Cell Injury and Cell Death Notes

Introduction to Pathology

  • Pathology is the study of structural, biochemical, and functional changes in cells, tissues, and organs that underlie disease.
  • It involves understanding the causes (aetiology) and the underlying mechanisms (pathogenesis) of disease.
  • Pathology uses molecular, microbiological, immunological, and morphologic techniques.
  • It provides a rational basis for clinical care, treatment, and medicine development.

Major Aspects of Disease Processes

  • Aetiology: Causes of the disease, which can be genetic or environmental (e.g., toxins, hormonal changes, mutations, polymorphisms, infections).
  • Pathogenesis: Sequence of cellular, biochemical, and molecular events that occur after exposure to an injurious agent.
  • Morphological Changes: Structural alterations in cells or tissues characteristic of a disease or diagnostic of an etiologic process.
  • Functional Abnormalities: The end result of genetic, biochemical, and structural changes in cells and tissues, leading to clinical manifestations.

Steps in the Development of Disease

  • Etiology: Causes of disease (e.g., hypoxia, ischemia, toxins, infections, abnormal immune reactions, genetic abnormalities, nutritional imbalances, physical agents).
  • Pathogenesis: Mechanisms of disease involving biochemical and structural changes at the molecular and cellular levels.
  • Abnormalities in Cells and Tissues: Molecular, functional, and morphologic changes.
  • Clinical Manifestations: Signs and symptoms of the disease.

Cellular Responses to Stress and Noxious Stimuli

  • Cells maintain physiological parameters within a narrow range (homeostasis).
  • When cells encounter stress or pathological stimuli, they undergo adaptations, which are reversible functional and structural responses to changes to reach a new steady state while preserving viability and function.
  • If adaptive capability is exceeded or stress is inherently harmful, cell injury develops.
  • Mild or transient stress results in reversible injury where cells return to their original state.
  • Severe or persistent stress leads to irreversible injury and cell death (e.g., changes in ion levels like K^+).

Adaptation

Response to increased load (e.g., hypertrophy in myocytes due to gym or hypertension; decreased oxygen supply due to hypoxia or ischemia).

Cellular Adaptation to Stress

Reversible changes in number, size, phenotype, metabolic activity, or functions of cells in response to environmental changes.
* Physiological adaptations: Responses of cells to normal stimulation by hormones or endogenous chemical mediators.
* Pathological adaptations: Responses to stress that allow cells to modulate their structure and function to escape injury.

Hypertrophy

  • Increase in size of cells resulting in an increased size of the organ.
  • Can be physiological (e.g., hormone-induced enlargement of breast and uterus during pregnancy) or pathological and is caused by increased functional demand or hormonal stimulation.
  • Occurs when cells are incapable of dividing.
  • Results from increased production of cellular proteins.

Hyperplasia

  • Increase in the number of cells in a tissue or organ.
  • Adaptive response in cells capable of replication.
  • Often occurs with hypertrophy.
  • Can be physiological or pathological.
    • Physiological hyperplasia: Hormonal (e.g. breast during puberty) or compensatory (e.g., after tissue removal).
    • Pathologic hyperplasia: Caused by excessive hormonal or growth factor stimulation (e.g., benign prostate hyperplasia).

Atrophy

  • Reduction in the size of an organ or tissue due to a decrease in cell size and number.
  • Shrinkage in size of cells due to loss of cell substance.
  • Cells may have diminished function but are not dead.
  • Can be physiological or pathological.
  • Causes include decreased workload, loss of innervation, decreased blood supply, inadequate nutrition, loss of endocrine stimulation, and aging.
  • Represents a retreat by the cell to a smaller size at which survival is still possible, indicating a new equilibrium between cell size and diminished blood supply, nutrition, and stimulation.
  • Results from decreased protein synthesis or increased protein degradation due to decreased metabolic activity.

Metaplasia

  • Reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type.
  • Cells sensitive to a particular stress are replaced by other cell types better able to withstand the adverse environment.
  • Results from reprogramming of stem cells in normal tissues or undifferentiated mesenchymal cells.
  • Often results in some loss of function.
  • Persistent metaplasia can initiate malignant transformation.
  • Example: Smoking-induced metaplasia in the trachea where squamous cells replace the normal epithelium, providing toughness but reducing cilia and mucus secretion.
  • Another example: Barrett's esophagus, where esophageal squamous cells are replaced with intestinal-like columnar cells due to acid reflux.

Cell Injury and Cell Death

  • Reversible Cell Injury: In early stages or mild forms, functional and morphologic changes are reversible if the damaging stimulus is removed.
  • Cell Death: With continuing damage, the injury becomes irreversible, and the cell cannot recover and dies.

Reversible Cell Injury Hallmarks

  • Characterized by reduced oxidative phosphorylation with resultant depletion of ATP.
  • Cellular swelling results from changes in ion concentrations and water influx.
  • Intracellular organelles (e.g., mitochondria and the cytoskeleton) may show alterations.

Cell Death

  • Cell death is a key event in the evolution of disease in any tissue or organ.
  • Results from diverse causes (e.g., ischemia, infection, and toxins).
  • Cell death is also a normal and essential process in the development of organs (embryogenesis) and the maintenance of homeostasis.
  • Two main pathways of cell death: necrosis and apoptosis.

Necrosis

  • Pathological process of cell death.
  • Main pathway of cell death from common insults (e.g., ischemia, toxins, infectious agents, trauma).
  • Involves unregulated enzymatic digestion of cell components.
  • Occurs when damage to membranes is severe.
  • Enzymes leak out of lysosomes into the cytoplasm and digest the cell.
  • Cell contents also leak out through damaged plasma membranes and initiate inflammation.

Apoptosis

  • Tightly regulated type of cell death.
  • Active, energy-dependent process.
  • Occurs in specific situations.
  • Serves many normal functions and is not necessarily associated with pathological injury.
  • Serves to eliminate cells that are no longer needed and to maintain a steady number of various cell populations in tissues.
  • Occurs when a cell is deprived of growth factors or DNA or proteins are damaged beyond repair, causing the cell to kill itself.
  • Mediated by the activation of caspases (protease enzymes).
  • Characterized by enzymatic degradation of proteins and DNA.

Necrosis vs. Apoptosis

  • Cell Size: Necrosis involves enlarged cells (swelling), while apoptosis involves reduced cells (shrinkage).
  • Nucleus: Necrosis shows pyknosis → karyorrhexis → karyolysis, while apoptosis shows fragmentation into nucleosome-sized fragments.
  • Plasma Membrane: Necrosis involves a disrupted plasma membrane, while apoptosis has an intact but altered structure.
  • Cellular Contents: Necrosis causes enzymatic digestion and leakage out of the cell, while apoptosis releases contents in apoptotic bodies.
  • Adjacent Inflammation: Necrosis frequently induces inflammation, while apoptosis does not.
  • Physiologic or Pathologic Role: Necrosis is invariably pathologic, while apoptosis is often a physiologic means of eliminating unwanted cells but can be pathologic after some forms of cell injury, especially DNA and protein damage.

Morphologic Alterations in Dying/Dead Cells

  • Necrosis: Increased eosinophilia, nuclear shrinkage, fragmentation and dissolution, breakdown of plasma membrane and organelle membranes, calcification, leakage, and enzymatic digestion of cellular contents.
  • Apoptosis: Nuclear chromatin condensation and formation of apoptotic bodies.

Irreversible Cell Injury - Necrosis

  • Swelling of endoplasmic reticulum and mitochondria.
  • Membrane blebs.
  • Swelling of endoplasmic reticulum and loss of ribosomes.
  • Lysosome rupture.
  • Clumping of chromatin.
  • Fragmentation of cell membrane and nucleus.
  • Myelin figures.
  • Nuclear condensation.
  • Swollen mitochondria with amorphous densities.

Mechanisms of Cell Injury

  • ATP depletion.
  • Reactive oxygen species.
  • ER stress/misfolded proteins.
  • DNA damage.
  • Inflammation.

Causes of Cell Injury

  1. Ischemia/hypoxia.
  2. Chemical agents/toxins.
  3. Infectious agents.
  4. Immune reactions.
  5. Mutations.
  6. Nutritional imbalances.
  7. Physical agents/radiation.
  8. Aging.
  • Cellular responses to injurious stimuli depend on the nature of the injury, duration, and severity.
  • Consequences depend on the type, state, and adaptability of the injured cell.
  • Cell injury results from different biochemical mechanisms acting on essential cellular components.

Endoplasmic Reticulum Stress

  • ER controls folding of proteins during synthesis.
  • Proteins may not fold into a normal configuration, leading to altered or dysfunctional proteins or accumulation.
  • Misfolded proteins are responsible for numerous disorders (proteopathies).
  • The ER membrane contains sensors that detect misfolded proteins, and accumulation of these can trigger apoptosis.

ATP Depletion

  • Reduction in ATP levels is a main cause of necrotic cell death.
  • Associated with both hypoxia and chemical injury (toxins).
  • Failure of energy-dependent functions leads to reversible injury and then necrosis.
  • Reversible if oxygenation is restored.
  • Damage due to decreased activity of the plasma membrane Na^+ K^+ ATPase.
  • Changes in cellular energy metabolism.
  • Influx of Ca^{++} due to failure of Ca^{++} pumps.
  • Reduction in protein synthesis.

Consequences of Decreased ATP

  • Ischemia leads to decreased oxidative phosphorylation and decreased ATP.
  • Decreased Na^+ pump, increased anaerobic glycolysis, detachment of ribosomes, influx of Ca^{2+}, H_2O, and Na^+, decreased glycogen and pH, decreased protein synthesis, efflux of K^+, ER swelling, cellular swelling, loss of microvilli, and blebs.

Reactive Oxygen Species

  • Highly unstable “free radicals.”
  • ROS include superoxide radicals, hydrogen peroxide, and hydroxyl radicals.
  • Cause covalent modification of cell proteins, lipids, and nucleic acids.
  • Uncontrolled free radical production causes damage to cell membranes, proteins, inactivation of enzymes, and damage to nucleic acids.
  • Increased permeability of cellular membranes, typically culminating in necrosis.
  • Accumulation of damaged DNA and misfolded proteins triggers apoptosis.

Production of ROS: Pathologic Effects

  • Lipid peroxidation causes membrane damage.
  • Protein modifications cause breakdown and misfolding.
  • DNA damage leads to mutations.

Autophagy

  • Process in which a cell eats its own contents.
  • Survival mechanism.
  • Initiated by nutrient-sensing proteins.
  • Sequestration of cellular organelles into cytoplasmic autophagic vacuoles that fuse with lysosomes and digest the enclosed material.
  • Plays a role in human diseases including cancer, neurodegenerative disorders, and infections.

Cellular Aging

  • As cells age, function and viability decrease.
  • Caused by the accumulation of cellular and molecular damage due to the effects of exposure to exogenous influences.
    • Main mechanisms:
      • Accumulation of DNA damage and defective DNA repair mechanisms.
      • Replicative senescence - reduced capacity of cells to divide.
      • Defective protein homeostasis.

Cell Senescence

  • Healthy human cells are mortal and have a limited capacity for replication.
  • After a fixed number of divisions, cells become arrested in a terminally nondividing state.
  • Reduced capacity of cells to divide because of decreasing amounts of telomerase and progressive shortening of chromosomal ends (telomeres) after around 50 divisions (Hayflick limit).