Cell Injury (Pathology)

1. Causes of Cell Injury

• Hypoxia/Ischemia - the most common cause. Hypoxia is oxygen deficiency (from lung disease, anemia, or poor oxygen-carrying capacity of blood); ischemia is reduced blood supply, which also deprives cells of nutrients. Most hypoxia results from ischemia due to arterial blockage.
• Toxins - air pollutants, insecticides, carbon monoxide, asbestos, cigarette smoke, ethanol, and many therapeutic drugs at excessive or inappropriate doses.
• Infectious agents - viruses, bacteria, fungi, parasites - injure cells directly or via toxin release and harmful immune responses.
• Immunologic reactions - autoimmune attack on self-tissue, allergic reactions, or chronic immune responses to microbes; the resulting inflammation itself damages tissue.
• Genetic abnormalities - mutations or chromosomal defects causing loss or gain of protein function, accumulation of misfolded proteins, or damaged DNA (e.g., sickle cell anemia, inborn errors of metabolism).
• Nutritional imbalances - protein-calorie deficiency, vitamin deficiencies, or excessive intake (obesity contributing to diabetes, atherosclerosis).
• Physical agents - trauma, extremes of temperature, radiation, electric shock, sudden pressure changes.

2. Reversible vs. Irreversible Injury

• Cellular (hydropic) swelling - due to failure of ATP-dependent ion pumps, causing Na+ and water influx
• Fatty change - lipid vacuoles, especially in liver, heart, muscle
• Cytoplasmic changes: swollen ER and mitochondria, detachment of ribosomes, clumping of nuclear chromatin
• Formation of "myelin figures" from damaged membranes

• Severe mitochondrial dysfunction with inability to reverse (loss of oxidative phosphorylation even after reoxygenation)
• Marked disturbances of membrane function (plasma membrane, lysosomal, mitochondrial)
• Massive influx of calcium into the cell, activating destructive enzymes (proteases, phospholipases, endonucleases)

3. Mechanisms of Cell Injury

1. Mitochondrial dysfunction - hypoxia, toxins, and radiation damage mitochondria, causing (a) failure of oxidative phosphorylation with ATP depletion, and (b) formation of the mitochondrial permeability transition pore, which can trigger necrosis, and release of cytochrome c and other proteins that activate apoptosis.
2. ATP depletion - loss of energy needed for ion pumps (leading to cell swelling), protein synthesis, and lipid metabolism; anaerobic glycolysis compensates partially but causes lactic acid accumulation and intracellular acidification.
3. Influx of calcium - increased cytosolic Ca2+ activates enzymes (ATPases, phospholipases, proteases, endonucleases) that damage membranes, cytoskeleton, and chromatin.
4. Accumulation of reactive oxygen species (oxidative stress) - free radicals cause lipid peroxidation of membranes, oxidative modification of proteins, and DNA damage.
5. Defects in membrane permeability - direct toxin/complement damage or downstream effects of the mechanisms above.
6. Damage to DNA and proteins - misfolded proteins and DNA damage trigger apoptosis via checkpoint pathways.
7. Autophagy - a survival response where cells "self-cannibalize" damaged organelles via lysosomal digestion during stress (e.g., nutrient deprivation, ischemia); if overwhelmed, it can also trigger cell death.

4. Patterns of Cell Death

• Coagulative necrosis - protein denaturation preserves the basic cell/tissue outline (classic in myocardial infarction, most solid organ infarcts)
• Liquefactive necrosis - enzymatic digestion produces a liquid, viscous mass (brain infarcts, bacterial abscesses)
• Caseous necrosis - "cheese-like" friable necrosis, characteristic of tuberculosis (a combination of coagulative and liquefactive features surrounded by granulomatous inflammation)
• Fat necrosis - enzymatic (lipase) destruction of fat, as in acute pancreatitis
• Fibrinoid necrosis - seen in immune-mediated vascular injury, with immune complex/protein deposition in vessel walls
• Gangrenous necrosis - not a distinct pattern but coagulative necrosis of a limb with superimposed liquefactive change from bacterial infection (wet gangrene)

Summary Table