![Structural changes of cells undergoing necrosis or apoptosis](https://upload.wikimedia.org/wikipedia/commons/6/69/Structural_changes_of_cells_undergoing_necrosis_or_apoptosis.png)
Necrosis () is a form of
cell injury
Cell damage (also known as cell injury) is a variety of changes of stress that a cell suffers due to external as well as internal environmental changes. Amongst other causes, this can be due to physical, chemical, infectious, biological, nutritiona ...
which results in the premature
death
Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...
of
cells in living
tissue by
autolysis.
Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated digestion of cell components. In contrast,
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
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.
Cellular death due to necrosis does not follow the apoptotic signal transduction pathway, but rather various receptors are activated and result in the loss of
cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
integrity and an uncontrolled release of products of cell death into the
extracellular space
Extracellular space refers to the part of a multicellular organism outside the cells, usually taken to be outside the plasma membranes, and occupied by fluid. This is distinguished from intracellular space, which is inside the cells.
The compos ...
.
This initiates in the surrounding tissue an
inflammatory response
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecu ...
, which attracts
leukocytes
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
and nearby
phagocyte
Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek ', "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek ...
s which eliminate the dead cells by
phagocytosis
Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...
. However, microbial damaging substances released by leukocytes would create collateral damage to surrounding tissues. This excess collateral damage inhibits the healing process. Thus, untreated necrosis results in a build-up of
decomposing
Decomposition or rot is the process by which dead organic substances are broken down into simpler organic or inorganic matter such as carbon dioxide, water, simple sugars and mineral salts. The process is a part of the nutrient cycle and is e ...
dead tissue and cell debris at or near the site of the cell death. A classic example is
gangrene
Gangrene is a type of tissue death caused by a lack of blood supply. Symptoms may include a change in skin color to red or black, numbness, swelling, pain, skin breakdown, and coolness. The feet and hands are most commonly affected. If the ga ...
. For this reason, it is often necessary to remove necrotic tissue
surgically
Surgery ''cheirourgikē'' (composed of χείρ, "hand", and ἔργον, "work"), via la, chirurgiae, meaning "hand work". is a medical specialty that uses operative manual and instrumental techniques on a person to investigate or treat a pa ...
, a
procedure known as
debridement
Debridement is the medical removal of dead, damaged, or infected tissue to improve the healing potential of the remaining healthy tissue. Removal may be surgical, mechanical, chemical, autolytic (self-digestion), and by maggot therapy.
In p ...
.
Classification
Structural signs that indicate irreversible cell injury and the progression of necrosis include dense clumping and progressive disruption of
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
tic material, and disruption to membranes of cells and
organelles
In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' the ...
.
Morphological patterns
There are six distinctive morphological patterns of necrosis:
#
Coagulative necrosis Coagulative necrosis is a type of accidental cell death typically caused by ischemia or infarction. In coagulative necrosis, the architectures of dead tissue are preserved for at least a couple of days. It is believed that the injury denatures struc ...
is characterized by the formation of a gelatinous (gel-like) substance in dead tissues in which the architecture of the tissue is maintained,
and can be observed by light microscopy. Coagulation occurs as a result of protein
denaturation, causing
albumin
Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...
to transform into a firm and opaque state.
This pattern of necrosis is typically seen in
hypoxic
Hypoxia means a lower than normal level of oxygen, and may refer to:
Reduced or insufficient oxygen
* Hypoxia (environmental), abnormally low oxygen content of the specific environment
* Hypoxia (medical), abnormally low level of oxygen in the t ...
(low-oxygen) environments, such as
infarction
Infarction is tissue death (necrosis) due to inadequate blood supply to the affected area. It may be caused by artery blockages, rupture, mechanical compression, or vasoconstriction. The resulting lesion is referred to as an infarct
(from the ...
. Coagulative necrosis occurs primarily in tissues such as the kidney, heart and adrenal glands.
Severe
ischemia
Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...
most commonly causes necrosis of this form.
#
Liquefactive necrosis Liquefactive necrosis (or colliquative necrosis) is a type of necrosis which results in a transformation of the tissue into a liquid viscous mass.Robbins and Cotran: Pathologic Basis of Disease, 8th Ed. 2010. Pg. 15 Often it is associated with foc ...
(or colliquative necrosis), in contrast to coagulative necrosis, is characterized by the digestion of dead cells to form a viscous liquid mass.
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
leukocyte
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
s and is commonly known as
pus
Pus is an exudate, typically white-yellow, yellow, or yellow-brown, formed at the site of inflammation during bacterial or fungal infection. An accumulation of pus in an enclosed tissue space is known as an abscess, whereas a visible collection ...
.
Hypoxic
Hypoxia means a lower than normal level of oxygen, and may refer to:
Reduced or insufficient oxygen
* Hypoxia (environmental), abnormally low oxygen content of the specific environment
* Hypoxia (medical), abnormally low level of oxygen in the t ...
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.
#
Gangrenous necrosis
Gangrene is a type of tissue death caused by a lack of blood supply. Symptoms may include a change in skin color to red or black, numbness, swelling, pain, skin breakdown, and coolness. The feet and hands are most commonly affected. If the ga ...
can be considered a type of coagulative necrosis that resembles mummified tissue. It is characteristic of ischemia of lower limb and the gastrointestinal tracts. If superimposed infection of dead tissues occurs, then liquefactive necrosis ensues (wet gangrene).
#
Caseous necrosis
Caseous necrosis or caseous degeneration () is a unique form of cell death in which the tissue maintains a cheese-like appearance.Robbins and Cotran: Pathologic Basis of Disease, 8th Ed. 2010. Pg. 16 It is also a distinctive form of coagulative nec ...
can be considered a combination of coagulative and liquefactive necrosis,
typically caused by
mycobacteria
''Mycobacterium'' is a genus of over 190 species in the phylum Actinomycetota, assigned its own family, Mycobacteriaceae. This genus includes pathogens known to cause serious diseases in mammals, including tuberculosis ('' M. tuberculosis'') and ...
(e.g.
tuberculosis
Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in ...
), fungi and some foreign substances. The necrotic tissue appears as white and
friable
Friability ( ), the condition of being friable, describes the tendency of a solid substance to break into smaller pieces under duress or contact, especially by rubbing. The opposite of friable is indurate.
Substances that are designated hazardous, ...
, like clumped cheese. Dead cells disintegrate but are not completely digested, leaving granular particles.
Microscopic examination shows
amorphous
In condensed matter physics and materials science, an amorphous solid (or non-crystalline solid, glassy solid) is a solid that lacks the long-range order that is characteristic of a crystal.
Etymology
The term comes from the Greek ''a'' ("wi ...
granular debris enclosed within a distinctive inflammatory border.
Some
granuloma
A granuloma is an aggregation of macrophages that forms in response to chronic inflammation. This occurs when the immune system attempts to isolate foreign substances that it is otherwise unable to eliminate. Such substances include infectious ...
s contain this pattern of necrosis.
#
Fat necrosis
Fat necrosis is a form of necrosis characterized by the action upon fat by digestive enzymes.
In fat necrosis the enzyme lipase releases fatty acids from triglycerides. The fatty acids then complex with calcium to form soaps. These soaps appe ...
is specialized necrosis of fat tissue,
resulting from the action of activated
lipase
Lipase ( ) is a family of enzymes that catalyzes the hydrolysis of fats. Some lipases display broad substrate scope including esters of cholesterol, phospholipids, and of lipid-soluble vitamins and sphingomyelinases; however, these are usually tr ...
s on fatty tissues such as the
pancreas
The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an end ...
. In the pancreas it leads to acute
pancreatitis
Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic pancr ...
, a condition where the
pancreatic enzymes
Digestive enzymes are a group of enzymes that break down polymeric macromolecules into their smaller building blocks, in order to facilitate their absorption into the cells of the body. Digestive enzymes are found in the digestive tracts of anima ...
leak out into the
peritoneal
The peritoneum is the serous membrane forming the lining of the abdominal cavity or coelom in amniotes and some invertebrates, such as annelids. It covers most of the intra-abdominal (or coelomic) organs, and is composed of a layer of mesothe ...
cavity, and liquefy the membrane by splitting the
triglyceride
A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and ''glyceride'').
Triglycerides are the main constituents of body fat in humans and other vertebrates, as w ...
esters into
fatty acids
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...
through fat
saponification
Saponification is a process of converting esters into soaps and alcohols by the action of aqueous alkali (for example, aqueous sodium hydroxide solutions). Soaps are salts of fatty acids, which in turn are carboxylic acids with long carbon chains. ...
.
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
Fibrinoid necrosis is a specific pattern of irreversible, uncontrolled cell death that occurs when antigen-antibody complexes are deposited in the walls of blood vessels along with fibrin. It is common in the immune-mediated vasculitides which a ...
is a special form of necrosis usually caused by immune-mediated vascular damage. It is marked by complexes of
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
and
antibodies
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
, referred to as
immune complex
An immune complex, sometimes called an antigen-antibody complex or antigen-bound antibody, is a molecule formed from the binding of multiple antigens to antibodies. The bound antigen and antibody act as a unitary object, effectively an antigen of ...
es deposited within
arterial
An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pul ...
walls
together with
fibrin
Fibrin (also called Factor Ia) is a fibrous, non-globular protein involved in the clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerize. The polymerized fibrin, together with platele ...
.
Other clinical classifications of necrosis
# There are also very specific forms of necrosis such as
gangrene
Gangrene is a type of tissue death caused by a lack of blood supply. Symptoms may include a change in skin color to red or black, numbness, swelling, pain, skin breakdown, and coolness. The feet and hands are most commonly affected. If the ga ...
(term used in clinical practices for limbs which have had severe hypoxia),
gummatous
A gumma (plural gummata or gummas) is a soft, non-cancerous growth resulting from the tertiary stage of syphilis (and yaws). It is a form of granuloma. Gummas are most commonly found in the liver (''gumma hepatis''), but can also be found in br ...
necrosis (due to
spirochaetal
A spirochaete () or spirochete is a member of the phylum Spirochaetota (), (synonym Spirochaetes) which contains distinctive diderm (double-membrane) gram-negative bacteria, most of which have long, helically coiled (corkscrew-shaped or ...
infections) and hemorrhagic necrosis (due to the blockage of venous drainage of an organ or tissue).
# Some
spider bite
A spider bite, also known as arachnidism, is an injury resulting from the bite of a spider. The effects of most bites are not serious. Most bites result in mild symptoms around the area of the bite. Rarely they may produce a necrotic skin wound ...
s may lead to necrosis. In the United States, only spider bites from the
brown recluse spider
The brown recluse (''Loxosceles reclusa''), Sicariidae (formerly placed in a family "Loxoscelidae") is a recluse spider with necrotic venom. Similar to those of other recluse spiders, their bites sometimes require medical attention. The brown r ...
(genus
Loxosceles
The recluse spiders (''Loxosceles'' (), also known as brown spiders, fiddle-backs, violin spiders, and reapers, is a genus of spiders that was first described by R. T. Lowe in 1832. They are venomous spiders known for their bite, which sometimes ...
) reliably progress to necrosis. In other countries, spiders of the same genus, such as the
Chilean recluse
The Chilean recluse spider, ''Loxosceles laeta'', is a highly venomous spider of the family Sicariidae. In Spanish, it (and other South American recluse spiders) is known as ', or "corner spider"; in Brazilian Portuguese, as ' or "brown spider". ...
in South America, are also known to cause necrosis. Claims that
yellow sac spiders and
hobo spider
The hobo spider (''Eratigena agrestis'', formerly ''Tegenaria agrestis'') is a member of the family of spiders known colloquially as funnel web spiders, but not to be confused with the Australian funnel-web spider. Individuals construct a funnel ...
s possess necrotic
venom
Venom or zootoxin is a type of toxin produced by an animal that is actively delivered through a wound by means of a bite, sting, or similar action. The toxin is delivered through a specially evolved ''venom apparatus'', such as fangs or a sti ...
have not been substantiated.
# In blind mole rats (genus ''
Spalax
''Spalax'' is a genus of rodent in the family Spalacidae, subfamily '' Spalacinae'' (blind mole-rats). It is one of two extant genera in the subfamily Spalacinae, alongside ''Nannospalax''.'
Species in this genus are found in eastern Europe ...
''), the process of necrosis replaces the role of the systematic
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
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
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
protein
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
(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
The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...
(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.
Causes
![Necrotic leg wound](https://upload.wikimedia.org/wikipedia/commons/3/37/Necrotic_leg_wound.png)
Necrosis may occur due to external or internal factors.
External factors
External factors may involve mechanical trauma (physical damage to the body which causes cellular breakdown), damage to blood vessels (which may disrupt blood supply to associated tissue), and
ischemia
Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...
.
Thermal effects (extremely high or low temperature) can result in necrosis due to the disruption of cells.
In
frostbite
Frostbite is a skin injury that occurs when exposed to extreme low temperatures, causing the freezing of the skin or other tissues, commonly affecting the fingers, toes, nose, ears, cheeks and chin areas. Most often, frostbite occurs in the han ...
, 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
Internal factors causing necrosis include: trophoneurotic disorders (diseases that occur due to defective nerve action in a part of an organ which results in failure of nutrition); injury and paralysis of nerve cells. Pancreatic enzymes (lipases) are the major cause of fat necrosis.
Necrosis can be activated by components of the immune system, such as the
complement system
The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and at ...
;
bacterial toxin
Microbial toxins are toxins produced by micro-organisms, including bacteria, fungi, protozoa, dinoflagellates, and viruses. Many microbial toxins promote infection and disease by directly damaging host tissues and by disabling the immune system. ...
s; activated
natural killer cells
Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...
; and
peritoneal
The peritoneum is the serous membrane forming the lining of the abdominal cavity or coelom in amniotes and some invertebrates, such as annelids. It covers most of the intra-abdominal (or coelomic) organs, and is composed of a layer of mesothe ...
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s.
Pathogen-induced necrosis programs in cells with immunological barriers (
intestinal mucosa
The gastrointestinal wall of the gastrointestinal tract is made up of four layers of specialised tissue. From the inner cavity of the gut (the lumen) outwards, these are:
# Mucosa
# Submucosa
# Muscular layer
# Serosa or adventitia
The mucosa is ...
) may alleviate invasion of
pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
s through surfaces affected by inflammation.
Toxins and pathogens may cause necrosis; toxins such as
snake venom
Snake venom is a highly toxic saliva containing zootoxins that facilitates in the immobilization and digestion of prey. This also provides defense against threats. Snake venom is injected by unique fangs during a bite, whereas some species are a ...
s may inhibit enzymes and cause cell death.
Necrotic wounds have also resulted from the stings of ''
Vespa mandarinia.''
Pathological
Pathology is the study of the causal, causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when us ...
conditions are characterized by inadequate secretion of
cytokines
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
.
Nitric oxide
Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
(NO) and
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
(ROS) are also accompanied by intense necrotic death of cells.
A classic example of a necrotic condition is
ischemia
Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...
which leads to a drastic depletion of
oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...
,
glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
, and othe
trophic factorsand induces massive necrotic death of endothelial cells and non-proliferating cells of surrounding tissues (neurons, cardiomyocytes, renal cells, etc.).
Recent
cytological
Cell biology (also cellular biology or cytology) is a branch of biology that studies the structure, function, and behavior of cells. All living organisms are made of cells. A cell is the basic unit of life that is responsible for the living and ...
data indicates that necrotic death occurs not only during pathological events but it is also a component of some
physiological
Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical ...
process.
Activation-induced death of primary
T lymphocyte
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...
s and other important constituents of the immune response are
caspase
Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cystei ...
-independent and necrotic by morphology; hence, current researchers have demonstrated that necrotic cell death can occur not only during pathological processes, but also during normal processes such as tissue renewal,
embryogenesis
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
, and immune response.
Pathogenesis
Pathways
Until recently, necrosis was thought to be an unregulated process.
However, there are two broad pathways in which necrosis may occur in an organism.
The first of these two pathways initially involves
oncosis Ischemic cell death, or oncosis, is a form of accidental cell death. The process is characterized by an ATP depletion within the cell leading to impairment of ionic pumps, cell swelling, clearing of the cytosol, dilation of the endoplasmic reticul ...
, where swelling of the cells occurs.
Affected cells then proceed to
blebbing
In cell biology, a bleb is a bulge of the plasma membrane of a cell, characterized by a spherical, bulky morphology. It is characterized by the decoupling of the cytoskeleton from the plasma membrane, degrading the internal structure of the cell, ...
, and this is followed by
pyknosis
Pyknosis, or karyopyknosis, is the irreversible condensation of chromatin in the nucleus of a cell undergoing necrosis or apoptosis. It is followed by karyorrhexis, or fragmentation of the nucleus.
Pyknosis (from Ancient Greek meaning "thick, clo ...
, in which nuclear shrinkage transpires.
In the final step of this pathway cell nuclei are dissolved into the cytoplasm, which is referred to as
karyolysis
Karyolysis (from Greek κάρυον ''karyon—''kernel, seed, or nucleus), and λύσις ''lysis'' from λύειν ''lyein'', "to separate") is the complete dissolution of the chromatin of a dying cell due to the enzymatic degradation by endonuc ...
.
The second pathway is a secondary form of necrosis that is shown to occur after apoptosis and budding.
In these cellular changes of necrosis, the nucleus breaks into fragments (known as
karyorrhexis
Karyorrhexis (from Greek κάρυον ''karyon'', "kernel, seed or nucleus", and ῥῆξις ''rhexis'', "bursting") is the destructive fragmentation of the nucleus of a dying cell whereby its chromatin is distributed irregularly throughout the c ...
).
Histopathological changes
The nucleus changes in necrosis and characteristics of this change are determined by the manner in which its DNA breaks down:
*
Karyolysis
Karyolysis (from Greek κάρυον ''karyon—''kernel, seed, or nucleus), and λύσις ''lysis'' from λύειν ''lyein'', "to separate") is the complete dissolution of the chromatin of a dying cell due to the enzymatic degradation by endonuc ...
: the
chromatin
Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...
of the nucleus fades due to the loss of the DNA by degradation.
*
Karyorrhexis
Karyorrhexis (from Greek κάρυον ''karyon'', "kernel, seed or nucleus", and ῥῆξις ''rhexis'', "bursting") is the destructive fragmentation of the nucleus of a dying cell whereby its chromatin is distributed irregularly throughout the c ...
: the shrunken nucleus fragments to complete dispersal.
*
Pyknosis
Pyknosis, or karyopyknosis, is the irreversible condensation of chromatin in the nucleus of a cell undergoing necrosis or apoptosis. It is followed by karyorrhexis, or fragmentation of the nucleus.
Pyknosis (from Ancient Greek meaning "thick, clo ...
: the nucleus shrinks, and the chromatin condenses.
Other typical cellular changes in necrosis include:
* Cytoplasmic hypereosinophilia on samples with
H&E stain
Hematoxylin and eosin stain ( or haematoxylin and eosin stain or hematoxylin-eosin stain; often abbreviated as H&E stain or HE stain) is one of the principal tissue stains used in histology. It is the most widely used stain in medical diagnos ...
. It is seen as a darker stain of the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
.
* The
cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
appears discontinuous when viewed with an
electron microscope
An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hi ...
. This discontinuous membrane is caused by cell blebbing and the loss of
microvilli
Microvilli (singular: microvillus) are microscopic cellular membrane protrusions that increase the surface area for diffusion and minimize any increase in volume, and are involved in a wide variety of functions, including absorption, secretion, ...
.
On a larger histologic scale, pseudopalisades (false
palisades) are hypercellular zones that typically surround necrotic tissue. Pseudopalisading necrosis indicates an aggressive tumor.
File:4 Bd obs 4 680x512px.tif, Pyknosis
Pyknosis, or karyopyknosis, is the irreversible condensation of chromatin in the nucleus of a cell undergoing necrosis or apoptosis. It is followed by karyorrhexis, or fragmentation of the nucleus.
Pyknosis (from Ancient Greek meaning "thick, clo ...
in a bile infarct
File:Histopathology of cytoplasmic hypereosinophilia in a pituitary adenoma.jpg, Cytoplasmic hypereosinophilia (seen in left half of image)
File:GBM pseudopalisading necrosis.jpg, Pseudopalisading seen around necrosis in glioblastoma
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ch ...
Treatment
There are many causes of necrosis, and as such treatment is based upon how the necrosis came about. Treatment of necrosis typically involves two distinct processes: Usually, the underlying cause of the necrosis must be treated before the dead tissue itself can be dealt with.
*
Debridement
Debridement is the medical removal of dead, damaged, or infected tissue to improve the healing potential of the remaining healthy tissue. Removal may be surgical, mechanical, chemical, autolytic (self-digestion), and by maggot therapy.
In p ...
, referring to the removal of dead tissue by surgical or non-surgical means, is the standard therapy for necrosis. Depending on the severity of the necrosis, this may range from removal of small patches of skin to complete
amputation
Amputation is the removal of a limb by trauma, medical illness, or surgery. As a surgical measure, it is used to control pain or a disease process in the affected limb, such as malignancy or gangrene. In some cases, it is carried out on indi ...
of affected limbs or organs. Chemical removal of necrotic tissue is another option in which enzymatic debriding agents, categorised as
proteolytic
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, ...
,
fibrinolytic
Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. Primary fibrinolysis is a normal body process, while secondary fibrinolysis is the breakdown of clots due to a medicine, a medical disorder, or some other ...
or
collagenase
Collagenases are enzymes that break the peptide bonds in collagen. They assist in destroying extracellular structures in the pathogenesis of bacteria such as ''Clostridium''. They are considered a virulence factor, facilitating the spread of ...
s, are used to target the various components of dead tissue.
In select cases, special
maggot therapy
Maggot therapy (also known as larval therapy) is a type of biotherapy involving the introduction of live, disinfected maggots (fly larvae) into non-healing skin and soft-tissue wounds of a human or other animal for the purpose of cleaning out the ...
using ''
Lucilia sericata
The common green bottle fly (''Lucilia sericata'') is a blowfly found in most areas of the world and is the most well-known of the numerous green bottle fly species. Its body is in length – slightly larger than a house fly – and has brilli ...
'' larvae has been employed to remove necrotic tissue and infection.
* In the case of
ischemia
Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...
, which includes
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
, the restriction of blood supply to tissues causes
hypoxia and the creation of
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
(ROS) that react with, and damage proteins and membranes.
Antioxidant
Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricant ...
treatments can be applied to scavenge the ROS.
* Wounds caused by physical agents, including physical
trauma
Trauma most often refers to:
* Major trauma, in physical medicine, severe physical injury caused by an external source
* Psychological trauma, a type of damage to the psyche that occurs as a result of a severely distressing event
*Traumatic i ...
and
chemical burns
A chemical burn occurs when living tissue is exposed to a corrosive substance (such as a strong acid, base or oxidizer) or a cytotoxic agent (such as mustard gas, lewisite or arsine). Chemical burns follow standard burn classification and may cau ...
, can be treated with
antibiotics
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention o ...
and
anti-inflammatory
Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...
drugs to prevent bacterial infection and inflammation. Keeping the wound clean from infection also prevents necrosis.
* Chemical and toxic agents (e.g. pharmaceutical drugs, acids, bases) react with the skin leading to skin loss and eventually necrosis. Treatment involves identification and discontinuation of the harmful agent, followed by treatment of the wound, including prevention of infection and possibly the use of
immunosuppressive
Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reacti ...
therapies such as
anti-inflammatory drugs
Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...
or immunosuppressants.
In the example of a
snake bite
A snakebite is an injury caused by the bite of a snake, especially a venomous snake. A common sign of a bite from a venomous snake is the presence of two puncture wounds from the animal's fangs. Sometimes venom injection from the bite may oc ...
, the use of
anti-venom
Anti-Venom is a fictional antihero appearing in Comic books published by Marvel Comics. It first appeared in '' The Amazing Spider-Man'' #569 (August 2008), and was created by Dan Slott and John Romita Jr. The creature belongs to a race of amorp ...
halts the spread of toxins whilst receiving
antibiotics
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention o ...
to impede infection.
Even after the initial cause of the necrosis has been halted, the necrotic tissue will remain in the body. The body's immune response to apoptosis, which involves the automatic breaking down and recycling of cellular material, is not triggered by necrotic cell death due to the apoptotic pathway being disabled.
In plants
If calcium is deficient,
pectin
Pectin ( grc, πηκτικός ': "congealed" and "curdled") is a heteropolysaccharide, a structural acid contained in the primary lamella, in the middle lamella, and in the cell walls of terrestrial plants. The principal, chemical component of ...
cannot be synthesized, and therefore the cell walls cannot be bonded and thus an impediment of the meristems. This will lead to necrosis of stem and root tips and leaf edges.
For example, necrosis of tissue can occur in
''Arabidopsis thaliana'' due to plant pathogens.
Cacti such as the Saguaro and Cardon in the Sonoran Desert experience necrotic patch formation regularly; a species of Dipterans called
Drosophila ''mettleri'' has developed a p450 detoxification system to enable it to use the exudates released in these patches to both nest and feed larvae.
See also
*
Avascular necrosis
Avascular necrosis (AVN), also called osteonecrosis or bone infarction, is death of bone tissue due to interruption of the blood supply. Early on, there may be no symptoms. Gradually joint pain may develop which may limit the ability to move. Co ...
*
Frostbite
Frostbite is a skin injury that occurs when exposed to extreme low temperatures, causing the freezing of the skin or other tissues, commonly affecting the fingers, toes, nose, ears, cheeks and chin areas. Most often, frostbite occurs in the han ...
*
Gangrene
Gangrene is a type of tissue death caused by a lack of blood supply. Symptoms may include a change in skin color to red or black, numbness, swelling, pain, skin breakdown, and coolness. The feet and hands are most commonly affected. If the ga ...
*
Necrotizing fasciitis
Necrotizing fasciitis (NF), also known as flesh-eating disease, is a bacterial infection that results in the death of parts of the body's soft tissue. It is a severe disease of sudden onset that spreads rapidly. Symptoms usually include red or p ...
*
Osteonecrosis of the jaw
Osteonecrosis of the jaw (ONJ) is a severe bone disease (osteonecrosis) that affects the jaws (the maxilla and the mandible). Various forms of ONJ have been described since 1861, and a number of causes have been suggested in the literature.
Osteo ...
*
Toxic epidermal necrolysis
Toxic epidermal necrolysis (TEN) is a type of severe skin reaction. Together with Stevens–Johnson syndrome (SJS) it forms a spectrum of disease, with TEN being more severe. Early symptoms include fever and flu-like symptoms. A few days later th ...
*
Necroptosis
Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell dea ...
References
External links
Life In The Fast Lane: toxicology Conundrum #018*
Secondary necrosis of a neutrophil
{{Authority control
Cellular processes
Cell death