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Necrosis versus Apoptosis

Necrosis vs Apoptosis: Pathogenesis and clinical findings Toxic chemicals (poisons, drug toxicities) Hypoxia (↓ Oxygen delivered to tissues) Physical agents (extreme temperatures, trauma, radiation) Bacterial, viral, or fungal infections &/or microbe toxins Necrosis Uncontrolled & pathologic cell death Harmful stimuli trigger ↓ ATP (cellular energy) ↓ ATP leads to ion pump failure & ↑ cell permeability (“leakiness”) ↑ Cellular ion influx causes cell to swell & lyse (rupture its plasma membrane) Intracellular contents spill into the extracellular space Intracellular contents activate inflammasomes (cytoplasmic multiprotein complexes) Pro-inflammatory cytokine interleukin-1β is secreted & activates the immune system Excessive cytokine release provokes a large inflammatory response Inflammation damages surrounding healthy tissues & organs Ischemia (↓ Blood flow) to organs except brain ↓ Oxygen denatures enzymes à dead cell skeletons cannot breakdown Cells remain “coagulated” (firm) for days Coagulative necrosis ↓ Blood flow to limb(s) +/- bacterial invasion Gangrenous necrosis ↑ Pain or ↓ feeling in affected limb(s) Skin color changes (red, purple, black) Damaged adipocytes (fat cells) release triglyceride (fat) contents that group into oil cysts Scars form & calcify (harden) Fat necrosis Damaged endothelium (blood vessel wall) becomes leaky Fibrin (blood protein) deposits in endothelium with immune complexes Fibrinoid necrosis Brain ischemia &/or infection kills cells Digestive enzymes transform dead tissue into creamy liquid pus Liquefactive necrosis Coagulative + liquefactive necrosis mechanisms à granular debris Caseous necrosis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications ----------------------------------------------------------------------------------------------------- Authors: Tyra Fernandes Catherine R Jarvis Reviewers: Mitchell Chorney Sarah Smith* * MD at time of publication Apoptosis Programmed cell death via an energy-dependent process Extrinsic pathway: cellular stress or damage signals in the extracellular environment trigger apoptosis Intrinsic pathway: internal cellular stressors (damage from chemotherapy, UV radiation, drugs) trigger apoptosis Ligands such as TNF-α (tumor necrosis factor-alpha, produced by macrophages) & FasL (Fas ligand, produced by T cells) bind to apoptotic receptors on the cell’s surface Pro-apoptotic factors recognize cellular stressors Cytochrome C releases from the intermembrane space of the mitochondria to the cytoplasm Ligand binding activates initiator caspases (protease (protein breakdown)-like enzymes) 2, 8, 9, 10 Cytochrome C activates Caspase-9 Initiator caspases activate effector caspases 3, 6, 7 Caspase-9 activates effector caspases 3 & 7 Effector caspases begin execution pathway Caspases degrade the cell’s nuclear envelope & DNA à DNA repair is inhibited & cell shrinks Cellular shrinkage forms apoptotic bodies Phagocytes engulf apoptotic bodies to prevent inflammation Ineffective phagocytosis à inflammation Published Feb 8, 2026 on www.thecalgaryguide.com Final Slide is 1st Necrosis vs Apoptosis: Pathogenesis and clinical findings Toxic chemicals (poisons, drug toxicities) Hypoxia (↓ Oxygen delivered to tissues) Physical agents (extreme temperatures, trauma, radiation) Toxin release from bacteria, viruses, or fungi Necrosis Uncontrolled & pathologic cell death Harmful stimuli trigger ↓ ATP (cellular energy) ↓ ATP leads to ion pump failure & ↑ cell permeability ↑ Cellular ion influx causes cell to swell & lyse (rupture its plasma membrane) Intracellular contents spill into the extracellular space Intracellular contents activate inflammasomes (cytoplasmic multiprotein complexes) Pro-inflammatory cytokine interleukin-1β is secreted and activates the immune system Excessive cytokine release provokes a large inflammatory response Inflammation damages surrounding healthy tissues & organs Ischemia (↓ Blood flow) to organs except brain ↓ Oxygen denatures enzymes à cell skeleton cannot be broken down Cell is preserved in “coagulated” state for days Coagulative necrosis ↓ Blood flow to limbs +/- bacterial invasion Gangrenous necrosis ↑ Pain or ↓ feeling in limb Skin color changes (red, purple, black) Damaged adipocytes (fat cells) release triglycerides (fat) contents that group into oil cysts Scars form & calcify (harden) Fat necrosis Damaged endothelium (blood vessel wall) becomes leaky Fibrin (blood protein) deposits in endothelium with immune complexes Fibrinoid necrosis Brain ischemia &/or infection kills cells Digestive enzymes transform dead tissue into creamy liquid pus Liquefactive necrosis Coagulative & liquefactive necrosis mixture à granular debris Caseous necrosis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding ----------------------------------------------------------------------------------------------------- Complications Authors: Tyra Fernandes Catherine R Jarvis Reviewers: Mitchell Chorney Sarah Smith* * MD at time of publication Apoptosis Programmed cell death via an energy-dependent process Extrinsic pathway: cellular stress or damage signals in the extracellular environment trigger apoptosis Intrinsic pathway: internal cellular stressors (chemotherapy, UV radiation, drugs, misfolded proteins) trigger apoptosis Ligands such as TNF-α (tumor necrosis factor-alpha, produced by macrophages) & FasL (Fas ligand, produced by T cells) bind to apoptotic receptors on the cell’s surface Pro-apoptotic factors recognize cellular stressors Cytochrome C releases from the intermembrane space of the mitochondria to the cytoplasm Ligand binding activates initiator caspases (protease (protein breakdown)-like enzymes) 2, 8, 9, 10 Cytochrome C activates Caspase-9 Initiator caspases activate effector caspases 3, 6, 7 Caspase-9 activates effector caspases 3 & 7 Effector caspases begin execution pathway Caspases degrade the cell’s nuclear envelope & DNA à DNA repair is inhibited & cell shrinks Cellular shrinkage forms apoptotic bodies Phagocytes engulf apoptotic bodies to prevent inflammation Ineffective phagocytosis à inflammation Published MONTH, DAY, YEAR on www.thecalgaryguide.com Necrosis vs Apoptosis Toxic chemicals (poisons, drug toxicities) Hypoxia (↓ Oxygen delivered to tissues) Physical agents (extreme temperatures, trauma, radiation) Biological agents (bacteria, viruses, fungi) Necrosis Non-physiologic & uncontrolled cell death Noxious (harmful) stimuli trigger increased cell permeability and ion pump failure Cell swells & ruptures its plasma membrane à cell lysis (breakdown) Intracellular contents spill into the extracellular space Intracellular contents activate inflammasomes (cytoplasmic multiprotein complexes) Pro-inflammatory cytokine interleukin-1β is secreted and activates the immune system Excessive cytokine release provokes a large inflammatory response Inflammation damages surrounding healthy tissues & organs Acute tubular necrosis (damaged kidney tubule cells) Gangrene (body tissue death) Myocardial infarction (heart attack) Steatohepatitis (progressive liver disease) ↓ Blood flow to a Myocardium (heart portion of the body muscle) is deprived Necrotic renal (usually limbs) of oxygen & (kidney) tubular becomes damaged epithelial cells deteriorate & slough off ↑ Extracellular matrix proteins (especially collagen) are produced and deposit in liver Granular casts on urine microscopy ↑ Pain or ↓ Feeling Skin color change (red, purple, black) ↑ Blood troponin levels ↓ Heart function Liver fibrosis (scarring) Legend: Authors: Tyra Fernandes Catherine R Jarvis Reviewers: ----------------------------------------------------------------------------------------------------- Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Mitchell Chorney Name Name* * MD at time of publication Apoptosis Programmed cell death via an energy-dependent process Extrinsic Pathway: Apoptotic signals from other cells cause initiation Intrinsic Pathway: Internal cellular stressors (chemotherapy, UV radiation, drugs, misfolded proteins) cause initiation Ligands such as TNF-α (tumor necrosis factor-alpha, produced by macrophages) & FasL (Fas ligand, produced by T cells) bind to apoptotic receptors on the cell’s surface Pro-apoptotic factors recognize cellular stressors Cytochrome P releases from the intermembrane space of the Ligand binding activates initiator mitochondria to the cytoplasm caspases (protease (protein breakdown)-like enzymes) 2, 8, 9, 10 Cytochrome P activates Caspase-9 Initiator caspases activate effector caspases 3, 6, 7 Caspase-9 activates caspases 3 & 7 Execution Pathway Caspases degrade the cell’s nuclear envelope & DNA à DNA repair is inhibited & cell shrinks Cellular shrinkage forms apoptotic bodies Phagocytes engulf apoptotic bodies to prevent inflammation Ineffective phagocytosis à inflammation Published MONTH, DAY, YEAR on www.thecalgaryguide.com Necrosis vs Apoptosis Hypoxia Chemical agents Physical agents Biological agents Necrosis Non-physiologic & uncontrolled cell death Oncolysis (ion pump failure and increased cell permeability cause cell swelling) occurs due to noxious stimuli Plasma membrane ruptures and cell is lysed (broken down) Intracellular contents spill into the extracellular space Authors: Tyra Fernandes Reviewers: Mitchell Chorney Catherine R Jarvis Name Name* * MD at time of publication Renal tubule is damaged due to reduced oxygen supply and toxicity Granular casts on urine microscopy Acute tubular necrosis (kidney disorder of the tubule cells Extracellular matrix proteins accumulate in liver causing collagen deposition Liver fibrosis Steatohepatitis (progressive liver disease) Intracellular contents activate inflammasomes (cytoplasmic multiprotein complexes) Myocardium (heart muscle) is deprived of oxygen ↑ Blood troponin levels Myocardial infarction ----------------------------------------------------------------------------------------------------- Apoptosis Programmed cell death via an energy-dependent process Extrinsic Pathway: Apoptotic signals from other cells cause initiation Ligands such as TNF-α (tumor necrosis factor-alpha, produced by macrophages) and FasL (Fas ligand, produced by T cells) bind to apoptotic receptors on the cell’s surface Ligand binding activates initiator caspases (protease-like enzymes) 2, 8, 9, 10 Initiator caspases activate effector caspases 3, 6, 7 Intrinsic Pathway: Internal cellular stressors (chemotherapy, UV radiation, drugs, & misfolded proteins) cause initiation Pro-apoptotic factors recognize cellular stressors Cytochrome P releases from the intermembrane space of the mitochondria to the cytoplasm Cytochrome P activates Caspase-9 Caspase-9 activates caspases 3 & 7 Pro-inflammatory cytokine interleukin-1β is secreted and activates the immune system Excessive cytokine release provokes a large inflammatory response Legend: Inflammatory damage to the surrounding healthy tissues Microscopic Effects: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Execution Pathway Caspases degrade the cell’s nuclear envelope. DNA fragments inhibit DNA repair, which shrinks the cell Cellular shrinkage forms apoptotic bodies Phagocytes engulf apoptotic bodies to prevent inflammation Ineffective phagocytosis à inflammation Published MONTH, DAY, YEAR on www.thecalgaryguide.com Necrosis vs Apoptosis Authors: Tyra Fernandes Reviewers: Mitchell Chorney Catherine R Jarvis Hypoxia, physical agents, chemical agents, biologic agents Necrosis (Non-physiologic & uncontrolled cell death) Oncolysis (cell swelling due to the failure of ion pumps and increased cell permeability) occurs due to noxious stimuli Plasma membranes rupture leading to cell lysis Intracellular contents spill into the extracellular space Inflammasomes (cytoplasmic multiprotein complexes) are activated Pro-inflammatory cytokine interleukin-1β is secreted and activates the immune system Excessive cytokine release provokes a large inflammatory response Legend: Microscopic Effects: Steatohepatitis Collagen deposition due to the accumulation of extracellular matrix proteins Liver fibrosis Myocardial Infarction Ischemic or toxic injury to the renal tubule Granular casts on urine microscopy Acute tubular necrosis Oxygen supply deprivation to the myocardium Elevated blood troponin levels ----------------------------------------------------------------------------------------------------- Extrinsic Pathway: Apoptotic Signals from other cells cause initiation Ligands such as TNF-α (tumor necrosis factor-alpha, produced by macrophages) and FasL (Fas ligand, produced by T cells) bind to apoptotic receptors on the cell’s surface Ligand binding activates initiator caspases (protease-like enzymes) 2, 8, 9, 10 Initiator caspases activate effector caspases 3, 6, 7 Apoptosis (Programmed cell death via an energy- dependent process) Name Name* * MD at time of publication Intrinsic Pathway: Internal cellular stressors chemotherapy, UV radiation, drugs, & misfolded proteins) cause initiation Pro-apoptotic factors recognize cellular stressors Cytochrome P releases from the intermembrane space of the mitochondria to the cytoplasm Cytochrome P activates Caspase-9 Caspase-9 activates caspases 3 and 7 Execution Pathway Cellular shrinkage forms apoptotic bodies Inflammatory damage to surrounding healthy tissues à potential organ failure Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications The nuclear envelope degrades and DNA fragments which inhibits DNA repair which shrinks the cell Phagocytes engulf apoptotic bodies to prevent inflammation Ineffective phagocytosis à inflammation Published MONTH, DAY, YEAR on www.thecalgaryguide.com Authors: Necrosis vs Apoptosis Tyra Fernandes Reviewers: Mitchell Chorney Necrosis Apoptosis Catherine R Jarvis Hypoxia: ischemia, respiratory insufficiency Physical agents: trauma, radiation, Non-physiologic & temperature, electrical shock uncontrolled cell death Biological agents: bacteria, viruses, fungi Chemical agents: poisons, drugs, Cell swelling (oncosis) due to occupational exposures the failure of ion pumps and increased cell permeability Collagen deposition leading to liver fibrosis Cell lysis due to the rupture of the plasma membrane Steatohepatitis Microscopic Spillage of intracellular contents Effects: into the extracellular space Acute tubular Myocardial Activation of cytoplasmic necrosis Infarction multiprotein complexes, known as inflammasomes Ischemic or toxic Oxygen supply injury to the renal deprivation to the tubule myocardium Secretion of pro-inflammatory cytokine interleukin-1β, which ----------------------------------------------------------------------------------------------------- Name Name* * MD at time of publication Programmed cell death via an energy-dependent process Extrinsic pathway Intrinsic pathway The cell receives apoptotic signals Initiated by internal cellular from other cells stressors such as chemotherapy drugs, UV radiation, and misfolded Apoptosis is activated via ligands proteins binding to apoptotic receptors on the cell surface Pro-apoptotic factors recognize cellular stressors Ligand binding activates initiator caspases (2, 8, 9, 10), which are Cytochrome P releases from the protease-like enzymes intermembrane space of the mitochondria to the cytoplasm Examples of ligands include: TNF-α (produced by macrophages) and Caspase-9 is activated FasL (produced by T cells) Activation of downstream effector Effector caspases (3, 6, 7) are caspases 3 and 7 activated activates the immune system Excessive cytokine release provokes a large inflammatory response Legend: Granular casts on urine microscopy Elevated blood troponin levels Damage to surrounding healthy tissues may lead to organ failure Prevention of inflammation Execution pathway The nuclear envelope degrades and DNA fragments which inhibits DNA repair Cellular shrinkage forms apoptotic bodies Phagocy engulfment of apoptotic bodies Published MONTH, DAY, YEAR on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Necrosis versus apoptosis Necrosis Non-physiologic & uncontrolled cell death due to noxious stimuli Cell swelling (oncosis) à cell lysisà spillage of intracellular contents à tissue damage Inflammatory response, leading to inflammasome activation and the secretion of pro-inflammatory cytokine interleukin-1β Macroscopic Effects: Hypoxia: ischemia, respiratory insufficency Physical agents: trauma, radiation, temperature, electrical shock Biological agents: bacteria, viruses, fungi Chemical agents: poisons, drugs, occupational exposures Acute tubular necrosis due to chemical agents Myocardial infarction due to hypoxia Microscopic Effects: Stroke due to hypoxia in the brain Gangrene due to hypoxia of the limbs Steatohepatitis due to chemical agents ----------------------------------------------------------------------------------------------------- Apoptosis Programmed cell death via an energy-dependent process Execution phase: pro-& anti- apoptotic proteins mediate cell breakdown by caspases Caspase activity blocks DNA repair à leading to fragmented DNA and cell shrinkage Apoptosis is inhibited in cancer the overexpression of anti-apoptotic proteins Authors: Tyra Fernandes Reviewers: Mitchell Chorney Name Name* * MD at time of publication Extrinsic pathway: immune cell activation activates executioner caspases; ligands such as TNF-α & FasL bind to receptors on the cell membrane Intrinsic pathway: internal cellular factors cause pro-apoptotic factors to increase mitochondrial membrane permeability. Cytochrome c is released from the inner mitochondrial membrane, which ultimately activates caspases Cellular fragments are engulfed by immune cells which prevents an inflammatory response Organism death via necrosis Menstruation Embryogenesis Endometrial shedding of the inner lining of the uterus is an apoptotic mechanism The tissue between the fingers and toes degrades via apoptosis in utero à separation of the digits Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Abbreviations: • IL-1β– interleukin-1β • TNF-α– tumour necrosis factor - alpha • FasL– CD95 ligand; mediates apoptosis Published MONTH, DAY, YEAR on www.thecalgaryguide.com Complications References • https://next.amboss.com/us/article/VP0GdT?q=apoptosis#Y0d79977cce8fc2c548ac720f8060d667 • https://www.ncbi.nlm.nih.gov/books/NBK557627/ • https://www.ncbi.nlm.nih.gov/books/NBK499821/ • https://pmc.ncbi.nlm.nih.gov/articles/PMC5855670/ • https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/oncosis • https://www.nature.com/articles/s41421-020-0167-x • https://pmc.ncbi.nlm.nih.gov/articles/PMC3714593/ • https://www.ncbi.nlm.nih.gov/books/NBK537076/ Hypoxia Physical agents Biological agents Chemical agents