Necrosis

Emerging research led by Dr Carina Kern in 2025 has shown that necrosis is a potential key target as a driver of aging and chronic disease{{Cite journal |last=Kern |first=Carina |last2=Bonventre |first2=Joseph V. |last3=Justin |first3=Alexander W. |last4=Kashani |first4=Kianoush |last5=Reynolds |first5=Elizabeth |last6=Siew |first6=Keith |last7=Davis |first7=Bill |last8=Karakoy |first8=Halime |last9=Grzesiak |first9=Nikodem |last10=Bailey |first10=Damian Miles |date=2025-05-29 |title=Necrosis as a fundamental driver of loss of resilience and biological decline: what if we could intervene? |url=https://www.nature.com/articles/s41388-025-03431-y |journal=Oncogene |language=en |pages=1–12 |doi=10.1038/s41388-025-03431-y |issn=1476-5594}}. Feed back loops created by spillage from necrotic cells affects wider tissues leading to damage and loss of resilience over time. This is accompanied by maladaptive wound healing that drives chronic inflammation, senescent cell accumulation and fibrosis. [https://doi.org/10.1038/s41388-025-03431-y]

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.{{cite book |vauthors=Craft J, Gordon C, Tiziani A, Huether SE, McCance KL, Brashers VL | title = Understanding pathophysiology | year = 2010 | publisher = Elsevier Australia | location = Chatswood, N.S.W. | isbn = 978-0-7295-3951-7 |oclc=994801732}}

There are six distinctive morphological patterns of necrosis:{{cite book|vauthors=Kumar V, Abbas AK, Aster JC, Fausto N | title = Robbins and Cotran pathologic basis of disease | year = 2010 | publisher = Saunders/Elsevier | location = Philadelphia, PA | isbn = 978-1-4160-3121-5 | pages = 12–41 | edition = 8th |oclc=1409188915}}

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, and can be observed by light microscopy. Coagulation occurs as a result of protein denaturation, causing albumin to transform into a firm and opaque state. 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. Severe ischemia most commonly causes necrosis of this form.{{cite book | author = McConnell TH | title = The nature of disease: pathology for the health professions | year = 2007 | publisher = Lippincott Williams & Wilkins | location = Baltimore, Mar. | isbn = 978-0-7817-5317-3 |oclc=71139383}}
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. 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. 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. Gangrenous necrosis can be considered a type of coagulative necrosis that resembles mummified tissue. It is characteristic of ischemia of lower limb and the gastrointestinal tracts. Both dry gangrene and gas gangrene can lead to this type of necrosis. If superimposed infection of dead tissues occurs, then liquefactive necrosis ensues (wet gangrene).{{cite book| author = Sattar | title = Fundamentals of Pathology | year = 2015 | publisher = Pathoma LLC | location = Chicago, IL | isbn = 978-0-9832246-2-4| pages = 5 | edition = 2015th |oclc=1301972970}}
4. Caseous necrosis can be considered a combination of coagulative and liquefactive necrosis, 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. Microscopic examination shows amorphous granular debris enclosed within a distinctive inflammatory border. Some granulomas contain this pattern of necrosis.{{cite book|vauthors=Stevens A, Lowe JS, Young B, Deakin PJ | title = Wheater's basic histopathology: a colour atlas and text |year = 2002 | publisher = Churchill Livingstone | location = Edinburgh | isbn = 978-0-443-07001-3 | edition = 4th |oclc=606877653}}
5. Fat necrosis is specialized necrosis of fat tissue, 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.
6. Fibrinoid necrosis is a special form of necrosis usually caused by immune-mediated vascular damage. It is marked by complexes of antigen and antibodies, referred to as immune complexes deposited within arterial walls together with fibrin.

1. There are also very specific forms of necrosis such as gangrene (term used in clinical practices for limbs which have had severe hypoxia), gummatous necrosis (due to spirochaetal infections) and hemorrhagic necrosis (due to the blockage of venous drainage of an organ or tissue).{{citation needed|date=May 2023}}
2. Myonecrosis is the death of individual muscle fibres due to injury, hypoxia, or infection. Common causes include spontaneous diabetic myonecrosis (a.k.a. diabetic muscle infarction) and clostridial myonecrosis (a.k.a. gas gangrene).{{Cite web |title=Medical Definition of Myonecrosis; Doctor Written |url=https://www.rxlist.com/myonecrosis/definition.htm |access-date=2023-06-09 |website=RxList |language=en}}
3. 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.{{citation needed|date=May 2023}}
4. 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.{{cite web| vauthors = Saey TH |title=Cancer cells self-destruct in blind mole rats|url=http://www.sciencenews.org/view/generic/id/346267/description/Cancer_cells_self-destruct_in_blind_mole_rats|website=Science News|publisher=Society for Science and the Public|access-date=27 November 2012|date=5 November 2012|archive-date=19 June 2013|archive-url=https://web.archive.org/web/20130619171046/http://www.sciencenews.org/view/generic/id/346267/description/Cancer_cells_self-destruct_in_blind_mole_rats|url-status=live}}{{cite journal | vauthors = Gorbunova V, Hine C, Tian X, Ablaeva J, Gudkov AV, Nevo E, Seluanov A | title = Cancer resistance in the blind mole rat is mediated by concerted necrotic cell death mechanism | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 47 | pages = 19392–6 | date = November 2012 | pmid = 23129611 | pmc = 3511137 | doi = 10.1073/pnas.1217211109 | doi-access = free | bibcode = 2012PNAS..10919392G }}

File:Hand necrosis caused by plague.jpg]]

Necrosis may occur due to external or internal factors.

External factors may involve mechanical trauma (physical damage to the body which causes cellular breakdown), electric shock,{{cite book | vauthors = Khalid N, Azimpouran M | chapter = Necrosis |date=2023 | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK557627/ |title = StatPearls |access-date=2023-09-19 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=32491559 }} damage to blood vessels (which may disrupt blood supply to associated tissue), and ischemia.{{cite journal | vauthors = Raffray M, Cohen GM | title = Apoptosis and necrosis in toxicology: a continuum or distinct modes of cell death? | journal = Pharmacology & Therapeutics | volume = 75 | issue = 3 | pages = 153–177 | date = September 1997 | pmid = 9504137 | doi = 10.1016/s0163-7258(97)00037-5 }} Thermal effects (extremely high or low temperature) can often result in necrosis due to the disruption of cells, especially in bone cells.{{cite journal | vauthors = Kniha K, Heussen N, Weber E, Möhlhenrich SC, Hölzle F, Modabber A | title = Temperature Threshold Values of Bone Necrosis for Thermo-Explantation of Dental Implants-A Systematic Review on Preclinical In Vivo Research | journal = Materials | volume = 13 | issue = 16 | pages = 3461 | date = August 2020 | pmid = 32781597 | pmc = 7476012 | doi = 10.3390/ma13163461 | doi-access = free | bibcode = 2020Mate...13.3461K }}

Necrosis can also result from chemical trauma, with alkaline and acidic compounds causing liquefactive and coagulative necrosis, respectively, in affected tissues. The severity of such cases varies significantly based on multiple factors, including the compound concentration, type of tissue affected, and the extent of chemical exposure.

In frostbite, crystals form, increasing the pressure of remaining tissue and fluid causing the cells to burst.{{Cite web |date=2020-08-16 |title=Frostbite |url=https://www.health.harvard.edu/a_to_z/frostbite-a-to-z |access-date=2023-09-19 |website=Harvard Health |language=en}} Under extreme conditions tissues and cells may die through an unregulated process of membrane and cytosol destruction.{{cite journal | vauthors = Nazarian RM, Van Cott EM, Zembowicz A, Duncan LM | title = Warfarin-induced skin necrosis | journal = Journal of the American Academy of Dermatology | volume = 61 | issue = 2 | pages = 325–332 | date = August 2009 | pmid = 19615543 | doi = 10.1016/j.jaad.2008.12.039 }}

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; bacterial toxins; 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. Necrotic wounds have also resulted from the stings of Vespa mandarinia.{{cite journal | vauthors = Yanagawa Y, Morita K, Sugiura T, Okada Y | title = 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 | journal = Clinical Toxicology | volume = 45 | issue = 7 | pages = 803–7 | date = 10 October 1980 | pmid = 17952752 | doi = 10.1080/15563650701664871 | s2cid = 11337426 }}

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 which leads to a drastic depletion of oxygen, glucose, and other trophic factors{{Cite web|url=http://cellbiology.med.unsw.edu.au/units/science/project2004/Celldeathregulation.htm|title=Cell death regulation: trophic factors|archive-url=https://web.archive.org/web/20071010132549/http://cellbiology.med.unsw.edu.au/units/science/project2004/Celldeathregulation.htm|archive-date=10 October 2007}} and induces 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 other important constituents of the immune response are caspase-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, and immune response.

Until recently, necrosis was thought to be an unregulated process.{{cite journal | vauthors = Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, Hengartner M, Knight RA, Kumar S, Lipton SA, Malorni W, Nuñez G, Peter ME, Tschopp J, Yuan J, Piacentini M, Zhivotovsky B, Melino G | display-authors = 6 | title = Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009 | journal = Cell Death and Differentiation | volume = 16 | issue = 1 | pages = 3–11 | date = January 2009 | pmid = 18846107 | pmc = 2744427 | doi = 10.1038/cdd.2008.150 }} However, 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 occurs. Affected cells then proceed to blebbing, and this is followed by pyknosis, 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.

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).

{{Further|Myocardial infarction diagnosis}}

{{Anchor|Pseudopalisade|Cytoplasmic hypereosinophilia}}Image:MI_with_contraction_bands_very_high_mag.jpg (and contraction band necrosis) in myocardial infarction (heart attack)]]

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

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

Other typical cellular changes in necrosis include:

• Cytoplasmic hypereosinophilia on samples with H&E stain.{{cite book | chapter = Frozen Section Diagnosis | chapter-url = https://books.google.com/books?id=n8AtBQAAQBAJ&pg=PA320 | page = 320 | archive-url = https://web.archive.org/web/20200804105603/https://books.google.se/books?id=n8AtBQAAQBAJ&pg=PA320 | archive-date=2020-08-04 | vauthors = Marchevsky AM, Balzer B, Abdul-Karim FW |title=Intraoperative Consultation E-Book | series = Foundations in Diagnostic Pathology |year=2014|publisher=Elsevier |isbn=978-0-323-32299-7 |oclc=898153075}} It is seen as a darker stain of the cytoplasm.
• The cell membrane appears discontinuous when viewed with an electron microscope. This discontinuous membrane is caused by cell blebbing and the loss of microvilli.

On a larger histologic scale, pseudopalisades (false palisades) are hypercellular zones that typically surround necrotic tissue. Pseudopalisading necrosis indicates an aggressive tumor.{{cite journal | vauthors = Wippold FJ, Lämmle M, Anatelli F, Lennerz J, Perry A | title = Neuropathology for the neuroradiologist: palisades and pseudopalisades | journal = AJNR. American Journal of Neuroradiology | volume = 27 | issue = 10 | pages = 2037–41 | date = 2006 | pmid = 17110662 | pmc = 7977220 }}

File:4 Bd obs 4 680x512px.tif|Pyknosis 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

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.{{citation needed|date=June 2022}}

• 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.{{cite journal | vauthors = Singhal A, Reis ED, Kerstein MD | title = Options for nonsurgical debridement of necrotic wounds | journal = Advances in Skin & Wound Care | volume = 14 | issue = 2 | pages = 96–100; quiz 102–3 | year = 2001 | pmid = 11899913 | doi = 10.1097/00129334-200103000-00014 }} In select cases, special maggot therapy using Lucilia sericata larvae has been employed to remove necrotic tissue and infection.{{cite journal | vauthors = Horobin AJ, Shakesheff KM, Pritchard DI | title = 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 | journal = Wound Repair and Regeneration | volume = 13 | issue = 4 | pages = 422–433 | year = 2005 | pmid = 16008732 | doi = 10.1111/j.1067-1927.2005.130410.x | s2cid = 7861732 }}
• 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.{{cite journal | vauthors = Eum HA, Cha YN, Lee SM | title = Necrosis and apoptosis: sequence of liver damage following reperfusion after 60 min ischemia in rats | journal = Biochemical and Biophysical Research Communications | volume = 358 | issue = 2 | pages = 500–5 | date = June 2007 | pmid = 17490613 | doi = 10.1016/j.bbrc.2007.04.153 }}
• Wounds caused by physical agents, including physical trauma and chemical burns, 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.{{cite journal | vauthors = Cooper KL | title = Drug reaction, skin care, skin loss | journal = Critical Care Nurse | volume = 32 | issue = 4 | pages = 52–59 | date = August 2012 | pmid = 22855079 | doi = 10.4037/ccn2012340 | doi-access = free }} In the example of a snake bite, the use of anti-venom halts the spread of toxins whilst receiving antibiotics to impede infection.{{cite journal | vauthors = Chotenimitkhun R, Rojnuckarin P | title = Systemic antivenom and skin necrosis after green pit viper bites | journal = Clinical Toxicology | volume = 46 | issue = 2 | pages = 122–5 | date = February 2008 | pmid = 18259959 | doi = 10.1080/15563650701266826 | s2cid = 6827421 }}

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.{{cite journal | vauthors = Edinger AL, Thompson CB | title = Death by design: apoptosis, necrosis and autophagy | journal = Current Opinion in Cell Biology | volume = 16 | issue = 6 | pages = 663–9 | date = December 2004 | pmid = 15530778 | doi = 10.1016/j.ceb.2004.09.011 }}

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.{{cite book| author = Capon B | title = Botany for gardeners | date = 2010 | publisher = Timber Press | location = Portland, OR | isbn = 978-1-60469-095-8 | edition = 3rd |oclc=436623458}} For example, necrosis of tissue can occur in Arabidopsis thaliana due to plant pathogens.{{cite journal |vauthors=Summermatter K, Sticher L, Metraux JP |title=Systemic Responses in Arabidopsis thaliana Infected and Challenged with Pseudomonas syringae pv syringae |journal=Plant Physiol |volume=108 |issue=4 |pages=1379–85 |date=August 1995 |pmid=12228548 |pmc=157515 |doi=10.1104/pp.108.4.1379 }}

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.{{cite journal |vauthors=Giraudo M, Unnithan GC, Le Goff G, Feyereisen R |title=Regulation of cytochrome P450 expression in Drosophila: Genomic insights |journal=Pestic Biochem Physiol |volume=97 |issue=2 |pages=115–122 |date=June 2010 |pmid=20582327 |pmc=2890303 |doi=10.1016/j.pestbp.2009.06.009 }}

{{Div col|colwidth=15em}}

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

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{{Reflist|32em}}

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• [https://web.archive.org/web/20091124192117/http://lifeinthefastlane.com/2009/09/toxicology-conundrum-018/ Toxicology Conundrum #018]—Life in the Fast Lane
• {{cite web |url=http://www.uhms.org/ResourceLibrary/Indications/NecrotizingSoftTissueInfections/tabid/279/Default.aspx |title=Necrotizing Soft Tissue Infections |author=Undersea and Hyperbaric Medical Society |access-date=25 July 2008 |url-status=dead |archive-url=https://web.archive.org/web/20080705205656/http://www.uhms.org/ResourceLibrary/Indications/NecrotizingSoftTissueInfections/tabid/279/Default.aspx |archive-date=5 July 2008 }}
• [https://www.youtube.com/watch?v=OyHnXEgNL7Q Secondary necrosis of a neutrophil]

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Category:Cell death

Category:Causes of amputation

Category:Cellular processes