Structural changes of cells undergoing necrosis andapoptosis
Necrosis (from Ancient Greekνέκρωσις (nékrōsis)'death') is a form ofcell injury which results in the prematuredeath ofcells in livingtissue byautolysis.[1] The term "necrosis" came about in the mid-19th century and is commonly attributed to German pathologistRudolf Virchow, who is often regarded as one of the founders of modern pathology.[2] 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 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.[3]
Cellular death due to necrosis does not follow the apoptotic signal transduction pathway, but rather various receptors are activated and result in the loss ofcell membrane integrity[4] and an uncontrolled release of products of cell death into theextracellular space.[1] This initiates aninflammatory response in the surrounding tissue, which attractsleukocytes and nearbyphagocytes which eliminate the dead cells byphagocytosis. However, microbial damaging substances released by leukocytes would create collateral damage to surrounding tissues.[5] This excess collateral damage inhibits the healing process. Thus, untreated necrosis results in a build-up ofdecomposing dead tissue and cell debris at or near the site of the cell death. A classic example isgangrene. For this reason, it is often necessary to remove necrotic tissuesurgically, aprocedure known asdebridement.[citation needed]
Structural signs that indicate irreversible cell injury and the progression of necrosis include dense clumping and progressive disruption ofgenetic material, and disruption to membranes of cells andorganelles.[6]
There are six distinctive morphological patterns of necrosis:[7]
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,[7] and can be observed by light microscopy. Coagulation occurs as a result of proteindenaturation, causingalbumin to transform into a firm and opaque state.[6] This pattern of necrosis is typically seen inhypoxic (low-oxygen) environments, such asinfarction. Coagulative necrosis occurs primarily in tissues such as the kidney, heart and adrenal glands.[6] Severeischemia most commonly causes necrosis of this form.[8]
Liquefactive necrosis (or colliquative necrosis), in contrast to coagulative necrosis, is characterized by the digestion of dead cells to form a viscous liquid mass.[7] 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 deadleukocytes and is commonly known aspus.[7]Hypoxicinfarcts 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.[6]
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).[9]
Caseous necrosis can be considered a combination of coagulative and liquefactive necrosis,[6] typically caused bymycobacteria (e.g.tuberculosis), fungi and some foreign substances. The necrotic tissue appears as white andfriable, like clumped cheese. Dead cells disintegrate but are not completely digested, leaving granular particles.[6] Microscopic examination showsamorphous granular debris enclosed within a distinctive inflammatory border.[7] Somegranulomas contain this pattern of necrosis.[10]
Fat necrosis is specialized necrosis of fat tissue,[10] resulting from the action of activatedlipases on fatty tissues such as thepancreas. In the pancreas it leads to acutepancreatitis, a condition where thepancreatic enzymes leak out into theperitoneal cavity, and liquefy the membrane by splitting thetriglyceride esters intofatty acids through fatsaponification.[7] Calcium, magnesium or sodium may bind to these lesions to produce a chalky-white substance.[6] The calcium deposits are microscopically distinctive and may be large enough to be visible on radiographic examinations.[8] To the naked eye, calcium deposits appear as gritty white flecks.[8]
There are also very specific forms of necrosis such asgangrene (term used in clinical practices for limbs which have had severe hypoxia),gummatous necrosis (due tospirochaetal infections) and hemorrhagic necrosis (due to the blockage of venous drainage of an organ or tissue).[citation needed]
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).[11]
In blind mole rats (genusSpalax), the process of necrosis replaces the role of the systematicapoptosis 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 thetumor suppressor proteinp53 (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 releaseinterferon-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 otherspalacids are resistant to cancer.[12][13]
External factors may involve mechanical trauma (physical damage to the body which causes cellular breakdown), electric shock,[14] damage to blood vessels (which may disrupt blood supply to associated tissue), andischemia.[15] Thermal effects (extremely high or low temperature) can often result in necrosis due to the disruption of cells, especially in bone cells.[16]
Necrosis can also result from chemical trauma, withalkaline andacidic compounds causingliquefactive andcoagulative 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.
Infrostbite, crystals form, increasing the pressure of remaining tissue and fluid causing the cells to burst.[17] Under extreme conditions tissues and cells may die through an unregulated process of membrane and cytosol destruction.[18]
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.[15]
Pathological conditions are characterized by inadequate secretion ofcytokines.Nitric oxide (NO) andreactive oxygen species (ROS) are also accompanied by intense necrotic death of cells.[15] A classic example of a necrotic condition isischemia which leads to a drastic depletion ofoxygen,glucose, and othertrophic factors[20] and induces massive necrotic death of endothelial cells and non-proliferating cells of surrounding tissues (neurons, cardiomyocytes, renal cells, etc.).[1] Recentcytological data indicates that necrotic death occurs not only during pathological events but it is also a component of somephysiological process.[15]
Activation-induced death of primaryT lymphocytes and other important constituents of the immune response arecaspase-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.[15]
Until recently, necrosis was thought to be an unregulated process.[21] However, there are two broad pathways in which necrosis may occur in an organism.[21]
The first of these two pathways initially involvesoncosis, where swelling of the cells occurs.[21] Affected cells then proceed toblebbing, and this is followed bypyknosis, in which nuclear shrinkage transpires.[21] In the final step of this pathway cell nuclei are dissolved into the cytoplasm, which is referred to askaryolysis.[21]
The second pathway is a secondary form of necrosis that is shown to occur after apoptosis and budding.[21] In these cellular changes of necrosis, the nucleus breaks into fragments (known askaryorrhexis).[21]
On a larger histologic scale,pseudopalisades (falsepalisades) are hypercellular zones that typically surround necrotic tissue. Pseudopalisading necrosis indicates an aggressive tumor.[23]
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]
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 completeamputation of affected limbs or organs. Chemical removal of necrotic tissue is another option in which enzymatic debriding agents, categorised asproteolytic,fibrinolytic orcollagenases, are used to target the various components of dead tissue.[24] In select cases, specialmaggot therapy usingLucilia sericata larvae has been employed to remove necrotic tissue and infection.[25]
Wounds caused by physical agents, including physicaltrauma andchemical burns, can be treated withantibiotics andanti-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 ofimmunosuppressive therapies such asanti-inflammatory drugs or immunosuppressants.[27] In the example of asnake bite, the use ofanti-venom halts the spread of toxins whilst receivingantibiotics to impede infection.[28]
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.[29]
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.[30] For example, necrosis of tissue can occur inArabidopsis thaliana due to plant pathogens.[31]
Cacti such as the Saguaro and Cardon in the Sonoran Desert experience necrotic patch formation regularly; a species of Dipterans calledDrosophilamettleri has developed aP450 detoxification system to enable it to use the exudates released in these patches to both nest and feed larvae.[32]
^abcdeProskuryakov SY, Konoplyannikov AG, Gabai VL (February 2003). "Necrosis: a specific form of programmed cell death?".Experimental Cell Research.283 (1):1–16.doi:10.1016/S0014-4827(02)00027-7.PMID12565815.
^Kasper DL, Zaleznik DF (2001). "Gas gangrene, antibiotic associated colitis, and other Clostridial infections". In Stone RM (ed.).Harrison's principles of internal medicine self-assessment and board review (15th ed.). McGraw-Hill. pp. 922–7.ISBN978-0-07-138678-4.
^abcdefgCraft J, Gordon C, Tiziani A, Huether SE, McCance KL, Brashers VL (2010).Understanding pathophysiology. Chatswood, N.S.W.: Elsevier Australia.ISBN978-0-7295-3951-7.OCLC994801732.
^abcdefghijklKumar V, Abbas AK, Aster JC, Fausto N (2010).Robbins and Cotran pathologic basis of disease (8th ed.). Philadelphia, PA: Saunders/Elsevier. pp. 12–41.ISBN978-1-4160-3121-5.OCLC1409188915.
^abcMcConnell TH (2007).The nature of disease: pathology for the health professions. Baltimore, Mar.: Lippincott Williams & Wilkins.ISBN978-0-7817-5317-3.OCLC71139383.
^abStevens A, Lowe JS, Young B, Deakin PJ (2002).Wheater's basic histopathology: a colour atlas and text (4th ed.). Edinburgh: Churchill Livingstone.ISBN978-0-443-07001-3.OCLC606877653.
^Khalid N, Azimpouran M (2023)."Necrosis".StatPearls. Treasure Island (FL): StatPearls Publishing.PMID32491559. Retrieved2023-09-19.
^abcdefRaffray M, Cohen GM (September 1997). "Apoptosis and necrosis in toxicology: a continuum or distinct modes of cell death?".Pharmacology & Therapeutics.75 (3):153–177.doi:10.1016/s0163-7258(97)00037-5.PMID9504137.
^Nazarian RM, Van Cott EM, Zembowicz A, Duncan LM (August 2009). "Warfarin-induced skin necrosis".Journal of the American Academy of Dermatology.61 (2):325–332.doi:10.1016/j.jaad.2008.12.039.PMID19615543.
^Yanagawa Y, Morita K, Sugiura T, Okada Y (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.45 (7):803–7.doi:10.1080/15563650701664871.PMID17952752.S2CID11337426.
^Singhal A, Reis ED, Kerstein MD (2001). "Options for nonsurgical debridement of necrotic wounds".Advances in Skin & Wound Care.14 (2):96–100, quiz 102–3.doi:10.1097/00129334-200103000-00014.PMID11899913.
^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 and Regeneration.13 (4):422–433.doi:10.1111/j.1067-1927.2005.130410.x.PMID16008732.S2CID7861732.
^Eum HA, Cha YN, Lee SM (June 2007). "Necrosis and apoptosis: sequence of liver damage following reperfusion after 60 min ischemia in rats".Biochemical and Biophysical Research Communications.358 (2):500–5.doi:10.1016/j.bbrc.2007.04.153.PMID17490613.
