Mechanisms of Cell Injury - Flow Chart

INJURIOUS STIMULUS
│
├─ Hypoxia / ischemia
├─ Physical agents: trauma, heat, cold, radiation, electric shock
├─ Chemical agents / drugs / toxins
├─ Infectious agents
├─ Immunologic reactions
├─ Genetic defects
└─ Nutritional imbalance
          ↓
CELLULAR TARGETS AFFECTED
│
├─ Mitochria
├─ Cell membrane
├─ Endoplasmic reticulum
├─ Lysosomes
├─ DNA and proteins
└─ Cytosolic calcium balance
          ↓
MAJOR BIOCHEMICAL MECHANISMS
│
├─ 1. ATP depletion
│     ↓ failure of Na+/K+ pump
│     ↓ Na+ and water influx
│     ↓ cellular swelling, ER dilatation
│     ↓ anaerobic glycolysis → lactic acidosis → ↓ pH
│     ↓ ribosomal detachment → ↓ protein synthesis
│
├─ 2. Mitochondrial damage
│     ↓ ↓ oxidative phosphorylation and ATP
│     ↓ ↑ reactive oxygen species (ROS)
│     ↓ leakage of cytochrome c
│     └─ apoptosis
│
├─ 3. Increased intracellular Ca2+
│     ↓ activation of phospholipases
│     ↓ activation of proteases
│     ↓ activation of endonucleases
│     ↓ activation of ATPases
│     └─ membrane, cytoskeletal, DNA, and mitochondrial damage
│
├─ 4. Oxidative stress: ROS generation
│     ↓ lipid peroxidation of membranes
│     ↓ protein oxidation / misfolding
│     ↓ DNA strand breaks and mutations
│
├─ 5. Membrane permeability defects
│     ├─ Plasma membrane damage
│     │     ↓ loss of cellular contents and ion homeostasis
│     ├─ Mitochrial membrane damage
│     │     ↓ ATP depletion and apoptosis
│     └─ Lysosomal membrane damage
│           ↓ enzyme leakage → autodigestion of cell
│
└─ 6. DNA damage and protein misfolding
      ↓ p53 activation / unfolded-protein response
      └─ apoptosis
          ↓
OUTCOME
│
├─ Mild or transient insult
│     └─ Reversible cell injury
│          • cell swelling (hydropic change)
│          • fatty change
│          • membrane blebs
│          • mitochondrial swelling
│
└─ Severe or persistent insult
      └─ Irreversible cell injury
           ↓
           CELL DEATH
           ├─ Necrosis: membrane rupture, enzyme leakage, inflammation
           └─ Apoptosis: programmed cell death, usually no inflammation