). Collagen fibers and smooth muscles of the middle lining of blood vessels are most severely damaged. Fibrinoid necrosis of arterioles occurs with malignant hypertension. Fibrinoid necrosis is characterized by a loss of normal structure and the accumulation of a homogeneous, bright pink necrotic material that is microscopically similar to fibrin. Note that the term "fibrinoid" is different from the concept of "fibrinous", since the latter refers to the accumulation of fibrin, for example, during blood coagulation or during inflammation. The areas of fibrinoid necrosis contain different amounts of immunoglobulins and complement, albumin, collagen and fibrin breakdown products.
5) Fatty necrosis:
- enzymatic fat necrosis (most often occurs in acute pancreatitis and pancreatic injuries),
- non-enzymatic fat necrosis (observed in the mammary gland, subcutaneous adipose tissue and in the abdominal cavity).
6) Gangrene (from the Greek. gangraina - fire): it is a necrosis of tissues communicating with the external environment and changing under its influence. The term "gangrene" is widely used to denote a clinico-morphological state in which tissue necrosis is often complicated by a secondary bacterial infection of varying severity, or, being in contact with the external environment, undergoes secondary changes. There are dry, wet, gas gangrene and pressure sores.
- Dry gangrene - it is necrosis of tissues in contact with the external environment, proceeding without the participation of microorganisms. Dry gangrene most often occurs on the extremities as a result of ischemic coagulation tissue necrosis.
- atherosclerotic gangrene - gangrene of the extremity in atherosclerosis and thrombosis of its arteries, obliterating endarteritis,
- with frostbite or burns,
- fingers when Raynaud's disease or vibration disease
- skin in typhus and other infections.
- Wet gangrene: develops as a result of layering on necrotic changes in the tissue of a severe bacterial infection. Wet gangrene usually develops in tissues rich in moisture. It can occur on the extremities, but more often in the internal organs, for example, in the intestines with obstruction of the mesenteric arteries (thrombosis, embolism), in the lungs as a complication of pneumonia (influenza, measles). In children weakened by an infectious disease (most often measles), wet gangrene of the soft tissues of the cheeks, the perineum, which is called the noma (from Greek nome, water cancer), can develop. As a result of the vital activity of bacteria, a specific odor occurs. A very high mortality rate.
- Gas gangrene: gas gangrene occurs when a wound is infected with anaerobic flora, for example, Clostridium perfringens and other microorganisms of this group. It is characterized by extensive tissue necrosis and the formation of gases as a result of the enzymatic activity of bacteria. The main manifestations are similar to wet gangrene, but with the additional presence of gas in the tissues. Crepitus (the phenomenon of crackling during palpation) is a frequent clinical symptom in gas gangrene. The mortality rate is also very high.
- Bedsore (decubitus): as a type of gangrene, pressure sores are released - necrosis of the superficial parts of the body (skin, soft tissues), which are subjected to compression between the bed and the bone. Therefore, bedsores often appear in the sacrum, spinous processes of the vertebrae, the greater trochanter of the femur. In its genesis, it is trophanevrotic necrosis, because the vessels and nerves are compressed, which aggravates tissue trophism disorders in seriously ill patients suffering from cardiovascular, oncological, infectious or nervous diseases.
Colliquational (Wet) Necrosis: characterized by the melting of dead tissue. It develops in tissues that are relatively poor in proteins and rich in liquid, where there are favorable conditions for hydrolytic processes. Cell lysis occurs as a result of the action of its own enzymes (autolysis). A typical example of a wet colliquation necrosis is the center of gray softening (ischemic infarction) of the brain.
Necrosis Outcomes mainly associated with the processes of delimitation and reparation, spreading from the zone of demarcation inflammation.
- necrotic cells are fragmented and removed by phagocytes (macrophages and leukocytes) and proteolysis by lysosomal leukocyte enzymes,
- organization (scarring) - replacement of necrotic masses with connective tissue,
- encapsulation - delimitation of the area of necrosis connective tissue capsule,
- petrification (calcification) - soaking the area of necrosis with calcium salts (dystrophic calcification) (if the cells or their residues are not completely destroyed and not reabsorbed),
- ossification - the appearance of bone tissue in the area of necrosis (very rarely, in particular, in Gon foci - healed foci of primary tuberculosis),
- cyst formation (in the outcome of colliquation necrosis),
- purulent fusion of necrotic masses with the possible development of sepsis.
Adverse Necrosis Outcome - purulent (septic) melting of the center of death. Sequestration is the formation of a portion of dead tissue that does not undergo autolysis, is not replaced by connective tissue, and is freely located among living tissues.
Necrosis value determined by its essence - "local death" and disabling such zones from function, therefore, necrosis of vital organs, especially large areas of them, often leads to death. These are myocardial infarctions, ischemic necrosis of the brain, necrosis of the cortical substance of the kidneys, progressive liver necrosis, acute pancreatitis, complicated by pancreatic necrosis. Often, tissue necrosis is the cause of severe complications of many diseases (rupture of the heart during myomalacia, paralysis during hemorrhagic and ischemic strokes, infections with massive bedsores, intoxication due to effects on the body of tissue breakdown, for example, gangrene of the limb, etc.). Clinical manifestations of necrosis can be very diverse. Abnormal electrical activity that occurs in areas of necrosis in the brain or myocardium can lead to epileptic seizures or cardiac arrhythmias. Peristalsis in the necrotic bowel can cause functional (dynamic) intestinal obstruction. Hemorrhages in necrotic tissue, such as hemoptysis (hemoptysis) with necrosis of the lung, are not uncommonly observed.
The metastasis stage is the final stage of tumor morphogenesis. The process of metastasis is associated with the spread of tumor cells from the primary tumor to other organs through the lymphatic, blood vessels, perineurally, implantationally, which formed the basis for the selection of metastasis.
The process of metastasis is explained by the theory of the metastatic cascade. In accordance with it, the tumor cell undergoes a chain (cascade) of rearrangements that ensure distribution to distant organs. During metastasis, the tumor cell must have certain qualities that allow it to penetrate into the adjacent tissues and vascular lumens (small veins and lymphatic vessels), separate from the tumor layer into the blood stream (lymph) in the form of cells or small groups of cells, and maintain viability after contact with specific and non-specific factors of immune protection, migrate to the venules (lymphatic vessels) and attach to their endothelium in certain organs, penetrate into microvessels and grow in a new place in a new environment.
In the metastatic cascade, the following stages can be singled out:
∨ formation of a metastatic tumor subclone,
∨ invasion into the vessel lumen,
∨ circulation of the tumor embolus in the bloodstream (lymph flow),
Settling in a new place with the development of a secondary tumor.
The process of metastasis begins with the appearance of a metastatic subclone of tumor cells with an altered plasmolemma. These cells lose cell-to-cell contact and acquire the ability to move. Then, the tumor cells migrate through the extracellular matrix, attaching with the help of integrins to laminin, fibronectin, collagen molecules of the basal membrane of the vessel, and proteolize it by isolating collagenases, cathepsin, elastase, glycosaminogrolase, plasmin, etc. This allows the tumor cells to invade the basal membrane and the membrane. to attach to its endothelium, and then, by changing its adhesive properties (suppression of adhesive molecules), to separate from the tumor layer and vessel endothelium.
The next stage is the formation of tumor emboli consisting only of tumor cells or in combination with platelets and lymphocytes. The fibrin coating of such emboli can protect tumor cells from the cells killing the immune system and the action of non-specific protection factors.
The final stage is the interaction of tumor cells with the endothelium of venules through homing receptors and CD44 molecules, attachment and proteolysis of the basement membrane, penetration into perivascular tissue and growth of the secondary tumor.
Metastasis - transfer of blastoma cells to the distance from the main (maternal) node, and the development of a tumor of the same histological structure in another tissue or organ.
This is one of the fatal manifestations of atypism of tumor growth.
♦ Lymphogenous (with lymph flow through the lymphatic vessels) is the most common way of tumor metastasis, especially carcinoma.
♦ Hematogenous (with blood flow through the blood vessels) the path is most characteristic of sarcomas.
♦ Tissue or implantation. Metastasis takes place when a tumor cell touches the surface of a normal tissue or organ (for example, when a stomach tumor contacts the surface of the peritoneum or lung cancer with the pleura), and when the blast cells in the body fluids, such as the abdominal, pleural cavity, are inserted in the cerebrospinal fluid, the surface of the organs, respectively the abdominal and thoracic cavity, the spinal cord and the brain.
Often, tumors metastasize in several ways simultaneously or sequentially.
The main stages of metastasis are:
• Separation of a malignant cell from a tumor and its invasion into the wall of a lymphatic or blood vessel (intravasation /
• Embolism - circulation in the lymphatic and blood vessels of a tumor cell with its subsequent implantation on the inner surface of the endothelium of the vessel wall.
• Invasion of the blastoma cell into the vessel wall and further into the surrounding tissue (extravasation). Subsequently, the cells proliferate and form another tumor site - metastasis.
Metastases are often characterized by organ selectivity (tropism). Thus, lung cancer cells more often metastasize to the bone, liver, brain, stomach cancer - to the ovaries, pelvic floor tissue, breast cancer - to the bone, lungs, and liver. Basically, the tropicity of metastasis is determined by: the specificity of metabolism in the organ, the peculiarities of the lymph and circulatory system, the low efficiency of the antiblastoma resistance mechanisms, positive chemotaxis.
The main types of metastases, based metastasis pathways, the following: lymphogenous, hematogenous, implantational and mixed. Some histogenetic groups of tumors (for example, sarcomas) are characterized by hematogenous metastases, for others (for example, cancers) - lymphogenous. Metastases, as a rule, grow faster than the main tumor, and therefore are often larger. The time required for the development of metastases is different. In some cases, metastases appear very quickly, after the emergence of the primary node, in others - they develop several years after its appearance. There are also so-called latent, or dormant metastases, which can develop in 7-10 years after the radical removal of the primary tumor.
1. Lymphogenous metastases - lymphogenous metastases are characteristic of cancers and melanomas, but sometimes sarcomas, for which hematogenous metastasis is more characteristic, can metastasize in this way. Malignant cells in the lymphatic ducts first enter the regional lymph nodes, where their distribution can be temporarily stopped as a result of the immune response, then during surgical treatment regional lymph nodes are removed along with the tumor, which prevents the development of early metastases.
2. Hematogenous metastases - the entry of tumor cells into the bloodstream is believed to occur in the early stages of development of many malignant neoplasms. Most of these malignant cells are thought to be destroyed by the immune system, but some of them become covered by fibrin and are retained in capillaries (anticoagulants, for example, heparin, which prevent fibrin from enveloping cells, reduce the risk of metastasis in experimental animals.) Metastasis occurs only when A sufficient number of tumor cells remain alive in the tissues. Neoplastic cell production tumor factor angiogenesis stimulates the growth of new capillaries around the tumor cells and contributes to the vascularization of growing metastasis.
3. Metastasis of the body cavities (seeding) - the entry of malignant cells into the serous cavities of the body (for example, pleura, peritoneum or pericardium) or the subarachnoid space may be accompanied by the spread of cells along these cavities (transcelomic metastases), for example, rectal and cystic space (in men) and rectal uterine space and ovaries (in women) - the most frequent localization of metastases to the peritoneum in patients with gastric cancer. To confirm metastasis, cytological examination of fluid from these cavities is used for the presence of atypical cells.
4. Dormant metastases - tumor cells that spread throughout the body may remain inactive (or at least grow very slowly) for many years. For the destruction of such metastases after a radical surgical treatment of the primary lesion, a course of chemotherapy is necessarily performed. Prior to the use of chemotherapy in some types of disseminated cancer, including malignant lymphoma, choriocarcinoma and tumors from germinal cells of the testicles, it was not possible to obtain satisfactory results. After the start of chemotherapy, the results of treatment improved dramatically. The presence of dormant metastases does not allow to speak about the complete cure of the patient. To assess the effectiveness of treatment for tumors, a survival criterion for 5 years after treatment is used (five year survival). However, the survival rate for 10 and 20 years is almost always lower than the survival rate for 5 years, which is explained by the late activation of dormant metastases.
1. Cell damage: damaging factors, main cellular targets and damage mechanisms. Reversible and irreversible cell damage.
Cell- structural and functional unit of tissue. Damage to the cell is to change its structural, metabolic, physico-chemical properties that lead to dysfunction. The nature of the damage depends on the cause, the mechanisms of protection, the depth of the damage and their consequences.
The causes of cell damage can be exogenous or endogenous factors. Exogenous factors of damage include physical, chemical, biological effects.
• Physical effects. Damage occurs under the action of mechanical (shock, tension, compression), thermal (high or low temperature) factors, radiant energy.
• Chemical factors. The action of acids, alkalis, salts of heavy metals, drugs.
• Biological causes. The action of bacteria, protozoa, fungi, parasites, cytotoxic antibodies, T-lymphocytes.
Endogenous factors of cell damage can be various effects associated with impaired metabolism of cells.
Distinguish specific(cyanides selectively disrupt cellular cytochrome oxidase, carbon monoxide forms a stable compound with hemoglobin - carboxyhemoglobin) andnon-specificdamagethat occurs under the action of many pathogenic factors (violation of the permeability of the capillary wall can be caused by a variety of effects on it).
Pathology of the structure and function of cells also occurs when the regulation of their vital activity is violated. There are disorders of positive and negative feedbacks. An example of positive feedback may be excessive production of hormones by the thyroid gland, adrenal glands, which inhibits the work of the anterior pituitary gland, which regulates these glands. Disorders of the mechanism of negative feedbacks occur when the sensory receptors are damaged, and the transmission paths of the information signal (during a pituitary tumor, inadequate excessive production of its hormones occurs).
Syndromecancellations. Artificial stimulation of negative feedbacks by the prolonged introduction of a hormone from the outside can lead to the development of withdrawal syndrome. As a result, after a sudden cessation of hormone intake, its acute insufficiency arises, associated with the atrophy of the glands that produce this hormone (adrenal insufficiency with prolonged treatment with prednisone).
Positive feedback also takes place in biological systems in the conditions of the norm and pathology. For example, the development of an embryo in the uterine cavity promotes the growth of the placenta and vascular ingrowth, which in turn promotes the growth of the embryo. Positive feedbacks can form "vicious circles" of pathogenesis, participating in the development of the disease (high blood pressure in the arteries contributes to the formation of atherosclerotic plaques, which reduces the elasticity of the blood vessels and aggravates the course of hypertension).
Extra- and intracellular regulatory influences are antagonistic in nature (the effect of excitatory and inhibitory mediators on the nerve cell, the effect on the vessels of the sympathetic and parasympathetic vegetative nervous system).
The body has a hierarchical system of regulation, which coincides with the levels of the structural organization of the body. Allocate disorders of regulation of metabolism, subcellular structures, cells, tissues, organs, systems and the organism as a whole. According to the type of influences, there are disorders of the nervous, endocrine, hormone (biologically active substances of tissue origin) and metabolic regulation.
The disorder of subordinate relations may underlie the pathology. For example, damage to the central motor neuron of the brain, releases the activity of the peripheral spinal motor neuron, leading to muscle spasm during spastic paralysis. With the weakening of the inhibitory processes in the central nervous system with neurosis, osteochondrosis of the cervical spine, sensitivity to afferent signals coming from internal organs, and ordinary subliminal signals from internal organs, can give unusual sensations and pain that are the source of complaints of these patients.
Pathological phenomena can be realized through the viscero-visceral reflex. For example, thrombosis of the pulmonary artery leads to cardiac fibrillation, calculous cholecystitis provokes extrasystoles. Pathological reflexes are fixed and arise by the conditional-reflex mechanism. At the same time, a previously indifferent stimulus can become a pathogenic signal. For example, the recollection of previously experienced troubles or the situation in which they first arose may cause an attack of angina.