Necrosis is death of cells and tissues in a living


Necrosis can be caused by various factors such as hypoxia (ischaemia), chemical and physical agents, microbial agents, immune injury, disturbances of nervous trophism. Two essential changes bring about irreversible cell injury, cell digestion by lyitic enzymes and denaturation of proteins. These processes are morphologically identified by characteristic cytoplasmic and nuclear changes in necrotic cells. Microscopic study demonstrates characteristic changes both in the nucleus and cytoplasm of the cell and intracellular substance.

Nuclear changes. At first nucleus becomes wrinkled, the process is called karyopicnosis. After that karyorrhexis develops. Karyorrhexis is decomposition of the nucleus into small grains. And after that karyolysis develops, when the nucleus dissolution is observed.

In the cytoplasm, protein denaturation and coagulation, or hydration and colliquation take place. Coagulation completes in plasmorhexis. Plasmorhexis, that is when cytoplasm decomposition into iumps are observed. Then plasmolysis takes place. Plasmolysis is hydrolytic fusion of cytoplasm. Sometimes we can observe vacuolization and calcification in the cytoplasm.

In the interstitial (base) substance of the intercellular space depolymerization with glucosamine glycane and saturation with blood plasma proteins develops. As a result interstitial substance becomes swollen and fUses. The same happens to the collagen fibers. Elastic fibers are fUsed (elastolysis). Reticular fibers are preserved longer than the other structures. Then they dissociate to lumps.

There are several stages in necrosis morphogenesis:

1) paranecrosis reversible changes; as a rule, reversible degeneration;

2) necrobiosis irreversible degenerative changes;

3) cell death;

4) cell autolysis decomposition of dead ultra- structures with hydrolytic enzymes.

Necrosis classification

I. According to the cause:

1) traumatic (caused by chemical or physical factors);

2) toxic (toxins of bacteria);

3) trophoneurotic (in disturbances of nervous trophism), e.g. bedsore; 4) allergic (develops in the sensibilized organism as hypersensitivity reaction of immediate type);

5) vascular (infarction).

II. According to the clinico-morphological forms:

1) coagulation (dry) necrosis;

2) colliquative (liquefactive) necrosis;

3) gangrene (originates from Greek <<gangraina>> fire) necrosis of tissue adjacent to the outer environment:


b) wet, c) gas;

4) sequestration;

5) infarction.

III. According to mechanism of its development it may be direct and indirect.

Direct necrosis may be toxic and traumatic, indirect necrosis may be vascular and trophoneurotic.

Necrosis zone is limited from a healthy tissue by a demarcation inflammation.

Microscopically we observe a wide zone of leukocytes between the normal area and necrosis. The normal area is bordered by a hemorrhagic belt. In the area of necrosis the tissues are homogenous and the nuclei are absent.

Some forms of necrosis

Coagulative necrosis. This is the most common type of necrosis which is caused by ischaemia, and less often by bacterial and chemical agents. The organs commonly affected are the heart, kidney and spleen. Macroscopically the foci of coagulative necrosis in the early stage are pale, firm and slightly swollen. With progression, they become more yellowish, softer and shrunken. The hallmark of coagulative necrosis is the conversion of normal cells into their <<tombstones>> i.e., the outlines of the cells are retained so that the cell type can still be recognized but their cytoplasmic and nuclear details are lost. The narcotized cells are swollen and appear more eosinophilic than the normal, along with nuclear changes. This pattern of microscopic change probably results from denaturation of structural and enzymatic proteins but cell digestion and liquefaction fail to occur. Eventually, the narcotized focus is infiltrated by inflammatory cells and the dead cells are phagocytosed leaving granuar debris and fragments of cells.

Colliquative necrosis occurs due to ischaemic injury and bacterial infections, because of hydration and colliquation of tissue by the action of powerful hydrolytic enzymes. The common examples are brain infarct and abscess cavity.

Macroscopically, the affected area is soft and swollen. Late a cyst wall is formed. Microscopically, the cystic space contains necrotic cell debris and macrophages filled with phagocytosed material. The cyst wall is formed by proliferating capillaries, inflammatory cells, and gliosis (proliferating glial cells) in the case of brain, and proliferating fibroblasts in the case of abscess cavity.

Gangrene is a form of necrosis of tissue with superadded putrefaction. The type of necrosis is usually coagulative due to ischemia. In either case, the coagulative necrosis undergoes liquefaction by the action of putrefactive bacteria.

There are 3 main forms of gangrene dry, wet and gas gangrene.

Dry gangrene begins in the distal part of a limb due to ischaemia. The typical example is the dry gangrene in the toes and feet of an old patient due to arteriosclerosis. The gangrene spreads slowly upwards until it reaches a point where the blood supply is adequate to keep the tissue viable. A line of separation is formed at this point between the gangrenous part and the viable part.

Macroscopically, the affected part is dry, shrunken and dark black, resembling the foot of a mummy. It is black due to liberation of hemoglobin from hemolysed red blood cells which is acted upon by the hydrogendisulfide (HG) produced by the bacteria resulting in formation of black iron sulfide. The line of separation usually brings about complete separation with eventual falling off of the gqngrenous tissue if it is not removed surgically. Microscopically, there is necrosis with smudging of the tissue. The line of separation consists of inflammatory granulation tissue. Wet gangrene occurs in naturally moist tissues and organs such as the mouth, bowel, lung, cervix, vulva, etc. Diabetic foot is another example of wet gangrene due to high sugar content in the necrosed tissue which favors growth of bacteria. Bedsores occurring in a bed-ridden patient due to pressure on sites like the sacrum, buttocks and heels are the other important clinical conditions included in wet gangrene. In wet gangrene, the tissue is effected by saprogenic microorganisms (Bac. perfringes, fusiformis, putrificans, etc.), becomes swollen and emits fetid smell. It develops in the tissues rich in water: lungs, intestine, noma (water cancer) gangrene of cheek in children at measles. Wet gangrene usually develops rapidly due to blockage of venous and/or arterial blood flow. The affected part is stuffed with blood which favours the rapid growth of putrefactive bacteria. The toxic products formed by bacteria are absorbed causing systemic manifestations of septicemia, and finally death. The spreading wet gangrene lacks clear cut line of separation and may spread to peritoneal cavity causing peritonitis.

         Macroscopically, the affected part is soft, swollen edematous, putrid, rotten and dark. The part is stained dark due to the same mechanism as in dry gangrene. Microscopically, there is coagulative necrosis with stuffing of affected part with blood. There is ulceration of the mucosa and intensive inflammatory infiltration. The lumen of the bowel contains mucus and blood. The line of separation between gangrenous segment and viable intestine is generally not clear cut.

          Gas gangrene is a special form of wet gangrene caused by gas-forming clostridia (gram-positive anaerobic bacteria) which gain entry into the tissues through open contaminated wounds, especially in the muscles, or as a complication of operation on the colon which normally contains clostridia. Clostridia produce various toxins which cause necrosis and edema locally and are also absorbed producing profound systemic manifestations. Macroscopically, the affected area is swollen, edematous, painful and crepitant due to accumulation of gas bubbles within the tissues. Subsequently, the affected tissue becomes dark black and foul-smelling. Microscopically, the muscle fibers undergo coagulative necrosis with liquefaction. Large number of gram-positive bacilli can be identified. At the periphery, a zone of leucocytic infiltration, edema and congestion are found. Capillary and venous thrombi are common.

Bedsore is a kind of gangrene, death of the tissue under the influence of pressure (sacral area, spinous processes, great trochanter). It is trophoneurotic necrosis in severily ill patients.

             Sequestration is an area of dead tissue which does not experience autolization, does not sclerotize and is freely located in the living tissue. It is characteristic for osteomyelitis (purulent inflammation of the bone). Infaret (originates from Latin <<stuff, fill>>) is vascular necrosis, the most frequent form of necrosis. It may be wedge-shaped or it may have an irregular shape.

According to the propagation it may be total (when the whole organ is affected), subtotal (when only a part of the organ is affected), microinfarct (when observed only microscopically).

                According to the color it is divided into white, white with hemorrhagic rim and red. The color of infarct depends on the peculiarities of the blood supply of the organ. When an organ is supplied through the irtain vessel (spleen), infarct is white.

If under the background of the supply through the main vessel, microcirculatory system is well developed, infarct is white with hemorrhagic rim (kidney).

In the lungs, infarct is red as the lungs are supplied through the system of two arteries (pulmonary and bronchial).

                   The causes of infarction are prolonged stasis, thrombosis, embolism.

There are several special forms of necrosis. They are: caseous, fat and fibrinoid necrosis.

Caseous necrosis looks like cottage cheese (curd), the tissue is soft, granular and yellowish. As a rule it is observed in the center oftuberculous infection.

Fat necrosis is a special form of cell death occurnng in two anatomically different locations but morphologically similar lesions. They are acute pancreatic necrosis and traumatic fat necrosis commonly in breasts.

MacrOscOpically fat necrosis appears as yellowish- white and firm deposits. Calcium usually accumulates in these areas.

               Fibrinoid necrosis develops due to fibrinoid swelling in mesenchymatous albumin degeneration.

                The outcome of necrosis may be either favorable or unfavorable. Favorable outcomes: 1) organization, replacement by connective tissue with formation of a scar or a capsule; 2) petrifaction; 3) ossification, formation of bone; 4) aseptic autolysis. Unfavorable outcome- saprogenic fusion of necrosis focus followed by sepsis.


This pattern of cell death has long been recognized by pathologists, but only recently it has been appreciated as a distinctive and important mode of cell injury, which should be differentiated from the common coagulative necrosis.

Apoptosis is an important means of reducing the number of cells in a tissue. It is a process which brings about deith of established cells in an organ or tissue, causing a reduction in the number of functioning cells. There is activation of specific genes, which act to bring about cellular dissolution. One of the morphological manifestations of this type of cell death is termed ;ipoptosis.

Apoptosis of cells is a programmed and energy- dependent process designed specifically to switch cells o (land eliminate them. This controlled pattern of cell (loath termed programmed cell death is very different horn that which occurs as a direct result of a severe, damagrng stimulus to cells. -

Apoptosis is thought to be responsible for numerous physiologic and pathologic events including the following: the programmed destruction of cells during embryogenesis (including implantation, organogenesis, developmental involution) and iietamorphosis, hormone-dependent involution in the adult, cell deletion in proliferating cell populations, such as intestinal crypt epithelia; cell death in tumors, most frequently during regression but also in tumors with active cell growth; death of immune cells; putliologic atrophy of hormone-dependent tissues and parenchymal organs after duct obstruction, cell injury in certain viral diseases; cell death produced by a variety of injurious stimuli.

The following morphologic features, best seen with the electron microscope, characterize cells undergoing apoptosis.

The cell shrinkage is observed. The cell is smaller in size: the cytoplasm is dense; and the organelles, although relatively normal, are more tightly packed.

The chromatin condensation develops. This is the most characteristic feature of apoptosis. The chromatin aggregates peripherally, under the nuclear membrane, into well-delimited dense masses of various shapes and sizes. The nucleus itself may break up, producing two or more fragments.

Formation of cytoplasmic blebs and apoptotic bodies is observed. The apoptotic cell first shows extensive surface blebbing, then undergoes fragmentation into a number of membrane-bound apoptotic bodies composed of cytoplasm and tightly packed organelles, with or without a nuclear fragment.

Phagocytosis of apoptotic cells or bodies by adjacent healthy cells, either parenchymal cells or macrophages. The apoptotic bodies are rapidly degraded within lysosomes, and the adjacent cells migrate or proliferate to replace the space occupied by the now deleted apoptotic cell.

Microscopically, in tissues stained with hematoxylin and eosin, apoptosis involves single cells or small clusters of cells. The apoptotic cell appears as a round or oval mass of intensely eosinophilic cytoplasm with dense nuclear chromatin fragments. Because the cell shrinkage and formation of apoptotic bodies are rapid, and the fragments are quickly phagocytosed, degraded, or extruded into the lumen, considerable apoptosis may occur in tissues before it becomes apparent in histologic sections.

Thus, apoptosis is a distinctive form of cell death manifested by characteristic chromatin condensation and DNA fragmentation, whose function is the deletion of cells in normal development, organogenesis, immune function, and tissue growth, but which can also be induced by pathologic stimuli.

Necrosis (from the Greek νεκρός, "dead", νέκρωσις, "death, the stage of dying, the act of killing") is a form of cell injury that results in the premature death of cells in living tissue.[1] Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma that result in the unregulated digestion of cell components. In contrast, apoptosis is a naturally occurring programmed and targeted cause of cellular death. While apoptosis often provides beneficial effects to the organism, necrosis is almost always detrimental and can be fatal.[2]

Cells that die due to necrosis do not follow the apoptotic signal transduction pathway but rather various receptors are activated that result in the loss of cell membrane integrity and an uncontrolled release of products of cell death into the intracellular space.[1] This initiates an inflammatory response in the surrounding tissue: Nearby phagocytes are prevented from locating and engulfing the dead cells.[2] The result is a build-up of dead tissue and cell debris at, or near, the site of the cell death. A classic example is gangrene. For this reason, it is often necessary to remove necrotic tissue surgically, a process known as debridement.


1 Classification

1.1 Morphological patterns

1.2 Other clinical classifications of necrosis

2 Causes

3 Pathogenesis

3.1 Cellular changes

4 Treatment

5 In plants

6 See also

7 References

8 Notes

9 External links


Necrosis is the sum of cell changes after localized cellular death through a process known as autolysis. Structural signs that indicate irreversible cell injury and the progression of necrosis include: dense clumping and progressive disruption of genetic material: and disruption to membranes of cells and organelles.[3]

Morphological patterns

There are five distinctive morphological patterns of necrosis:

Coagulative necrosis is characterized by the formation of a gelatinous (gel-like) substance in dead tissues in which the architecture of the tissue is maintained,[4] and can be observed by light microscopy. Coagulation occurs as a result of protein denaturation, causing the albumin in protein to form a firm and opaque state.[3] This pattern of necrosis is typically seen in hypoxic (low-oxygen) environments, such as infarction. Coagulative necrosis occurs primarily in tissues such the kidney, heart and adrenal glands.[3] Severe ischemia most commonly causes necrosis of this form.[5]

Liquefactive necrosis (or colliquative necrosis), in contrast to coagulative necrosis, is characterized by the digestion of dead cells to form a viscous liquid mass.[4] This is typical of bacterial, or sometimes fungal, infections because of their ability to stimulate an inflammatory response. The necrotic liquid mass is frequently creamy yellow due to the presence of dead leukocytes and is commonly known as pus.[4] Hypoxic infarcts in the brain presents as this type of necrosis, because the brain contains little connective tissue but high amounts of digestive enzymes and lipids, and cells therefore can be readily digested by their own enzymes.[3]

Caseous necrosis can be considered a combination of coagulative and liquefactive necroses,[3] typically caused by mycobacteria (e.g. tuberculosis), fungi and some foreign substances. The necrotic tissue appears as white and friable, like clumped cheese. Dead cells disintegrate but are not completely digested, leaving granular particles.[3] Microscopic examination shows amorphous granular debris enclosed within a distinctive inflammatory border.[4] Granuloma has this characteristic.[6]

Fat necrosis is specialized necrosis of fat tissue,[6] resulting from the action of activated lipases on fatty tissues such as the pancreas. In the pancreas it leads to acute pancreatitis, a condition where the pancreatic enzymes leak out into the peritoneal cavity, and liquefy the membrane by splitting the triglyceride esters into fatty acids through fat saponification. Calcium, magnesium or sodium may bind to these lesions to produce a chalky-white substance. The calcium deposits are microscopically distinctive and may be large enough to be visible on radiographic examinations. To the naked eye, calcium deposits appear as gritty white flecks.

Fibrinoid necrosis is a special form of necrosis usually caused by immune-mediated vascular damage. It is marked by complexes of antigen and antibodies, sometimes referred to as “immune complexes” deposited within arterial walls together with fibrin.

Other clinical classifications of necrosis

There are also very specific forms of necrosis such as gangrene (term used in clinical practices for limbs which have suffered severe hypoxia), gummatous necrosis (due to spirochaetal infections) and hemorrhagic necrosis (due to the blockage of venous drainage of an organ or tissue).

Some spider bites may lead to necrosis. In the United States, only spider bites from the brown recluse spider (genus Loxosceles) have been proven to cause necrosis. Other spiders of the same genus such as the Chilean recluse in South America, have similarly been shown to cause necrosis in other countries. While both the yellow sac spiders and Hobo spider are often claimed to possess necrotic venom, these claims have been challenged.

In blind mole rats (genus Spalax), the process of necrosis replaces the role of the systematic apoptosis normally used in many organisms. Low oxygen conditions, such as those common in blind mole rats’ burrows, usually cause cells to undergo apoptosis. In adaptation to higher tendency of cell death, blind mole rats evolved a mutation in the tumor suppressor protein (which is also used in humans) to prevent cells from undergoing apoptosis. Human cancer patients have similar mutations, and blind mole rats were thought to be more susceptible to cancer because their cells cannot undergo apoptosis. However, after a specific amount of time (within 3 days according to a study conducted at the University of Rochester), the cells in blind mole rats release interferon-beta (which the immune system normally uses to counter viruses) in response to over-proliferation of cells caused by the suppression of apoptosis. In this case, the interferon-beta triggers cells to undergo necrosis, and this mechanism also kills cancer cells in blind mole rats. Because of tumor suppression mechanisms such as this, blind mole rats and other spalacids are resistant to cancer.


Necrotic leg wound caused by a brown recluse spider bite

Necrosis may occur due to external or internal factors. External factors may involve mechanical trauma, physical damage to the body (that causes cellular breakdown), any damage to blood vessels (which may disrupt the blood supply to that area); and ischemia. Thermal effects (extremely high or low temperature) can result in necrosis due to the disruption of cells. In frostbite, crystals form, increasing the pressure of remaining tissue and fluid causing the cells to burst. Under extreme conditions tissues and cells die through an unregulated process of destruction of membranes and cytosol.

Internal factors causing necrosis include trophoneurotic disorders; injury and paralysis of nerve cells. Pancreatic enzymes (lipases) are the major cause of fat necrosis. Necrosis can be activated by bacterial toxins and components of the immune system, such as the complement system, activated natural killer cells, and peritoneal macrophages. Pathogen-induced necrosis programs in cells with immunological barriers (intestinal mucosa) may alleviate invasion of pathogens through surfaces affected by inflammation. Toxins and pathogens may cause necrosis; toxins such as snake venoms may inhibit enzymes and cause cell death.

Pathological conditions are characterized by inadequate secretion of cytokines. Nitric oxide (NO) and reactive oxygen species (ROS) are also accompanied by intense necrotic death of cells. A classic example of a necrotic condition is ischemia that leads to a drastic depletion of oxygen, glucose and other trophic factors and evokes massive necrotic death of endothelial cells and non-proliferating cells of surrounding tissues (neurons, cardiomyocytes, renal cells, etc.). Recent cytological data indicates that necrotic death occurs not only during pathological events but it is also a component of some physiological process

Activation-induced death of primary T-lymphocytes, and important constituents of the immune response, are caspase-independent and necrotic by morphology; hence current researchers have demonstrated that the occurrence of necrotic cell death can not only occur during pathological processes but also during normal processes such as tissue renewal, embryogenesis and immune response.


Until recently, necrosis was thought to be an unregulated process. There are two broad pathways in which necrosis may occur in an organism.

The first of these two pathways initially involves oncosis, where swelling of the cells occur. The cell then proceeds to blebbing, and this is followed by pyknosis, in which nuclear shrinkage transpires. In the final step of this pathway the nucleus is dissolved into the cytoplasm, which is referred to as karyolysis.

The second pathway is a secondary form of necrosis that is shown to occur after apoptosis and budding. Cellular changes of necrosis occur in this secondary form of apoptosis, where the nucleus breaks into fragments, which is known as karyorrhexis.

Cellular changes

The nucleus changes in necrosis, and characteristics of this change are determined by the way in which the DNA is broken down, as shown in figure 3. There are three different ways in which the DNA can be broken down: karyolysis, pyknosis, or karyorrhexis.

Karyolysis is a process where the chromatin of the nucleus fades due to the loss of the DNA by degradation. Pyknosis is where the nucleus shrinks and the chromatin in the nucleus condenses. Karyorrhexis follows on from the process of pyknosis, and involves the shrunken nucleus proceeding to fragmentation until the nucleus completely disappears.

Plasma alterations are also seen in necrosis. Plasma membranes appear discontinuous when viewed with an electron microscope. This discontinuous membrane is caused by cell blebbing and the loss of microvilli.