Necrosis (from the Greek νέκρωσις "death, the stage of dying, the act of killing" from νεκρός "dead") is a form of cell injury which results in the premature death of cells in living tissue by autolysis.
Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, 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.
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 integrity and an uncontrolled release of products of cell death into the extracellular space.
This initiates in the surrounding tissue an inflammatory response which attracts leukocytes and nearby phagocytes which eliminate the dead cells by phagocytosis. 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 dead tissue and cell debris at or near the site of the cell death. A classic example is gangrene. For this reason, it is often necessary to remove necrotic tissue surgically, a procedure known as debridement.
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.
There are six distinctive morphological patterns of necrosis:
Necrosis may occur due to external or internal 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. Thermal effects (extremely high or low temperature) can result in necrosis due to the disruption of cells.
In frostbite, crystals form, increasing the pressure of remaining tissue and fluid causing the cells to burst. Under extreme conditions tissues and cells die through an unregulated process of destruction of membranes and cytosol.
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.
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 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 the occurrence of necrotic cell death can not only occur during pathological processe, but also during normal processes such as tissue renewal, embryogenesis, and immune response.
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).
The nucleus changes in necrosis and characteristics of this change are determined by manner in which its DNA breaks down:
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.
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.
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.
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. For example, necrosis of tissue can occur in Arabidopsis thaliana due to plant pathogens.
ADAM metallopeptidase domain 17 (ADAM17), also called TACE (tumor necrosis factor-α-converting enzyme), is a 70-kDa enzyme that belongs to the ADAM protein family of disintegrins and metalloproteases.Acute pancreatitis
Acute pancreatitis is a sudden inflammation of the pancreas. Causes in order of frequency include a gallstone impacted in the common bile duct beyond the point where the pancreatic duct joins it; heavy alcohol use; systemic disease; trauma; and, in minors, mumps. Acute pancreatitis may be a single event; it may be recurrent; or it may progress to chronic pancreatitis.
Mild cases are usually successfully treated with conservative measures: hospitalization, pain control, nothing by mouth, intravenous nutritional support, and intravenous fluid rehydration. Severe cases often require admission to an intensive care unit to monitor and manage complications of the disease. Complications are associated with a high mortality, even with optimal management.Acute tubular necrosis
Acute tubular necrosis (ATN) is a medical condition involving the death of tubular epithelial cells that form the renal tubules of the kidneys. ATN presents with acute kidney injury (AKI) and is one of the most common causes of AKI. Common causes of ATN include low blood pressure and use of nephrotoxic drugs. The presence of "muddy brown casts" of epithelial cells found in the urine during urinalysis is pathognomonic for ATN. Management relies on aggressive treatment of the factors that precipitated ATN (e.g. hydration and cessation of the offending drug). Because the tubular cells continually replace themselves, the overall prognosis for ATN is quite good if the underlying cause is corrected, and recovery is likely within 7 to 21 days.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. Complications may include collapse of the bone or nearby joint surface.Risk factors include bone fractures, joint dislocations, alcoholism, and the use of high-dose steroids. The condition may also occur without any clear reason. The most commonly affected bone is the femur. Other relatively common sites include the upper arm bone, knee, shoulder, and ankle. Diagnosis is typically by medical imaging such as X-ray, CT scan, or MRI. Rarely biopsy may be used.Treatments may include medication, not walking on the affected leg, stretching, and surgery. Most of the time surgery is eventually required and may include core decompression, osteotomy, bone grafts, or joint replacement. About 15,000 cases occur per year in the United States. People 30 to 50 years old are most commonly affected. Males are more commonly affected than females.CD120
CD120 (Cluster of Differentiation 120) can refer to two members of the tumor necrosis factor receptor superfamily: tumor necrosis factor receptor 1 (TNFR1) and tumor necrosis factor receptor 2 (TNFR2).Caseous necrosis
Caseous necrosis is a form of cell death in which the tissue maintains a cheese-like appearance. The dead tissue appears as a soft and white proteinaceous dead cell mass.Cell death
Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, or may result from such factors as disease, localized injury, or the death of the organism of which the cells are part. Apoptosis or Type I cell-death, and autophagy or Type II cell-death are both forms of programmed cell death, while necrosis is a non-physiological process that occurs as a result of infection or injury.Coagulative necrosis
Coagulative necrosis is a type of accidental cell death typically caused by ischemia or infarction. In coagulative necrosis the architecture of dead tissue is preserved for at least a couple of days. It is believed that the injury denatures structural proteins as well as lysosomal enzymes thus blocking the proteolysis of the damaged cells. The lack of lysosomal enzymes allows it to maintain a "coagulated" morphology for some time. Like most types of necrosis if enough viable cells are present around the affected area regeneration will usually occur.
Coagulative necrosis can also be induced by high local temperature; it is a desired effect of treatments such as high intensity focused ultrasound applied to cancerous cells.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 appear as white chalky deposits.It is usually associated with trauma of the pancreas or acute pancreatitis.It can also occur in the breast, the salivary glands and neonates after a traumatic delivery.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 are a result of type III hypersensitivity. When stained with hematoxylin and eosin, they appear brightly eosinophilic and smudged.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. Certain types may present with a fever or sepsis.Risk factors include diabetes, peripheral arterial disease, smoking, major trauma, alcoholism, HIV/AIDS, frostbite, and Raynaud's syndrome. It can be classified as dry gangrene, wet gangrene, gas gangrene, internal gangrene, and necrotizing fasciitis. The diagnosis of gangrene is based on symptoms and supported by tests such as medical imaging.Treatment may involve surgery to remove the dead tissue, antibiotics to treat any infection, and efforts to address the underlying cause. Surgical efforts may include debridement, amputation, or the use of maggot therapy. Efforts to treat the underlying cause may include bypass surgery or angioplasty. In certain cases, hyperbaric oxygen therapy may be useful. How commonly the condition occurs is unknown.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. Often it is associated with focal bacterial or fungal infections, and can also manifest as one of the symptoms of an internal chemical burn. In liquefactive necrosis, the affected cell is completely digested by hydrolytic enzymes, resulting in a soft, circumscribed lesion consisting of pus and the fluid remains of necrotic tissue. Dead leukocytes will remain as a creamy yellow pus. After the removal of cell debris by white blood cells, a fluid filled space is left. It is generally associated with abscess formation and is commonly found in the central nervous system.Sheehan's syndrome
Sheehan's syndrome, also known as postpartum pituitary gland necrosis, is hypopituitarism (decreased functioning of the pituitary gland), caused by ischemic necrosis due to blood loss and hypovolemic shock during and after childbirth.TNF receptor superfamily
The tumor necrosis factor receptor superfamily (TNFRSF) is a protein superfamily of cytokine receptors characterized by the ability to bind tumor necrosis factors (TNFs) via an extracellular cysteine-rich domain. With the exception of nerve growth factor (NGF), all TNFs are homologous to the archetypal TNF-alpha. In their active form, the majority of TNF receptors form trimeric complexes in the plasma membrane. Accordingly, most TNF receptors contain transmembrane domains (TMDs), although some can be cleaved into soluble forms (e.g. TNFR1), and some lack a TMD entirely (e.g. DcR3). In addition, most TNF receptors require specific adaptor protein such as TRADD, TRAF, RIP and FADD for downstream signalling. TNF receptors are primarily involved in apoptosis and inflammation, but they can also take part in other signal transduction pathways, such as proliferation, survival, and differentiation. TNF receptors are expressed in a wide variety of tissues in mammals, especially in leukocytes.The term death receptor refers to those members of the TNF receptor superfamily that contain a death domain, such as TNFR1, Fas receptor, DR4 and DR5. They were named after the fact that they seemed to play an important role in apoptosis (programmed cell death), although they are now known to play other roles as well.In the strict sense, the term TNF receptor is often used to refer to the archetypal members of the superfamily, namely TNFR1 and TNFR2, which recognize TNF-alpha.Tumor necrosis factor alpha
Tumor necrosis factor (TNF, tumor necrosis factor alpha, TNFα, cachexin, or cachectin) is a cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction. It is produced chiefly by activated macrophages, although it can be produced by many other cell types such as CD4+ lymphocytes, NK cells, neutrophils, mast cells, eosinophils, and neurons. TNFα is a member of the TNF superfamily, consisting of various transmembrane proteins with a homologous TNF domain.
The primary role of TNF is in the regulation of immune cells. TNF, being an endogenous pyrogen, is able to induce fever, apoptotic cell death, cachexia, inflammation and to inhibit tumorigenesis and viral replication and respond to sepsis via IL1 & IL6 producing cells. Dysregulation of TNF production has been implicated in a variety of human diseases including Alzheimer's disease, cancer, major depression, psoriasis and inflammatory bowel disease (IBD). Though controversial, studies of depression and IBD are currently being linked to increased levels of TNFα. Recombinant TNF is used as an immunostimulant under the INN tasonermin. TNF can be produced ectopically in the setting of malignancy and parallels parathyroid hormone both in causing secondary hypercalcemia and in the cancers with which excessive production is associated.Tumor necrosis factor receptor 1
Tumor necrosis factor receptor 1 (TNFR1), also known as tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) and CD120a, is a ubiquitous membrane receptor that binds tumor necrosis factor-alpha (TNFα).Tumor necrosis factor receptor 2
Tumor necrosis factor receptor 2 (TNFR2), also known as tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) and CD120b, is a membrane receptor that binds tumor necrosis factor-alpha (TNFα).Tumor necrosis factor superfamily
The tumor necrosis factor (TNF) superfamily is a protein superfamily of type II transmembrane proteins containing TNF homology domain and forming trimers. Members of this superfamily can be released from the cell membrane by extracellular proteolytic cleavage and function as a cytokine. These proteins are expressed predominantly by immune cells and they regulate diverse cell functions, including immune response and inflammation, but also proliferation, differentiation, apoptosis and embryogenesis.The superfamily contains 19 members that bind to 29 members of TNF receptor superfamily. An occurrence of orthologs in invertebrates hints at ancient origin of this superfamily in evolution.The PROSITE pattern of this superfamily is located in a beta sheet in the central section of the protein that is conserved across all members.Vasculitis
Vasculitis is a group of disorders that destroy blood vessels by inflammation. Both arteries and veins are affected. Lymphangitis is sometimes considered a type of vasculitis. Vasculitis is primarily caused by leukocyte migration and resultant damage.
Although both occur in vasculitis, inflammation of veins (phlebitis) or arteries (arteritis) on their own are separate entities.
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