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Necrosis

Necrosis is the pathological death of cells and tissues in a living organism, typically resulting from acute and irreversible injury that overwhelms cellular repair mechanisms, leading to uncontrolled breakdown of cellular structures, plasma membrane rupture, and release of intracellular contents that trigger an inflammatory response.^[1] Unlike apoptosis, which is a programmed and orderly process that avoids inflammation, necrosis is passive and chaotic, often manifesting as swelling of organelles (oncosis), nuclear condensation (pyknosis), fragmentation (karyorrhexis), or dissolution (karyolysis), ultimately causing tissue damage.^[2] This form of cell death has been recognized since the 19th century, with the term derived from the Greek nekros meaning "dead body," and it serves as a hallmark in pathology for diagnosing various diseases.^[2] The primary causes of necrosis include hypoxia from ischemia or infarction, where insufficient blood supply deprives cells of oxygen and nutrients; physical trauma such as burns or mechanical injury; chemical and toxin exposure, including poisons or therapeutic agents; infectious agents like bacteria or viruses; and immunological reactions involving immune-mediated damage.^[1] These insults disrupt cellular homeostasis, leading to loss of membrane integrity, influx of ions and water, mitochondrial dysfunction, and activation of lysosomal enzymes that digest cellular components.^[1] In recent understandings, while classical necrosis is considered accidental and unregulated, emerging research highlights regulated forms such as necroptosis, a programmed necrotic pathway involving receptor-interacting protein kinases (RIPK1 and RIPK3) and mixed lineage kinase domain-like protein (MLKL), triggered by stimuli like tumor necrosis factor (TNF) under conditions where apoptosis is inhibited. Additionally, as of 2025, studies have described PANoptosis, a coordinated inflammatory cell death integrating apoptosis, pyroptosis, and necroptosis, highlighting further complexity in regulated necrosis pathways.^[2]^[3] Necrosis presents in distinct morphological types based on the underlying cause, affected tissue, and progression: coagulative necrosis, the most common, preserves cellular outlines with denatured proteins and is seen in hypoxic injury to organs like the heart or kidney; liquefactive necrosis, involving tissue digestion into a liquid viscous mass, occurs in bacterial infections or the central nervous system; caseous necrosis, with a cheese-like appearance, is characteristic of granulomatous diseases such as tuberculosis; fat necrosis, resulting from enzymatic digestion of adipose tissue, as in acute pancreatitis; gangrenous necrosis, a form of coagulative necrosis with bacterial superinfection leading to putrefaction, often in extremities; and fibrinoid necrosis, involving vessel wall damage in immune or hypertensive conditions.^[1] These patterns are identified histopathologically and guide etiological diagnosis.^[1] Clinically, necrosis contributes to numerous conditions, including myocardial infarction, stroke, gangrene, and organ failure, where it amplifies tissue injury through secondary inflammation and impairs organ function.^[1] Understanding necrosis not only aids in pinpointing disease mechanisms but also informs therapeutic interventions, such as restoring blood flow in ischemia or targeting regulated pathways like necroptosis with inhibitors of RIPK1 to mitigate inflammatory damage in autoimmune or neurodegenerative disorders.^[2] Ongoing research into the molecular regulators of necrosis continues to reveal its role in both pathology and potential therapeutic modulation.^[2]

Overview

Definition and characteristics

Necrosis is defined as the premature death of cells and living tissue resulting from irreversible damage, typically caused by external injuries such as ischemia, trauma, or toxins, in contrast to programmed cell death mechanisms.^[1] This process is passive and uncontrolled, distinguishing it from regulated forms of cell death like apoptosis.^[4] The term "necrosis" originates from the Greek word nekrosis, meaning "death" or "the act of killing," derived from nekros ("dead body"), and entered English medical usage in the late 16th century (first recorded in 1583), though its application in pathology became prominent in the mid-19th century with the work of Rudolf Virchow.^[2]^[5] Key characteristics include cellular swelling known as oncosis, rupture of the plasma membrane, and eventual lysis of the cell, leading to the release of intracellular contents into the surrounding tissue.^[1] This uncontrolled breakdown involves autolysis, where the cell's own enzymes digest its components, and heterolysis, where enzymes from neighboring cells or immune cells contribute to degradation, often provoking an inflammatory response.^[6] The leakage of cellular contents exposes damage-associated molecular patterns (DAMPs), which alert the immune system and amplify inflammation.^[7] Biologically, necrosis plays a critical role in tissue dysfunction across various pathologies, such as gangrene from vascular occlusion, myocardial infarction due to coronary artery blockage, and ischemic stroke from cerebral blood flow interruption.^[8] By disrupting tissue integrity and eliciting sterile inflammation through DAMP release, necrosis exacerbates organ damage and contributes to disease progression in these conditions.^[9] Unlike apoptosis, which is non-inflammatory and orderly, necrosis's messy nature often leads to secondary tissue injury via immune activation.^[10]

Comparison with other cell death types

Necrosis represents an uncontrolled, passive form of cell death induced by severe exogenous or endogenous insults, characterized by rapid plasma membrane rupture, organelle swelling, and uncontrolled release of intracellular contents that trigger inflammation via damage-associated molecular patterns (DAMPs) such as HMGB1.^[11] In stark contrast, apoptosis is a highly regulated, programmed process that promotes orderly cellular dismantling through caspase activation, resulting in non-inflammatory apoptotic bodies that are efficiently phagocytosed by neighboring cells or macrophages, thereby avoiding immune activation and tissue damage.^[12] While necrosis typically affects clusters of cells leading to widespread tissue injury, apoptosis proceeds in individual cells without compromising membrane integrity during execution.^[11] Necroptosis, often considered a regulated variant of necrosis, mimics the lytic and inflammatory morphology of classical necrosis but is genetically orchestrated through the receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) pathway, which forms membrane pores under conditions where apoptosis is blocked, such as caspase inhibition.^[12] This pathway enables necroptosis to serve adaptive roles in host defense against pathogens, distinguishing it from the accidental nature of unregulated necrosis, though both culminate in DAMP release and proinflammatory responses.^[13] Other regulated necrotic pathways further delineate necrosis. Pyroptosis, driven by inflammasome activation and gasdermin D-mediated pore formation, leads to cytokine release (e.g., IL-1β) and is tightly linked to innate immunity, differing from classical necrosis by its caspase-1 dependence and rapid execution in response to microbial stimuli.^[12] Ferroptosis, conversely, arises from iron-catalyzed lipid peroxidation accumulating toxic hydroperoxides in membranes, representing a metabolism-dependent death mode without the broad injury triggers of necrosis, though it similarly results in cell lysis and potential inflammation.^[14] Evolutionarily, necrosis embodies an primordial, unregulated cellular response to lethal stresses that likely predates the emergence of multicellular life, serving as a default failure mode without adaptive control.^[15] Programmed deaths like apoptosis, however, evolved subsequently in metazoans to enable precise tissue sculpting and homeostasis, integrating with developmental signaling to suppress inflammation and support organismal complexity.^[16]

Classification

Morphological patterns

Necrosis manifests in several distinct morphological patterns, each characterized by specific gross and microscopic features that reflect the nature of tissue destruction. These patterns are identified through histopathological examination and are crucial for diagnosing underlying pathological processes. The primary types include coagulative, liquefactive, caseous, fat, fibrinoid, and gangrenous necrosis, differentiated by the preservation or degradation of cellular architecture and the composition of necrotic debris.^[1] Coagulative necrosis is the most common pattern, where the basic outline of the tissue architecture is preserved despite cell death, due to protein denaturation that imparts an eosinophilic, anucleate appearance to cells under microscopy. Microscopically, affected cells retain their shape but lose nuclei and exhibit a ghostly, hypereosinophilic cytoplasm, eventually cleared by phagocytic cells. This pattern predominates in ischemic injuries to solid organs such as the heart, kidney, and spleen.^[1] Liquefactive necrosis involves rapid digestion of necrotic tissue by hydrolytic enzymes from neutrophils or the cells themselves, resulting in a viscous, liquid mass that transforms the area into a cyst-like structure. Grossly, it appears as a soft, liquefied area, while microscopically, there is complete loss of structural detail with fragmented debris and inflammatory cells. It is typical in bacterial abscesses and hypoxic brain infarcts, where the brain's high lipid and water content facilitates enzymatic breakdown.^[1] Caseous necrosis presents as a cheese-like, amorphous, whitish-gray debris with a crumbly texture on gross examination, lacking the preserved architecture seen in coagulative necrosis. Microscopically, it consists of acellular, eosinophilic to basophilic granular material surrounded by granulomatous inflammation. This pattern is hallmark of granulomatous infections, particularly tuberculosis, where it forms the central core of caseating granulomas.^[1] Fat necrosis features the enzymatic digestion of adipose tissue, leading to saponification where fats react with calcium to form chalky white deposits. Grossly, it appears as firm, opaque nodules, and microscopically, ghost-like adipocytes with basophilic calcium deposits and surrounding inflammation are evident. It commonly occurs in acute pancreatitis due to lipase release or in breast tissue following trauma.^[1] Fibrinoid necrosis is characterized by the deposition of fibrin and immune complexes within vessel walls, giving a bright pink, amorphous, smudgy appearance on hematoxylin and eosin staining. It primarily affects arterioles and small arteries, with necrosis limited to the vessel wall rather than surrounding parenchyma. This pattern is seen in immune-mediated conditions such as hypertensive crises and various vasculitides.^[1] Gangrenous necrosis is a clinical term describing extensive necrosis often involving limbs or digits, subclassified into dry and wet forms based on secondary infection. Dry gangrene results from pure ischemia, yielding a mummified, shrunken, black appearance with preserved coagulative features; wet gangrene involves superimposed bacterial infection, leading to liquefactive changes, edema, and a foul-smelling, moist tissue. It typically affects extremities in peripheral vascular disease.^[1]

Clinical and etiological types

Necrosis can be classified clinically based on its presentation and etiologically according to the underlying causative factors, providing insights into disease progression and management beyond mere histological appearance. These classifications highlight how necrosis manifests in specific body regions or contexts, often influenced by ischemia, infection, or toxins, and guide therapeutic approaches tailored to the clinical syndrome.^[1] Gangrene represents a severe clinical form of necrosis involving large tissue areas, typically in extremities, and is subdivided into subtypes based on etiology and presentation. Dry gangrene arises from arterial occlusion leading to progressive ischemia without significant bacterial involvement, resulting in mummified, shriveled tissue that appears black and dry; it is most common in peripheral artery disease.^[17] Wet gangrene develops when bacterial superinfection complicates ischemic tissue, causing edema, putrefaction, and a moist, foul-smelling appearance due to liquefactive processes; it spreads rapidly and requires urgent debridement.^[18] Gas gangrene, a life-threatening variant, is primarily caused by Clostridium perfringens infection in deep wounds, producing gas bubbles and systemic toxicity through toxin release, often exhibiting crepitus on palpation.^[19] Avascular necrosis, also known as osteonecrosis, is a clinically distinct type involving bone tissue death due to interrupted blood supply, commonly affecting weight-bearing joints like the hip. In sickle cell disease, vaso-occlusive crises lead to ischemia in the femoral head, with approximately 30% of patients developing this complication, progressing to joint collapse and arthritis if untreated.^[20] Etiologically, necrosis can stem from various origins, each presenting unique clinical features. Traumatic necrosis occurs following direct physical injury, such as crush wounds or burns, where mechanical damage disrupts vascular integrity and induces rapid cell death in affected tissues.^[6] Radiation-induced necrosis emerges as a delayed complication of cancer radiotherapy, particularly in brain or head-and-neck tumors, where ionizing radiation damages endothelial cells, causing vascular occlusion and focal tissue death months to years post-treatment.^[21] Chemical necrosis results from exposure to toxins, exemplified by brown recluse spider venom, which contains sphingomyelinase D that hydrolyzes cell membranes, leading to localized dermonecrotic lesions with ulceration and eschar formation.^[22] Special cases illustrate necrosis's role in broader biological contexts. In solid tumors, central necrosis arises from hypoxia due to inadequate vascularization, where rapid cell proliferation outpaces blood supply, creating avascular cores that undergo coagulative death and influence tumor aggressiveness.^[23] Conversely, in blind mole rats (Spalax ehrenbergi), a hyperactive necrotic pathway mediated by interferon-beta and p53 activation confers cancer resistance; aberrant cell crowding triggers rapid necrosis, preventing malignant transformation in this long-lived, hypoxia-tolerant species.^[24]

Causes

External factors

External factors encompass various environmental and physical agents that can trigger necrosis by directly damaging tissues or disrupting vascular integrity from outside the body. These include mechanical injuries, thermal extremes, infectious pathogens, chemical toxins, and radiation exposure, each capable of initiating cell death through distinct mechanisms such as vascular occlusion or direct cytotoxicity.^[25] Physical trauma represents a primary external cause of necrosis, where mechanical forces or thermal injuries lead to vascular disruption and subsequent tissue death. Mechanical injuries, such as crush wounds or lacerations, can sever blood vessels and cause immediate ischemia in affected areas, resulting in coagulative necrosis if not promptly addressed.^[26] Burns from extreme heat denature proteins and damage endothelial cells, often leading to vascular thrombosis and localized necrosis, particularly in deep second- or third-degree burns.^[27] Similarly, frostbite from prolonged cold exposure induces vasoconstriction and ice crystal formation, disrupting cellular membranes and causing progressive necrosis in extremities like fingers and toes.^[28] Ischemia and hypoxia, often resulting from external vascular compromise, deprive tissues of oxygen and nutrients, promoting necrotic cell death. Embolism, where a clot or foreign material blocks an artery, can rapidly induce ischemia in downstream tissues, as seen in acute limb ischemia leading to gangrenous necrosis.^[29] External compression, such as from tight bandages or casts, similarly restricts blood flow, causing hypoxic necrosis in compressed regions like the skin or muscles.^[30] Infections by external pathogens constitute another major category, with microbial toxins directly lysing cells or inducing widespread tissue destruction. Bacterial infections, exemplified by necrotizing fasciitis caused by Group A Streptococcus, release exotoxins that degrade fascia and subcutaneous tissues, leading to rapid liquefactive necrosis.^[31] Viral infections, such as herpes zoster, can cause necrotizing orbital or cutaneous lesions through direct cytopathic effects and vascular invasion.^[32] Fungal pathogens like Candida albicans or Mucorales species produce hyphae that invade vessels, resulting in thrombosis and ischemic necrosis, particularly in immunocompromised individuals.^[33] Toxins and chemicals from external sources can penetrate tissues and induce necrosis via cytotoxic effects. Snake venoms, containing metalloproteases and phospholipases, disrupt vascular integrity and cause local dermonecrosis, as observed in envenomations by species like Echis carinatus.^[34] Spider venoms, particularly from brown recluse (Loxosceles reclusa), contain sphingomyelinases that damage cell membranes and induce hemolytic necrosis at the bite site.^[35] Industrial solvents, such as xylene or tetrachloroethylene, can cause hepatic necrosis upon systemic absorption, with high doses leading to centrilobular cell death due to oxidative damage.^[36] Chronic alcohol exposure, acting as a hepatotoxic chemical, promotes centrilobular necrosis in the liver through hypoxia and reactive oxygen species generation.^[37] Radiation and environmental extremes further contribute to necrosis by altering cellular structures. Ionizing radiation from sources like X-rays or gamma rays damages DNA and vascular endothelium, leading to progressive skin and subcutaneous necrosis in high-dose exposures.^[38] Extreme temperatures beyond thermal trauma, such as hyperthermia from industrial heat, denature proteins and exacerbate ischemic necrosis in exposed tissues.^[39]

Internal factors

Internal factors contributing to necrosis arise from endogenous disruptions in physiological homeostasis, including dysregulated enzymatic activity, aberrant immune responses, metabolic derangements, genetic anomalies, and neoplastic processes. These mechanisms often involve intrinsic cellular or tissue vulnerabilities that compromise viability without external insults. Enzymatic digestion exemplifies an internal pathway to necrosis, particularly in acute pancreatitis, where premature activation of pancreatic proenzymes such as trypsinogen leads to autodigestion of pancreatic acinar cells. This process initiates a proteolytic cascade that degrades cellular structures, triggering inflammation and subsequent necrosis of pancreatic tissue. In severe cases, up to 10-20% of acute pancreatitis episodes progress to necrotizing pancreatitis due to this enzymatic overactivation.^[40]^[41] Immune-mediated mechanisms induce necrosis through dysregulated inflammatory responses, as seen in autoimmune vasculitis where antineutrophil cytoplasmic antibodies (ANCA) activate neutrophils to infiltrate and damage vessel walls, resulting in fibrinoid necrosis. Cytotoxic T cells and natural killer cells further contribute by releasing perforin and granzymes, forming pores in target cell membranes that lead to osmotic lysis and necrotic cell death during cytokine storms or hyperinflammatory states. These processes can escalate to widespread tissue necrosis in conditions like systemic vasculitis.^[42]^[43]^[44] Metabolic imbalances promote necrosis by altering cellular environments, such as in hypercalcemia, where elevated serum calcium levels cause renal vasoconstriction and direct toxicity to tubular epithelial cells, precipitating acute tubular necrosis and potential progression to chronic kidney damage. Similarly, chronic hyperglycemia in diabetes mellitus impairs wound healing and microvascular perfusion in the lower extremities, heightening susceptibility to ischemic necrosis in diabetic foot ulcers through oxidative stress and neuropathy-induced trauma.^[45]^[46] Genetic predispositions underlie necrosis via inherited defects that impair enzymatic function or structural integrity, as in Gaucher disease, where glucocerebrosidase deficiency leads to glucocerebroside accumulation, causing avascular necrosis of bones through vascular occlusion and infarction. Mutations in collagen genes, such as COL3A1 in vascular Ehlers-Danlos syndrome, confer vessel fragility, predisposing to spontaneous ruptures, ischemia, and downstream tissue necrosis in organs like the intestines or uterus.^[47]^[48] Tumor-related necrosis occurs when rapid neoplastic proliferation outstrips vascular supply, inducing hypoxia in central tumor regions and subsequent cell death. This ischemic necrosis is prevalent in aggressive solid tumors, where proliferating cells beyond 100-200 μm from capillaries experience oxygen deprivation, leading to coagulative necrosis and potential release of damage-associated molecular patterns that fuel further tumor progression.^[49]

Pathogenesis

Molecular pathways

Necrosis encompasses several molecular pathways that drive uncontrolled cell death, characterized by plasma membrane rupture and release of intracellular contents. One primary pathway is oncosis, which initiates with failure of ATP-dependent ion pumps, leading to Na⁺/K⁺ imbalance, osmotic cell swelling, and bleb formation on the plasma membrane.^[50] This energy depletion disrupts cellular homeostasis, culminating in membrane permeabilization and lysis, distinct from regulated forms of death.^[51] A regulated variant, necroptosis, operates through a well-defined signaling cascade involving receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL). Upon stimulation by death ligands or pathogen sensors in the absence of caspase-8 activity, RIPK1 undergoes ubiquitination and phosphorylation, recruiting RIPK3 to form the necrosome complex via RHIM domain interactions.^[52] RIPK3 then phosphorylates MLKL, inducing its oligomerization and translocation to the plasma membrane, where it forms pores that disrupt ion balance and cause osmotic lysis.^[53] This pathway, first elucidated in seminal studies on TNF-induced cell death, amplifies inflammation through damage-associated molecular patterns (DAMPs).^[54] Secondary necrosis arises when apoptotic cells evade timely phagocytosis, progressing to a necrotic phenotype. In this process, lysosomal membranes rupture, releasing hydrolytic enzymes that degrade cellular components and compromise plasma membrane integrity, leading to swelling and content leakage.^[55] This conversion, often observed in vivo under conditions of impaired clearance, shares morphological features with primary necrosis but stems from an initial apoptotic commitment.^[56] Across necrotic pathways, DAMPs such as high-mobility group box 1 (HMGB1), ATP, and DNA fragments are released, acting as danger signals to propagate inflammation. HMGB1 binds Toll-like receptors (TLRs), particularly TLR4, while extracellular ATP activates P2X7 receptors on immune cells, triggering NLRP3 inflammasome assembly and cytokine production like IL-1β.^[57] These signals recruit neutrophils and macrophages, exacerbating tissue damage in ischemic or infectious contexts.^[58] Recent advances highlight regulated necrosis's role in chronic inflammation, where necroptosis sustains autoimmune diseases via persistent DAMP signaling.^[59] In 2024-2025 studies, MLKL inhibitors have shown potential to "pause" necrosis, preserving cellular function in aging tissues and improving organ rejuvenation in mouse models of liver fibrosis and neurodegeneration.^[60] Additionally, non-lytic MLKL signaling has been implicated in tissue regeneration, diverting necroptotic cells toward proliferative pathways in wound healing.^[61]

Histopathological changes

Necrosis manifests through a sequential series of microscopic alterations in affected cells and tissues, beginning with subcellular disruptions and culminating in inflammatory and reparative responses. These changes are driven by the failure of cellular homeostasis, including ion imbalances that initiate organelle dysfunction.^[1] Early histopathological features include mitochondrial swelling, which arises from impaired energy production and membrane permeability, and dilation of the endoplasmic reticulum due to calcium overload and protein synthesis arrest.^[11] Concurrently, plasma membrane blebbing forms as sublethal protrusions filled with cytoplasmic contents, preceding eventual rupture and spillage of intracellular material into the extracellular space.^[1] Nuclear changes represent a defining progression in necrosis: pyknosis, characterized by chromatin condensation and nuclear shrinkage, occurs as DNA condenses irreversibly; this is followed by karyorrhexis, where the pyknotic nucleus fragments into irregular chromatin clumps; and karyolysis, the final enzymatic dissolution of nuclear material, rendering the nucleus indistinct.^[62] Cytoplasmic alterations involve a gradual loss of staining affinity, resulting in a pale, vacuolated appearance, alongside eosinophilic homogenization where denatured proteins impart a uniform, glassy texture to the cytoplasm.^[1] These effects reflect widespread proteolysis and organelle breakdown, distinguishing necrotic cells from viable ones under light microscopy.^[11] At the tissue level, necrotic foci elicit neutrophil infiltration as an acute response to damage-associated molecular patterns released from dying cells, often accompanied by interstitial edema due to increased vascular permeability.^[63] In subsequent stages, unresolved necrosis may progress to macrophage-mediated clearance, fibrosis with collagen deposition for tissue repair, or abscess formation if secondary infection occurs.^[1] The timeline of these changes varies by insult severity and tissue type; in acute scenarios such as myocardial infarcts, subcellular swelling emerges within 4-12 hours, nuclear pyknosis and early hypereosinophilia by 12-24 hours, neutrophil influx by 1-3 days, and granulation tissue with fibrosis by 10-14 days, leading to scar formation over weeks.^[63] Chronic necrosis, by contrast, unfolds over days to weeks, with persistent inflammation giving way to organized fibrotic replacement.^[62]

Clinical aspects

Signs and symptoms

Necrosis manifests through a variety of local and systemic clinical signs, depending on the affected tissue and extent of cell death. Locally, affected areas often exhibit severe pain that may initially be intense and disproportionate to visible changes but can progress to numbness as nerve tissues are compromised.^[18] Swelling and induration are common, accompanied by skin discoloration ranging from pale gray or blue to purple, black, bronze, or red hues, reflecting impaired blood flow and tissue breakdown.^[18] In cases of infection, such as gangrene, a foul odor may arise from necrotic tissue discharge, while gas-producing infections like gas gangrene produce crepitus—a crackling sensation under the skin due to subcutaneous gas bubbles.^[64] Systemic symptoms emerge particularly in extensive or infected necrosis, driven by inflammatory responses and potential bacterial spread. Patients may develop fever, tachycardia, and general malaise, progressing to sepsis with hypotension, confusion, and shortness of breath if the infection disseminates.^[18]^[31] In severe instances, such as bowel infarction from mesenteric ischemia, extensive necrosis can lead to shock, characterized by sudden abdominal distention, tenderness, and hemodynamic instability.^[65] Organ failure may ensue in widespread cases, contributing to multi-organ dysfunction syndrome (MODS) through unchecked inflammation and toxin release.^[31] Site-specific presentations highlight the diverse impacts of necrosis across body regions. In peripheral tissues, such as limbs affected by gangrene, initial severe pain often gives way to numbness and loss of sensation, with cool or cold skin to the touch.^[18] Myocardial necrosis, as seen in infarction, typically presents with retrosternal chest pressure or pain radiating to the shoulder, arm, neck, or jaw, alongside dyspnea, sweating, and nausea.^[66] Cerebral necrosis from ischemic stroke commonly causes unilateral neurological deficits, including facial droop, arm or leg weakness, slurred speech, vision impairment, and sudden severe headache with possible altered consciousness.^[67] Complications of necrosis can prolong morbidity and necessitate aggressive interventions. Unresolved necrotic tissue often results in chronic wounds that fail to heal due to persistent inflammation and bacterial biofilms, increasing infection risk and tissue loss.^[68] In limb-involving cases like gangrene, progression may lead to amputation to prevent further spread.^[18] Extensive necrosis heightens the likelihood of MODS, where systemic inflammation triggers cascading organ failures, significantly worsening prognosis.^[31]

Diagnosis

Diagnosis of necrosis typically begins with a thorough clinical evaluation, guided by symptoms such as persistent pain and swelling that suggest tissue damage. Physical examination involves careful inspection of the affected area for characteristic skin changes, including erythema, discoloration, blistering, or eschar formation, which indicate underlying tissue death. Palpation is essential to assess for tenderness disproportionate to visible inflammation, crepitus due to gas formation in infectious cases, or induration extending beyond the apparent lesion boundaries.^[31]^[69]^[70] Imaging modalities play a crucial role in confirming necrosis and delineating its extent. X-rays are often the initial imaging tool, particularly useful for detecting soft-tissue gas in cases like necrotizing fasciitis or gas gangrene, and for identifying bone collapse or sclerosis in avascular necrosis. Computed tomography (CT) provides detailed visualization of gas, fluid collections, and fascial involvement, offering superior assessment of disease spread compared to plain radiographs. Magnetic resonance imaging (MRI) is highly sensitive for early detection, revealing bone marrow edema, subchondral fractures, or non-viable tissue in avascular necrosis, while ultrasound excels at identifying subcutaneous gas, abscesses, or hypoechoic areas suggestive of fluid-filled necrotic regions.^[71]^[72]^[73] Laboratory tests support the diagnosis by indicating tissue damage and inflammation. Elevated levels of lactate dehydrogenase (LDH) serve as a biomarker of cellular necrosis due to its release from damaged cells, correlating with disease severity in conditions like sarcomas. C-reactive protein (CRP) levels rise in response to inflammation accompanying necrosis, aiding in monitoring progression. For suspected infectious necrosis, blood cultures are critical to identify causative pathogens, such as in necrotizing soft-tissue infections.^[74]^[75]^[76] Biopsy remains the gold standard for definitive diagnosis, providing histopathological confirmation. Hematoxylin and eosin (H&E) staining of tissue samples reveals hallmark nuclear changes, including pyknosis, karyorrhexis, and karyolysis, distinguishing necrotic tissue from viable cells. Immunohistochemistry can detect damage-associated molecular patterns (DAMPs), such as HMGB1, which are abundantly released during necrosis and contribute to inflammatory signaling.^[77]^[78] In research settings, techniques such as flow cytometry using propidium iodide uptake have been refined (as of 2023) to differentiate necrosis from apoptosis or necroptosis by assessing membrane integrity at the single-cell level.^[79] Live-cell imaging allows real-time observation of cellular changes like swelling and membrane rupture in experimental models.^[80] Emerging AI-assisted analysis of MRI scans (as of 2025) supports sarcoma grading, incorporating necrosis extent as a factor to improve prognostic assessment.^[81]

Treatment

Surgical interventions

Surgical interventions are critical in managing necrosis, particularly when the dead tissue poses risks of infection spread or systemic complications, aiming to excise necrotic areas and restore viable tissue function. These procedures are guided by diagnostic imaging to delineate the extent of necrosis, ensuring targeted removal. Primary approaches include debridement, amputation, revascularization, and specific interventions like fasciotomy or drainage, with early execution emphasized to improve prognosis.^[82] Debridement involves the systematic removal of necrotic tissue to promote healing and prevent infection progression, applicable in conditions such as wounds, gangrene, or necrotizing fasciitis. Sharp debridement, performed using instruments like scalpels, scissors, or curettes, selectively excises devitalized tissue down to healthy margins, often requiring multiple sessions until viable tissue is evident.^[83] Enzymatic debridement employs topical agents containing proteolytic enzymes to chemically lyse necrotic material, suitable for less extensive wounds where sharp methods are contraindicated.^[84] Autolytic debridement leverages the body's endogenous enzymes and wound moisture, facilitated by occlusive dressings, to gradually soften and liquefy dead tissue over days to weeks, ideal for selective, non-urgent cases.^[85] In necrotizing fasciitis, aggressive wide debridement is the cornerstone, involving extensive excision of affected fascia and surrounding tissue to halt bacterial dissemination.^[86] Amputation is reserved for extensive limb necrosis, such as in advanced gangrene, where debridement alone cannot salvage the extremity and life-threatening sepsis looms. This procedure involves transecting bone and soft tissue proximal to the necrotic zone, with careful hemostasis and beveling to minimize residual necrosis and facilitate prosthetic fitting.^[87] It is performed as a last resort to preserve overall survival, particularly in diabetic foot complications or peripheral artery disease.^[88] Revascularization addresses ischemic necrosis by restoring blood flow to hypoxic tissues, preventing further cell death in conditions like critical limb ischemia. Endovascular angioplasty uses balloon dilation to open occluded arteries, often combined with stenting for durability, while surgical bypass grafting reroutes blood via synthetic or autologous grafts to bypass blockages.^[89] These interventions are prioritized when viable tissue is potentially salvageable, with bypass preferred for long-segment occlusions based on long-term patency data.^[90] Specific procedures include fasciotomy for compartment syndrome-associated necrosis, where longitudinal incisions release fascial pressure to reperfuse ischemic muscle and avert further necrosis.^[91] In cases of abscess formation with necrotic content, incision and drainage evacuate purulent material and dead tissue, often followed by debridement to clear residual infection sources.^[84] Surgical interventions significantly reduce infection risk by eliminating necrotic tissue that harbors pathogens and impedes immune response, with early debridement linked to lower rates of septic shock and improved survival.^[92] The 2025 Consensus on the Diagnosis and Treatment of Adult Necrotizing Fasciitis strongly recommends immediate incision, wide debridement, and drainage as essential emergency measures, advocating repeated surgeries every 24-48 hours until necrosis is controlled, which has been associated with mortality reductions in high-risk cohorts.^[93] Overall outcomes emphasize timeliness, with debridement within 6-24 hours of diagnosis correlating to better tissue preservation and reduced morbidity.^[94]

Medical and pharmacological approaches

In cases of infected necrosis, such as necrotizing fasciitis, broad-spectrum antibiotics are essential to target the underlying bacterial pathogens and halt progression. Regimens typically include a combination of β-lactam antibiotics like penicillin G or a carbapenem with clindamycin, which inhibits toxin production by group A Streptococcus and other anaerobes, or linezolid as an alternative for its anti-toxin effects. For suspected methicillin-resistant Staphylococcus aureus involvement, vancomycin, daptomycin, or linezolid is added to the regimen. These therapies are administered intravenously and continued for 48-72 hours initially, with adjustments based on culture results, aiming to reduce systemic toxicity and support source control.^[95]^[96]^[97] Antioxidants and cytoprotectants play a key role in managing necrosis associated with ischemia-reperfusion injury by mitigating oxidative stress from reactive oxygen species. Allopurinol, a xanthine oxidase inhibitor, has demonstrated protective effects against myocardial and renal ischemia-reperfusion damage by reducing free radical production and preserving tissue viability. In experimental models, allopurinol preconditioning attenuates histological damage and inflammation in affected organs, such as the heart and kidneys, by blocking the hypoxanthine-xanthine oxidase pathway. These agents are particularly useful in scenarios like post-transplant or vascular surgery complications where reperfusion exacerbates necrosis.^[98]^[99]^[100] For immune-mediated necrosis, such as in autoinflammatory or autoimmune conditions involving necroptosis, anti-inflammatory agents like corticosteroids or tumor necrosis factor (TNF) inhibitors can modulate excessive cytokine-driven cell death. Corticosteroids suppress inflammatory cascades that promote necrosis in diseases like rheumatoid arthritis or inflammatory bowel disease, while TNF inhibitors, including etanercept or infliximab, block TNF-α signaling to reduce tissue damage and associated necrosis. Combination therapy with corticosteroids and TNF inhibitors has shown efficacy in managing immune-related endocrinopathies with necrotic components, improving outcomes by dampening necroptotic pathways. These treatments are selected based on the underlying etiology to prevent progression without compromising immune surveillance.^[101]^[102]^[103] Emerging pharmacological approaches target regulated necrosis pathways like necroptosis for therapeutic intervention in inflammatory and degenerative diseases. MLKL inhibitors, such as novel small molecules or PROTACs, block mixed lineage kinase domain-like protein activation downstream of RIPK3, attenuating necroptosis in conditions like atherosclerosis and lung injury; for instance, calycosin-mediated MLKL inhibition reduces necrotic core formation and vascular inflammation in preclinical models. As of 2024-2025, these inhibitors are being explored for anti-aging applications by limiting age-related necrotic accumulation in tissues and for regeneration in ischemic injuries. Gene therapies targeting necroptosis, including CRISPR-based editing of RIPK1 or MLKL genes, show promise in preclinical studies for inflammatory diseases like sepsis and neurodegeneration, by selectively inhibiting necroptotic signaling to curb chronic inflammation without broad immunosuppression. Clinical translation remains in early phases, with ongoing trials focusing on safety and specificity.^[104]^[105]^[106]^[59]^[107] Supportive care complements these targeted therapies, with hyperbaric oxygen therapy (HBOT) enhancing wound healing in hypoxic necrotic tissues by increasing oxygen delivery to promote angiogenesis and combat anaerobic infection. In necrotizing soft tissue infections, adjunctive HBOT reduces mortality and the need for repeated debridements by limiting bacterial proliferation and necrotic extension, as evidenced in clinical series where it improved demarcation and tissue salvage. For avascular necrosis, such as in osteonecrosis of the femoral head, HBOT facilitates stem cell integration and reduces inflammation when combined with other modalities. Pain management involves multimodal analgesia, including opioids and non-steroidal anti-inflammatory drugs, tailored to control discomfort from necrotic tissue breakdown while minimizing gastrointestinal or renal risks.^[108]^[109]^[110]^[111]

Necrosis in other organisms

In plants

In plants, necrosis refers to the localized death of cells or tissues, typically manifesting as browning or blackening, resulting from exposure to pathogens, toxins, or abiotic stresses such as drought or extreme temperatures.^[112] This process disrupts cellular integrity, leading to tissue collapse and potential spread if unchecked.^[113] Common causes include fungal and bacterial infections, which often trigger the hypersensitive response—a programmed cell death mechanism that confines the pathogen by forming necrotic lesions at the infection site.^[114] Nutrient deficiencies, particularly calcium, can induce tip necrosis in young leaves, where impaired cell wall strengthening leads to tissue breakdown and curling edges.^[115] Herbicides, especially auxinic types like 2,4-D, also provoke necrosis by mimicking plant hormones and causing uncontrolled growth followed by tissue death.^[116] Specific types encompass rapid necrosis observed in response to auxins, as seen in resistant Sumatran fleabane (Conyza sumatrensis), where environmental factors like high temperature accelerate symptom onset within hours of herbicide application, enhancing resistance mechanisms.^[117] Hybrid necrosis arises in interspecies crosses due to genetic incompatibilities, such as in Petunia species, where linked genes trigger autoimmune-like cell death and reproductive isolation. Detection methods rely on non-destructive techniques like chlorophyll fluorescence imaging, which measures photosystem II efficiency to quantify early necrotic damage, and electrolyte leakage assays that assess membrane integrity through ion release from dying cells; recent advancements in 2025 have integrated these for precise heat stress evaluations.^[118] Notable examples include maize lethal necrosis disease (MLN), a viral co-infection causing severe foliar necrosis and up to 100% yield loss in affected fields across East Africa.^[119] In cacti, necrotic patches from bacterial infections provide habitats for diverse arthropod communities, supporting insect biodiversity in desert ecosystems.^[120]

In animals

Necrosis manifests in various non-human animals, often as a response to infection, trauma, ischemia, or environmental stressors, with significant implications for veterinary medicine and wildlife conservation. In livestock, abdominal fat necrosis is a prevalent dystrophic-necrotic condition in dairy cattle, characterized by the formation of hard, irregular masses of necrotic adipose tissue in the abdominal cavity due to overconditioning, genetic predisposition, and dietary excess fat.^[121] This process can lead to severe reproductive disorders, including infertility and dystocia, by compressing reproductive organs and impairing ovarian function, as observed in affected herds where productive strain exacerbates the issue.^[122] In aquaculture, viral nervous necrosis (NNV), caused by betanodaviruses, induces widespread neuronal necrosis in over 50 fish species, leading to high mortality rates in larval and juvenile stages across global fisheries.^[123] Recent advancements include plant-based production of NNV antigens using genome-edited plants such as Nicotiana benthamiana and lettuce.^[124] Plant-produced virus-like particles (VLPs) as vaccines have demonstrated protective efficacy against NNV in species like European sea bass by eliciting humoral immunity without adjuvants.^[125] Wildlife species exhibit unique adaptations involving necrosis for survival. For instance, blind mole rats (Spalax spp.) employ a regulated necrotic cell death mechanism, activated via the RIP1/RIP3 pathway, to eliminate precancerous cells and confer exceptional cancer resistance, even under hypoxic burrow conditions.^[126] Pathological examples highlight necrosis's role in acute veterinary emergencies. In horses, intestinal necrosis from strangulating lesions, such as volvulus or epiploic foramen entrapment, is a leading cause of colic, resulting in ischemia-reperfusion injury and rapid tissue death if untreated.^[127] In swine, porcine circovirus disease can trigger granulomatous necrotizing myositis, featuring muscle fiber necrosis and inflammation that impair mobility and growth.^[128] Contemporary research leverages animal models to translate regulated necrosis insights to human diseases, particularly through studies on damage-associated molecular patterns (DAMPs). For example, investigations in rodent models have shown that necroptosis and other regulated necrotic pathways release DAMPs like HMGB1, perpetuating chronic inflammation in conditions mirroring human sepsis and neurodegeneration.^[129] These findings underscore necrosis's dual role as a pathological driver and therapeutic target in translational veterinary science.^[130]

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Damage-associated molecular patterns (DAMPs) in diseases
Aug 29, 2025 · Research has demonstrated that DAMPs play pivotal roles in various diseases, including cancer, cardiovascular disorders, and pulmonary diseases, ...