Cell Injury and Death

The cell undergoes a variety of changes in response to injury, which may or may not lead to cell death. Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. The principal targets of cell injury are the cell membranes, mitochondria, protein synthesis machinery, and DNA. Multiple cellular abnormalities resulting from the damage result in cell death. The 2 main types of cell death are necrosis and apoptosis. Necrosis is an uncontrolled cell death characterized by inflammatory changes in a pathologic condition. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects.

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Overview

Definitions

  • Homeostasis: 
    • Steady state
    • Cell is at optimal function, meeting physiologic demands.
  • Cellular adaptation: reversible changes in cell structures or functions in response to changes in the cell’s environment

Cell injury

  • Cells cannot adapt, or the maximum adaptive response to physiologic or pathologic stimuli is exceeded.
  • Occurs with damaging stimuli, loss of critical nutrients, or mutations 
  • Factors affecting cell injury:
    • Nature, duration, and severity of injury
    • Type and adaptability of the cell
    • Simultaneous injury mechanisms stimulated by the etiology
  • Types of cell injury:
    • Reversible injury
    • Irreversible injury (leads to cell death)
  • Mechanisms of cell injury (can occur at the same time):
    • Mitochondrial damage
    • Abnormal calcium homeostasis
    • DNA damage
    • Membrane damage
    • Endoplasmic reticulum (ER) stress
    • Oxidative stress

Cell death

  • State in which cell ceases to carry out functions
  • Part of embryogenesis, organ development, and maintenance of homeostasis where damaged and unneeded cells are removed 
  • Effect of irreversible injury, when the cell cannot overcome the damages 
  • Pathways:
    • Apoptosis
    • Necrosis

Cellular response to stress and injury

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Etiology and Types of Cell Injury

Injurious stimuli

  • Physical agents:
    • Mechanical trauma
    • Temperature and atmospheric pressure changes
    • Radiation
    • Electric shock 
  • Chemical agents and drugs:
    • Chemicals causing electrolyte derangements (e.g., glucose)
    • Poisons (e.g., cyanide, arsenic)
    • Environmental pollutants
    • Industrial hazards (e.g., asbestos)
    • Medications (toxic effects)
  • Oxygen deprivation:
    • Ischemia
    • Cardiorespiratory decompensation
    • ↓ oxygen-carrying capacity of the blood (anemia)
  • Infections: viruses, bacteria, parasites, other biological agents
  • Immunologic reactions:
    • Immune reactions to external agents
    • Autoimmune diseases 
  • Genetic abnormalities:
    • Congenital malformations
    • Deficient protein function from enzyme defects
    • Misfolded proteins 
  • Nutritional deficiencies and excess:
    • Nutritional deficiencies (vitamin deficiency)
    • Nutritional excess (obesity, increased lipids)

Types of cell injury

  • Reversible cell injury:
    • Effect of mild or transient damage 
    • Elimination of the pathologic stimuli or restoration of critical supply leads to cell returning to steady state.
    • Features:
      • Cellular swelling due to water influx (earliest manifestation of cell injury)
      • Hydropic change or vacuolar degeneration: small, clear vacuoles within the cytoplasm (from distended ER)
      • Plasma membrane alterations (blebbing, blunting, loss of microvilli)
      • Mitochondrial swelling and appearance of amorphous densities
      • ↑ Cytosol myelin figures (phospholipids from damaged membranes)
      • Changes in nucleus (granular and fibrillar elements disaggregate) 
      • Fatty change from accumulation of lipid vacuoles (in organs involved in lipid metabolism)
  • Irreversible injury:
    • “Point of no return”: cell cannot be restored → cell death 
    • Injurious stimulus is severe and/or persistent.
    • Features:
      • Inability to reverse mitochondrial dysfunction (loss of oxidative phosphorylation and adenosine triphosphate (ATP) production)
      • Significant damage to membrane function

Cell Injury by Mitochondrial Damage

Mitochandria

  • Major site of synthesis of adenosine triphosphate or ATP 
  • ATP: 
    • Energy required in synthetic and degradative processes
    • Sources:
      • From oxidative phosphorylation of adenosine diphosphate 
      • From the glycolytic pathway (anaerobic)
  • Subject to most injurious stimuli

Consequences of mitochondrial damage

  • Adenosine triphosphate (ATP) depletion: mitochondrial permeability transition pore formsloss of membrane potential and oxidative phosphorylation → reduced ATP
  • ATP depletion leads to:
    • Cell swelling: plasma membrane sodium pump (Na⁺, K⁺-ATPase) fails → sodium enters the cell → water accumulation
    • Reduced cytosolic enzyme activity: ↑ glycogenolysis and glycolysis to compensate for the ATP loss → depleted glycogen → ↑ lactic acid and inorganic phosphates → ↓ intracellular pH → impaired enzymes
    • Reduced protein synthesis: detachment of ribosomes 
  • Impaired oxidative phosphorylation: Reactive oxygen species (free radicals) are created, causing lipid/protein/nucleic acid damage.
  • Apoptosis/cell death: leakage of apoptotic proteins (e.g., cytochrome c) results in organelle damage

Mitochondrial damage from injurious stimuli (e.g., radiation, toxins) leads to:
Bottom left: Pro-apoptotic proteins leak from the mitochondria causing apoptosis.
Top right: Incomplete oxidative phosphorylation produces reactive oxygen species (ROS). Membranes, proteins and DNA are damaged.
Bottom right: Decreased ATP results in cell swelling, reduced enzyme activity and protein synthesis.
All processes lead to severe cell injury, then necrosis occurs.

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Cell Injury by Abnormal Calcium Homeostasis

Calcium homeostasis

  • Intracellular calcium (Ca²⁺): normally low (sequestered in the mitochondria and ER)
  • Common injurious stimuli: 
    • Oxygen deprivation/ischemia
    • Toxins 

Consequences of impaired calcium homeostasis

  • Release of Ca²⁺ from intracellular stores and ↑ Ca²⁺ influx through the plasma membrane 
  • Increased Ca²⁺ activates enzymes, which produce cell injury: 
    • Phospholipases → membrane damage
    • Proteases → membrane and cytoskeletal protein degradation
    • Endonucleases → DNA and chromatin fragmentation
    • ATPases → ATP depletion

Effects of impaired calcium homeostasis
Injurious stimuli cause release of calcium from the mitochondrion and endoplasmic reticulum.

Image by Lecturio.

Cell Injury by DNA and Membrane Damage

DNA damage

  • Common injurious stimuli: 
    • Radiation
    • Chemotherapeutic drugs
    • ROS
  • May be part of aging 

Consequences of damaged DNA

  • Triggers p53 pathway: arrests cell cycle in G1 phase, activating repair mechanisms
  • Apoptosis occurs:
    • If repairs cannot correct the damage 
    • To protect the tissue involved (cell dies rather than persists with an abnormal DNA, which has potential for malignant transformation)

DNA damage activates p53 which arrests cells in G1 phase and triggers DNA repair mechanisms. If damage is irreparable, p53 triggers apoptosis.

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Membrane damage

  • Normal membrane: made of lipids, with phospholipids as the most abundant form
  • Common injurious stimuli: 
    • Bacterial infection (toxins)
    • Viral proteins
    • Complement-mediated lysis
    • Physical/chemical agents 
    • Ischemia
  • Other mechanisms overlap and cause membrane damage:
    • Oxygen free radicals → lipid peroxidation → phospholipid loss
    • Mitochondrial damage → reduced ATP → decreased phospholipid synthesis
    • Calcium-dependent phospholipases → phospholipid breakdown → loss of membrane
    • Calcium-dependent proteases → cytoskeletal filament damage → increased cellular swelling and rupture 

Consequences of membrane damage

  • ↑ Permeability of plasma membrane → influx of fluids and ions + loss of cell osmotic balance
  • Injury to lysosomal membranes → lysosomal enzymes disrupt cytoplasmic organelles

Membrane damage occurs from the following:
An injurious stimulus (top left) leads to disrupted transport functions. The injurious stimulus also affects lysosomal membranes, leaking enzymes that damage the cell.
Other mechanisms: Abnormal calcium homeostasis (top right) releases enzymes that degrade the membrane; mitochondrial dysfunction (lower left) reduces ATP production needed for membrane synthesis.
Reactive oxygen species (lower right) cause lipid peroxidation, leading to membrane phospholipid loss.

Image by Lecturio.

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Cell Injury by ER Stress

Endoplasmic reticulum

  • Site of protein synthesis and folding, lipid synthesis, and free calcium storage
  • Chaperones: control protein folding 
  • Misfolded proteins: usually processed for proteolysis
  • Unfolded protein response: 
    • Signal transduction pathways that sense misfolded proteins
    • ↑ Chaperones, ↓ protein translation, and ↑ degradation of misfolded proteins
  • Injurious stimuli: 
    • Genetic abnormalities/mutations
    • Ischemia/hypoxia 
    • Viral infections

Consequences of ER stress

  • ER stress: Protein folding demand exceeds protein folding capacity.
  • Unrepaired proteins accumulate → apoptosis
  • Diseases and their associated misfolded proteins:
    • Cystic fibrosis: cystic fibrosis transmembrane conductance regulator (CFTR)
    • α1- antitrypsin deficiency: α1- antitrypsin
    • Alzheimer’s disease: Aβ peptide
    • Familial hypercholesterolemia: LDL receptor
    • Creutzfeldt-Jacob disease: prion

Endoplasmic reticulum (ER)
Chaperones control protein folding in the ER and misfolded proteins normally undergo proteolysis. When misfolded proteins increase, unfolded protein response occurs (increasing chaperones, decreasing protein synthesis and enhancing degradation of misfolded proteins).
ER stress: If protein folding demand increases (excessive misfolded proteins), the protein folding capacity gets saturated, leading to cell apoptosis.

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Cell Injury by Oxidative Stress

Free radicals

  • Molecular species with single unpaired electron in the outer orbit
  • Highly reactive: attack adjacent molecules (proteins, carbohydrates, nucleic acids)
  • ROS: an oxygen-derived free radical
  • Principal free radicals:
    • Superoxide anion (O2)
    • Hydrogen peroxide (H₂O₂)
    • Hydroxyl radical (OH): most reactive ROS
    • Peroxynitrite (ONOO⁻)
  • Injurious stimuli: 
    • Ischemia-reperfusion injury
    • Chemical and radiation injury
    • Aging
    • Phagocytosis of microbes

Oxidative stress

  • Accumulation of ROS → oxidative stress:
    • From increased production of free radicals
    • From decreased scavenging of ROS
  • The following generate free radicals:
    • Reduction-oxidation reactions:
      • O₂ is reduced with transfer of electrons to H₂ to form water molecules.
      • Partially reduced intermediates → free radicals
    • Exposure to ionizing radiation and ultraviolet rays
    • Polymorphonuclear neutrophils produce free radicals during inflammatory response.
    • Metabolism of exogenous chemicals (e.g., carbon tetrachloride)
    • Reactions with transition metals (e.g., iron or copper)
    • Nitric oxide reaction (with superoxide) in macrophages, producing peroxynitrite (ONOO⁻), a free radical

Consequences of oxidative stress

  • Membrane damage by lipid peroxidation:
    • ROS attack unsaturated fatty acids of the membrane.
    • Lipid hydroperoxides are produced → ↓ function of membranes
  • DNA damage or fragmentation 
  • Oxidative modification of proteins: ↑ protein cross-linking leads to ↑ degradation and ↓ activity

Antioxidants

  • Defense against free radicals (ROS scavengers)
  • Immediately eliminate ROS produced during mitochondrial respiration and energy generation
  • Low amount of free radicals may be present but are unable to induce damage.
  • Non-enzymatic mechanism:
    • Vitamins A, C, E
    • Glutathione
    • Ferritin
    • Transferrin
    • Ceruloplasmin
  • Enzymatic mechanism:
    • Glutathione peroxidase: catalyzes breakdown of hydroxyl radicals
    • Superoxide dismutase (SOD): converts superoxide to hydrogen peroxide (H₂O₂)
    • Catalase: breaks down H₂O₂

Oxidative stress causes cell injury by lipid peroxidation of membranes, oxidative modification of proteins, and DNA damage.

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Cell Death by Apoptosis

Programmed cell death (apoptosis)

  • Activated enzymes degrade DNA and proteins in cells that are destined to die
  • Features:
    • ↓ Cell size, eosinophilic cytoplasm
    • Chromatin condensation (chromatin aggregates peripherally)
    • Cytoplasmic blebs and apoptotic bodies
    • Phagocytosis of apoptotic cells by macrophages

Apoptosis in different conditions

  • Physiologic conditions:
    • Fetal development: 
      • Cells die off after their purpose has been fulfilled.
      • Removal of supernumerary cells during development
    • Involution of tissues with hormone withdrawal:
      • Endometrial shedding in menstrual cycle
      • Lactating breast regression (weaning)
    • Removal of self-reactive lymphocytes (may cause autoimmune disease)
    • Removal of neutrophils in an inflammatory response
    • Control of cell proliferation, maintaining a constant number of cell populations (immature lymphocytes in bone marrow) 
  • Pathologic conditions:
    • DNA damage: Apoptosis prevents survival of cells with DNA mutations (protective effect).
    • Removal of improperly folded proteins
    • Ductal obstruction (e.g., kidney, parotid gland): Atrophy occurs by apoptosis. 
    • Infections (particularly viral illness): Cytotoxic T lymphocytes induce apoptosis to eliminate infected cells.

Mechanisms of Apoptosis

Caspases:

  • Cystein aspartic acid proteases
  • Exist in inactive form, requiring enzymatic cleavage to be activated
  • Active caspases: a marker for cells undergoing apoptosis
  • Phases of apoptosis:
    • Initiation: activation of caspases → cascade of other caspases
      • Intrinsic pathway
      • Extrinsic pathway
    • Execution: terminal caspases → cellular fragmentation

Intrinsic pathway (initiation):

  • Mitochondrial pathway
  • In viable cells, growth factors and survival signals reduce mitochondrial leakage of cytochrome c by producing anti-apoptotic proteins (principal members):
    • BCL2
    • BCL-XL
    • MCL-1
  • In damaged cells, loss of survival signals, DNA damage, protein misfolding: 
    • Allow cytochrome c leakage from the mitochondria by producing pro-apoptotic proteins (main members):
      • BAX
      • BAK 
    • Activate apoptosis initiators (BH3-only proteins): BAD, BIM, BID, Puma, Noxa
  • Events:
    • Increased permeability of the mitochondrial outer membrane → release of cytochrome c into the cytoplasm 
    • Cytochrome c initiates apoptosis.
    • In the cytoplasm, cytochrome c binds with apoptosis-activating factor-1 (APAF-1), forming a structure, apoptosome.
    • Apoptosome leads to self-cleavage and activation of caspase-9, the initiator caspase.
    • Activated caspase-9 → cascade of executioner caspases 

Extrinsic pathway (initiation):

  • Death receptor-initiated pathway
  • Plasma membrane death receptors initiate this pathway.
  • Death receptors: 
    • Members of tumor necrosis factor (TNF) family with a cytoplasmic death domain (delivers the apoptotic signals)
    • Best known death receptors: 
      • Type 1 TNF receptor (TNFR1)
      • Fas (CD95)
  • Events:
    • FasL (Fas ligand on T cells and cytotoxic T lymphocytes) binds to Fas → a signal for apoptosis is given to the cell.
    • 3 or more Fas molecules combine to form the protein, Fas-associated death domain (FADD).
    • FADD binds pro-caspase-8.
    • Caspase-8 (or caspase-10) is activated → stimulates executioner caspases 

Execution phase:

  • Both pathways converge in the execution phase.
  • Events:
    • Starts with sequential activation of executioner caspases.
    • Inhibitor of deoxyribonuclease (DNase) is cleaved → active DNase → nuclear proteolysis and fragmentation
    • Cytoskeleton proteins break down.
    • Cell fragments → cytoplasmic blebs form → become apoptotic bodies
    • Apoptotic bodies are eaten by phagocytes.
  • Efferocytosis
    • Apoptotic cell phagocytosis
    • Rapid clearance with reduced production of pro-inflammatory cytokines → limited inflammatory reactions even with substantial apoptosis

Intrinsic and extrinsic apoptotic pathway
Intrinsic pathway starts with release of cytochrome c, eventually activating caspase 9. The extrinsic pathway starts with activation of Fas (death receptor), which leads to an active caspase 8/10. These caspases go through the execution phase, finally forming apoptotic bodies which undergo phagocytosis.

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Clinical correlation

  • Tumor suppressor genes: 
    • Prevent uncontrolled cell proliferation and lead cells to apoptosis. 
    • Inactivation → malignant neoplasm
  • Follicular lymphoma:
    • Associated with chromosomal translocations involving BCL2 gene
    • Has BCL2 over-expression
    • Increased anti-apoptotic mechanisms → expansion of malignant cells

Cell Death by Necrosis

Process of necrosis

  • Uncontrolled cell death after irreversible injury:
    • Cell membrane is disrupted; lysosomal enzymes enter and digest the cell.
    • Cellular contents are released and circulate into the extracellular space. 
    • Circulating contents elicit an inflammatory reaction and recruit leukocytes to the site of necrosis.
  • Clinical correlation (tests for tissue-specific injury represent circulating intracellular contents):
    • Troponin: from damaged cardiac muscle cells
    • Alkaline phosphatase: from bile duct epithelium
    • Transaminases: from hepatocytes

Cellular changes

  • Cytoplasmic changes
    • Eosinophilic cytoplasm: due to denatured cytoplasmic proteins (which bind to eosin dye) 
    • Vacuolated cytoplasm: Enzymes digest organelles, leaving “moth-eaten” appearance.
    • Myelin figures: large whorled phospholipid precipitates (from the damaged membrane), which are phagocytosed or degraded to fatty acids
  • Nuclear changes (1 of 3 patterns):
    • Karyolysis: reduced basophilia due to DNA loss (effect of DNAse)
    • Pyknosis: nuclear shrinkage and increased basophilia (condensation of chromatin into a dense basophilic mass)
    • Karyorrhexis: fragmentation of the nucleus
Table: Necrosis and apoptosis
Features of necrosisFeatures of apoptosis
Cell size Enlarged (swelling) Reduced (shrinkage)
Nucleus Pyknosis, karyorrhexis, karyolysis Fragmentation into nucleosome-size fragments
Plasma membrane Disrupted Intact but altered structure (orientation of lipids)
Cellular contents Enzymatic digestion; leak out of the cell Intact; released in apoptotic bodies
Adjacent inflammation Frequent No
Physiologic or pathologic role Pathologic (result of irreversible cell injury) Physiologic: elimination of unwanted cells
Pathologic: cell injury from DNA and protein damage

Patterns of Necrosis

Coagulative necrosis:

  • Cell outlines and tissue architecture maintained for several days
  • Injury also denatures enzymes, so initial proteolysis is blocked.
  • Eventually, leukocyte enzymes break down the dead cells.
  • Often in ischemia or hypoxic injury
  • Infarct: localized area of coagulative necrosis 
  • Seen in myocardial and renal infarction

Liquefactive necrosis:

  • Colliquative necrosis
  • Tissue is digested and dissolved into a viscous liquid.
  • Seen in bacterial and fungal infections, which stimulate leukocytes and the release of hydrolytic enzymes
  • Pus: creamy-yellow necrotic material 
  • Default necrosis mechanism used by hypoxic central nervous system cells
  • Coagulative and liquefactive necrosis: not mutually exclusive
  • Damaged cardiac myocytes undergo coagulative necrosis; as leukocytes set in and enzymes are released, liquefactive necrosis occurs.

Caseous necrosis :

  • Caseous: “cheese-like”
  • Fragmented cells and debris surrounded by an inflammatory border: granuloma
  • Seen in tuberculosis and some fungal infections
  • Mycolic acid from the mycobacterial cell wall induces granuloma formation.

Fat necrosis:

  • Change in adipose tissue due to trauma or enzymatic release
  • Release of pancreatic lipases into the pancreatic parenchyma and the peritoneum → destruction of adipocytes 
  • Liberated fatty acids combine with calcium, producing chalky-white areas (fat saponification).
  • Seen in acute pancreatitis, fat necrosis of the breast

Fibrinoid necrosis:

  • Microscopic change
  • Deposition of immune complexes in the walls of vessels
  • Fibrinoid: fibrin combined with immune complexes deposited in the vessel walls (homogeneously pink in hematoxylin and eosin stains)

Gangrenous necrosis:

  • Not a pattern of necrosis; a clinical description used when a limb becomes necrotic due to ischemia 
  • Indicates coagulative necrosis of multiple layers of tissue (dry gangrene)
  • With superimposed bacterial infection, liquefaction necrosis occurs due to enzymes from bacteria and leukocytes (wet gangrene).

Dystrophic calcification:

  • Necrotic cells: eliminated by enzymatic digestion and phagocytosis
  • Inadequately reabsorbed necrotic cells become a nidus of calcium and mineral deposition.

Other Cellular Mechanisms

Necroptossis

  • Programmed necrosis
  • Caspase-independent cell death
  • Similar to necrosis in morphology, with apoptotic type of cell death 
  • Clinical correlation:
    • Physiologic: mammalian growth plate
    • Pathologic: steatohepatitis, Parkinson’s disease

Pyroptosis

  • Apoptosis accompanied by cytokine IL-1 (interleukin-1: fever-inducing cytokine)
  • Pathway of apoptosis releases inflammatory mediators.
  • Clinical correlation: death of cells infected by microbes 

Ferroptosis

  • Iron-dependent pathway of cell death, characterized by lipid peroxidation
  • Results in the loss of membrane permeability (ruptured mitochondrial membrane)
  • Occurs with excessive iron or ROS, which glutathione-dependent defenses cannot handle
  • Clinical correlation: cancer, neurodegenerative diseases, and stroke

Autophagy

  • “Auto”: self; “phagy”: eat → cell eats its contents
  • Survival mechanism, such as in atrophic cells in states of nutrient deprivation
  • Triggers cell death, if unable to cope with stress
  • Mechanism:
    • Nucleation and formation of a phagophore, an isolation membrane derived from the ER or mitochondria or plasma membrane
    • The organelles are sequestered by the phagophore and a vesicle, autophagosome, forms.
    • Mature autophagosome fuses with a lysosome (autophagolysosome), resulting in the degradation of contents.
  • Clinical correlation:
    • Cancer
    • Neurodegenerative disorders (e.g., Alzheimer’s disease)
    • Infectious disease
    • Inflammatory bowel disease

Schematic diagram of the steps of autophagy
1. Formation of the phagophore or isolation membrane (vesicle nucleation and elongation step).
2. Expansion of the phagophore into an autophagosome.
3. Fusion of the autophagosome with a lysosome forming an autophagolysosome.
4. Sequestered material is degraded inside the autophagolyosome and recycled.

Image by Lecturio.

References

  1. Adigun, R., Basit, H., Murray, J. (2020). Cell liquefactive necrosis. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK430935/#!po=1.85185
  2. Kemp W.L., Burns D.K., Brown T.G. (Eds.) (2008). Cellular pathology. Pathology: The Big Picture. McGraw-Hill.
  3. Lin, J., Walter, P., Benedict Yen, T. (2008). Endoplasmic reticulum stress in Disease Pathogenesis. Annual Rev Patho 3, 399–425. https//:doi.org/10.1146/annurev.pathmechdis.3.121806.151434
  4. Kumar V, Abbas A, Aster J, Robbins, S. Robbins, and Cotran (Eds.) (2020). Pathologic Basis of Disease (10th ed.). Elsevier, Inc.

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