Necrosis

From Wikipedia, the free encyclopedia

For other uses, see Necrosis (disambiguation).
Not to be confused with Narcosis.

Structural changes of cells undergoing necrosis or apoptosis

Necrosis (from the Greek "death, the stage of dying, the act of killing" from "dead") is a form
of cell injury that results in the premature death of cells in living tissue by autolysis.[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 extracellular space.[1] This initiates in the surrounding tissue an inflammatory response
which prevents nearby phagocytes from locating and eliminating the dead cells by phagocytosis.[2] For this
reason, it is often necessary to remove necrotic tissue surgically, a procedure known as debridement. Untreated
necrosis results in a build-up of decomposing dead tissue and cell debris at or near the site of the cell death. A
classic example is gangrene.

Contents

1 Classification
o 1.1 Morphological patterns
o 1.2 Other clinical classifications of necrosis
2 Causes
3 Pathogenesis
o 3.1 Cellular changes
4 Treatment
5 In plants
6 See also
7 References
8 External links

Classification
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:
1. 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 proteins 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 as the kidney, heart and adrenal
glands.[3] Severe ischemia most commonly causes necrosis of this form.[5]
2. 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]
3. Caseous necrosis can be considered a combination of coagulative and liquefactive necrosis,[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]
4. 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.[4] Calcium, magnesium or sodium may bind
to these lesions to produce a chalky-white substance.[3] The calcium deposits are microscopically
distinctive and may be large enough to be visible on radiographic examinations.[5] To the naked eye,
calcium deposits appear as gritty white flecks.[5]
5. 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[4] together with fibrin.[4]

Other clinical classifications of necrosis

1. 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).
2. Some spider bites may lead to necrosis. In the United States, only spider bites from the brown recluse
spider (genus Loxosceles) reliably progress to necrosis. In other countries, spiders of the same genus,
such as the Chilean recluse in South America, are also known to cause necrosis. Claims that yellow sac
spiders and hobo spiders possess necrotic venom have not been substantiated.
3. 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 p53 (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.[7][8]

Causes

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), damage to blood vessels (which may disrupt
blood supply to associated tissue), and ischemia.[9] 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.[9] Under extreme conditions tissues and cells die through an
unregulated process of destruction of membranes and cytosol.[10]
Internal factors causing necrosis include trophoneurotic disorders; injury and paralysis of nerve cells. Pancreatic
enzymes (lipases) are the major cause of fat necrosis.[9] Necrosis can be activated by components of the immune
system, such as the complement system; bacterial toxins; activated natural killer cells; and peritoneal
macrophages.[1] Pathogen-induced necrosis programs in cells with immunological barriers (intestinal mucosa)
may alleviate invasion of pathogens through surfaces affected by inflammation.[1] Toxins and pathogens may
cause necrosis; toxins such as snake venoms may inhibit enzymes and cause cell death.[9]Necrotic wounds have
also resulted from the stings of Vespa mandarinia.[11]
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.[9] A classic example of a necrotic
condition is ischemia that leads to a drastic depletion of oxygen, glucose, and other trophic factors and induces
massive necrotic death of endothelial cells and non-proliferating cells of surrounding tissues (neurons,
cardiomyocytes, renal cells, etc.).[1] Recent cytological data indicates that necrotic death occurs not only during
pathological events but it is also a component of some physiological process.[9]
Activation-induced death of primary T-lymphocytes and other 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.[9]

Pathogenesis
[show]Graphic picture
of severe necrosis
following a snake bite

Until recently, necrosis was thought to be an unregulated process.[13] There are two broad pathways in which
necrosis may occur in an organism.[13]
The first of these two pathways initially involves oncosis, where swelling of the cells occur.[13] The cell then
proceeds to blebbing, and this is followed by pyknosis, in which nuclear shrinkage transpires.[13] In the final
step of this pathway the nucleus is dissolved into the cytoplasm, which is referred to as karyolysis.[13]
The second pathway is a secondary form of necrosis that is shown to occur after apoptosis and budding.[13]
Cellular changes of necrosis occur in this secondary form of apoptosis, where the nucleus breaks into
fragments, which is known as karyorrhexis.[13]

Cellular changes
The nucleus changes in necrosis, and characteristics of this change are determined by manner in which its DNA
breaks down:

Karyolysis: the chromatin of the nucleus fades due to the loss of the DNA by degradation.[4]
Pyknosis: the nucleus shrinks and the chromatin condenses.[4]
Karyorrhexis: the shrunken nucleus fragments to complete dispersal.[4]

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.[4]

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, 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 of affected limbs or organs. Chemical removal of necrotic tissue
is another option in which enzymatic debriding agents, categorised as proteolytic, fibrinolytic or
collagenases, are used to target the various components of dead tissue.[14] In select cases, special maggot
therapy using Lucilia sericata larvae has been employed to remove necrotic tissue and infection.[15]
In the case of ischemia, which includes myocardial infarction, the restriction of blood supply to tissues
causes hypoxia and the creation of reactive oxygen species (ROS) that react with, and damage proteins
and membranes. Antioxidant treatments can be applied to scavenge the ROS.[16]
Wounds caused by physical agents, including direct physical trauma and injury, can be treated with
antibiotics and anti-inflammatory 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 therapies such as anti-inflammatory drugs or immunosuppressants.[17] In the
example of a snake bite, the use of anti-venom halts the spread of toxins whilst receiving antibiotics to
impede infection.[18]

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.[19]

In plants

If calcium is deficient, pectin 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.[20]

See also

Avascular necrosis
Frostbite
Gangrene
Necrotizing fasciitis
Osteonecrosis of the jaw
Toxic epidermal necrolysis

References
1.

Proskuryakov SY, Konoplyannikov AG, Gabai VL (2003). "Necrosis: a specific form of

programmed cell death?". Exp. Cell Res. 283 (1): 116. doi:10.1016/S0014-4827(02)00027-7.
PMID 12565815.
2.
Kasper DL, Zaleznik DF (2001). "Gas gangrene, antibiotic associated colitis, and other
Clostridial infections". In Stone RM. Harrison's principles of internal medicine self-assessment and
board review (15th ed.). New York: McGraw-Hill, Medical Pub. Division. pp. 922927.
ISBN 0071386785.
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Craft J, Gordon C, Tiziani A, Huether SE, McCance KL, Brashers VL (2010). Understanding
pathophysiology (1st ed.). Chatswood, N.S.W.: Elsevier Australia. ISBN 0729539512.
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Kumar V, Abbas AK,Aster JC, Fausto N (2010). Robbins and Cotran pathologic basis of disease
(8th ed.). Philadelphia, PA: Saunders/Elsevier. p. 1241. ISBN 1416031219.
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McConnell TH (2007). The nature of disease: pathology for the health professions. Baltimore,
Mar.: Lippincott Williams & Wilkins. ISBN 0781753171.
6.
Stevens A, Lowe JS, Young B, Deakin PJ (2002). Wheater's basic histopathology: a colour atlas
and text (4th ed.). Edinburgh: Churchill Livingstone. ISBN 0443070016.
7.
Saey, Tina Hesman (5 November 2012). "Cancer cells self-destruct in blind mole rats". Science
News. Society for Science and the Public. Retrieved 27 November 2012.
8.
Gorbunova V, Hine C, Tian X, Ablaeva J, Gudkov AV, Nevo E, Seluanov A (2012). "Cancer
resistance in the blind mole rat is mediated by concerted necrotic cell death mechanism". Proc. Natl.
Acad. Sci. U.S.A. 109 (47): 193926. doi:10.1073/pnas.1217211109. PMC 3511137. PMID 23129611.
9.
Raffray M, Cohen GM (1997). "Apoptosis and necrosis in toxicology: a continuum or distinct
modes of cell death?". Pharmacol. Ther. 75 (3): 15377. doi:10.1016/s0163-7258(97)00037-5.
PMID 9504137.
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Nazarian RM, Van Cott EM, Zembowicz A, Duncan LM (2009). "Warfarin-induced skin
necrosis". J. Am. Acad. Dermatol. 61 (2): 32532. doi:10.1016/j.jaad.2008.12.039. PMID 19615543.
11.
Yanagawa, Youichi (10 October 1980). "Cutaneous hemorrhage or necrosis findings after Vespa
mandarinia (wasp) stings may predict the occurrence of multiple organ injury: A case report and review
of literature". Clinical Toxicology (Informa Healthcare USA).
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Leg necrosis
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MV, El-Deiry WS, Golstein P, Green DR, Hengartner M, Knight RA, Kumar S, Lipton SA, Malorni W,
Nuez G, Peter ME, Tschopp J, Yuan J, Piacentini M, Zhivotovsky B, Melino G (January 2009).
"Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009".
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14.
Singhal A, Reis ED, Kerstein MD (2001). "Options for nonsurgical debridement of necrotic
wounds". Adv Skin Wound Care 14 (2): 96100; quiz 1023. PMID 11899913.
15.
Horobin AJ, Shakesheff KM, Pritchard DI (2005). "Maggots and wound healing: an
investigation of the effects of secretions from Lucilia sericata larvae upon the migration of human
dermal fibroblasts over a fibronectin-coated surface". Wound Repair Regen 13 (4): 42233.
doi:10.1111/j.1067-1927.2005.130410.x. PMID 16008732.

16.

Eum HA, Cha YN, Lee SM (2007). "Necrosis and apoptosis: sequence of liver damage
following reperfusion after 60 min ischemia in rats". Biochem. Biophys. Res. Commun. 358 (2): 5005.
doi:10.1016/j.bbrc.2007.04.153. PMID 17490613.
17.
Cooper KL (2012). "Drug reaction, skin care, skin loss". Crit Care Nurse 32 (4): 529.
doi:10.4037/ccn2012340. PMID 22855079.
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Chotenimitkhun R, Rojnuckarin P (2008). "Systemic antivenom and skin necrosis after green pit
viper bites". Clin Toxicol (Phila) 46 (2): 1225. doi:10.1080/15563650701266826. PMID 18259959.
19.
Edinger AL, Thompson CB (2004). "Death by design: apoptosis, necrosis and autophagy". Curr.
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20.
Capon B (2010). Botany for gardeners (3rd ed.). Portland, Or.: Timber Press. ISBN 978-160469-095-8.