Cell Injury and Death: Necrosis vs Apoptosis

Cell Injury

• Cells strive to maintain a stable internal environment
• When cells are exposed to stress or stimuli they can adapt to preserve their viability
• If the cell's adaptive capacity is exceeded, cell injury results
• Two main types of cell death: necrosis and apoptosis

Necrosis

• Occurs due to exposure to harmful conditions
• Characterized by cell swelling, protein denaturation, and organelle breakdown

Apoptosis

• A programmed cell death that occurs under normal or physiological conditions

Causes of Cell Injury

• Hypoxia: Deprives cells of oxygen for aerobic respiration, a distinct condition from ischemia which also leads to hypoxic cell injury
• Physical Agents: Trauma, temperature extremes, radiation, electric shock, and sudden atmospheric pressure changes can all injure cells
• Chemicals and drugs: Alter membrane permeability, osmotic balance, or enzyme cofactor integrity
• Microbiologic Agents: Range from viruses to tapeworms
• Immunologic Reactions: The body's immune system can trigger cell injury, such as in anaphylactic reactions
• Genetic Defects: Examples include Down syndrome and sickle cell anemia
• Nutritional Imbalances: Protein-calorie deficiencies, vitamin deficiencies, and diets rich in animal fat can contribute to cell injury (e.g. atherosclerosis)
• Aging: A natural process that contributes to cell deterioration

Mechanisms of Cell Injury

• Membrane Integrity: Disruptions in membrane integrity lead to changes in cellular ionic and osmotic homeostasis
• Aerobic Respiration: Damage to this process severely impacts cellular energy production
• Protein Synthesis: Disruptions in protein production can lead to functional impairments
• Genetic Apparatus: Damage to DNA or RNA can have detrimental effects on cell function and survival
• Calcium Homeostasis: Increased intracellular calcium levels activate enzymes that damage cells (e.g., phospholipases, proteases, ATPases, endonucleases)
• Reactive Oxygen Species: These unstable molecules contribute significantly to cell death

Ischemic and Hypoxic Injury

• Reversible Injury: Initial effects on aerobic respiration result in reduced ATP, leading to calcium influx, membrane pump dysfunction, and cellular swelling
• Irreversible Injury: Characterized by:
  • Severely damaged mitochondria
  • Extensive plasma membrane damage
  • Swelling of lysosomes
  • Reperfusion injury
  • Loss of cellular components
  • Formation of myelin figures

Mechanisms of Irreversible Injury

• Phospholipid Loss: Progressive loss of membrane phospholipids weakens the cell membrane
• Cytoskeletal Damage: Protease activation and calcium influx can disrupt the structural integrity of the cell
• Toxic Oxygen Radicals: Released during reperfusion, damaging cells further
• Lipid Breakdown Products: Detergent-like effects on cell membranes

Necrosis

• Characterized by morphological changes that follow cell death in living tissue
• Results from enzymatic digestion and protein denaturation
• Cytoplasmic Changes: Eosinophilia, glassy appearance, vacuolation, and calcification
• Nuclear Changes:
  • Karyolysis: Nuclear DNA digestion
  • Pyknosis: Nuclear shrinkage and increased basophilia, common in apoptosis
  • Karyorrhexis: Fragmentation of the pyknotic nucleus

Types of Necrosis

• Coagulative Necrosis: Preservation of the structural outlines of dead cells, most common in myocardial infarction
• Liquefactive Necrosis: Associated with bacterial or fungal infections, characterized by the breakdown of tissue into a liquid mass, also seen in the CNS
• Gangrenous Necrosis: Ischemic coagulative necrosis with superimposed infection, often referred to as "wet gangrene"
• Caseous Necrosis: Associated with tuberculosis, characterized by a cheesy, white appearance microscopically consisting of amorphous granular debris
• Fat Necrosis: Occurs in acute pancreatitis, characterized by the enzymatic destruction of fat cells

Apoptosis

• Programmed cell death that is responsible for cell elimination under normal and pathological conditions
• Key characteristics:
  • Single or clustered cells with intensely eosinophilic cytoplasm
  • Condensed nuclear chromatin with well-defined masses
  • Karyorrhexis caused by endonucleases
  • Cell shrinkage, budding, and fragmentation into apoptotic bodies
  • No inflammatory response

Initiation of Apoptosis

• Withdrawal of growth factors or hormones: Absence of essential signals can trigger apoptosis
• Engagement of specific receptors: Receptors like FAS and TNF can activate apoptotic pathways
• Injury by radiation, toxins, and free radicals: These agents can damage cells leading to apoptosis
• Intrinsic protease activation: Activation of caspases, particularly in developmental scenarios

Intracellular Accumulations

• Normal cells can accumulate abnormal substances in a variety of circumstances
• Accumulations can be transient or permanent, harmful or injurious, and occur in the cytoplasm or nucleus
• Main categories:
  • Normal endogenous substances: Produced at a normal or increased rate with inadequate metabolism, common in fatty liver disease
  • Normal or abnormal substances: Unaffected by metabolism due to genetic defects, leading to storage diseases
  • Abnormal exogenous substances: The cell lacks the machinery to metabolize or transport these substances

Fatty Change (Steatosis)

• Abnormal accumulation of triglycerides within parenchymal cells
• Most often seen in the liver, but can affect other organs
• Caused by various factors: toxins, diabetes, malnutrition, obesity, anoxia
• Defects at any step of fatty acid entry or lipoprotein synthesis can contribute

Cholesterol and Cholesterol Esters

• Foamy cells: Macrophages that ingest lipid debris, accumulating cholesterol
• Atherosclerosis: Accumulation of cholesterol and cholesterol esters in smooth muscle cells and macrophages
• Xanthomas: Accumulation of fat within macrophages of subcutaneous connective tissues appearing as white nodules

Proteins

• Less common accumulations, often associated with proteinuria in glomerular diseases

Glycogen

• Accumulates in cases of abnormal glucose or glycogen metabolism
• Appears as vacuoles in cells

Pigments

• Colored substances, either exogenous or endogenous
• Melanin: Accumulates in epidermal cells, leading to freckles or dermal macrophage deposits
• Hemosiderin: Iron-containing pigment, golden brown in color, accumulates in local or systemic iron overload

Pathologic Calcification

• Abnormal accumulation of calcium salts, often with smaller amounts of other minerals
• Can occur in various tissues, often associated with tissue damage