Cell Injury & Death: Concepts and Mechanisms

Cell Injury & Death

• Cell injury occurs when cells are severely stressed, unable to adapt, or exposed to damaging agents or intrinsic abnormalities.

Learning Outcomes

• Reversible vs irreversible cell injury
• Necrosis: causes, mechanisms, morphology, and clinical correlates
• Apoptosis: causes, mechanisms, morphology, and clinical correlates
• Distinguishing necrosis and apoptosis
• Intracellular accumulations: clinical significance
• Pigments: exogenous vs endogenous
• Pathologic calcification: dystrophic vs metastatic

Definition

• Cell injury: occurs when cells are severely stressed, unable to adapt, or exposed to damaging agents or intrinsic abnormalities.

Reversible Cell Injury

• Functional and morphologic changes are reversible if the damaging stimulus is removed.
• Hallmarks include:
  • Reduced oxidative phosphorylation
  • Cellular swelling
  • Alterations in organelles
• Two morphological features on light microscopy:
  • Cellular swelling (hydropic change)
  • Fatty change

Cellular Swelling (Hydropic Change)

• First sign of cell injury
• Caused by changes in ion concentrations and water influx.
• Cells lose their ability to maintain ionic and fluid homeostasis.
• Results from failure of energy-dependent pumps in the plasma membrane.
• Macroscopic features: increased weight, increased turgor, pallor
• Microscopic features: small, clear vacuoles within the cytoplasm and increased eosinophilia of the cytoplasm

Fatty Change (Steatosis)

• Abnormal accumulation of lipid droplets (triglycerides) in parenchymal cells of organs.
• Causes:
  • Toxins
  • Protein malnutrition
  • Diabetes mellitus
  • Obesity
  • Hypoxia
  • Alcohol
• Example: Fatty Liver. In developed countries, alcohol abuse is a primary cause. Other causes of non-alcoholic fatty liver include diabetes and obesity

Irreversible Injury

• With continued damage, injury becomes irreversible, causing cell death.
• Difficult to pinpoint the exact time when reversible becomes irreversible.
• Two phenomena consistently characterize irreversibility:
  • Inability to reverse mitochondrial dysfunction
  • Profound disturbances in membrane function

Mechanisms of Cell Injury

• Depletion of ATP
• Mitochondrial damage
• Calcium influx
• Oxidative stress (accumulation of ROS)
• Defects in membrane permeability
• Damage to DNA and proteins

Causes of Cell Injury

• Oxygen deprivation:
  • Hypoxia (deficiency of oxygen) reduces aerobic oxidative respiration.
  • Causes of hypoxia: reduced blood flow (ischemia), inadequate oxygenation of the blood (cardiorespiratory failure), decreased oxygen-carrying capacity of the blood (anemia, carbon monoxide poisoning).
• Physical agents:
  • Mechanical trauma
  • Extreme temperatures (burns and deep cold)
  • Sudden changes in atmospheric pressure
  • Radiation
  • Electric shock
• Chemical agents and drugs:
  • Simple chemicals (e.g., glucose, salt) in abnormal concentrations can directly injure cells or disrupt electrolyte balance.
  • Trace amounts of poisons may cause sufficient cell death in minutes or hours.
  • Other: environmental and air pollutants, insecticides, herbicides, industrial occupational hazards, recreational drugs, and therapeutic drugs
• Infectious agents:
  • Includes viruses, rickettsiae, bacteria, fungi, and parasites
  • Serves an essential function in defense against infectious pathogens.
  • Immune reactions can also cause cell injury (e.g., autoimmune diseases and responses to pathogens).
• Genetic derangements:
  • Deficiency of functional proteins (e.g., enzyme defects in inborn errors of metabolism).
  • Accumulation of damaged DNA or misfolded proteins.
• Nutritional imbalances:
  • Deficiencies of specific vitamins
  • Self-imposed nutritional deficiencies (e.g., anorexia nervosa)
  • Excessive intake of nutrients (e.g., cholesterol predisposes to atherosclerosis)

Necrosis

• Definition: The death of tissues following bioenergetic failure and loss of plasma membrane integrity.
• Morphology:
  • Cytoplasm: increased eosinophilia, glassy and homogenous appearance, vacuolated or moth-eaten.
  • Nucleus: karyolysis, pyknosis, karyorrhexis
  • Types: coagulative, liquefactive, caseous, fibrinoid, fat, gangrenous.

Apoptosis

• Definition: A pathway of cell death induced by a tightly regulated suicide program. Cells destined to die activate intrinsic enzymes that degrade their own DNA and proteins.
• Causes: Physiological (destruction of cells during embryogenesis, involution of hormone-dependent tissues, cell loss in proliferating cell populations, elimination of potentially self-reactive lymphocytes, death of host cells), and Pathologic (DNA damage, accumulation of misfolded proteins, cell death in certain infections, pathologic atrophy in parenchymal organs).
• Morphology: cell shrinkage, chromatin condensation, formation of cytoplasmic blebs and apoptotic bodies, phagocytosis of apoptotic bodies, intensely eosinophilic cytoplasm with fragments of dense nuclear chromatin.
• Mechanisms:
  • Two pathways: intrinsic (mitochondrial) and extrinsic (death-receptor mediated)
  • Two phases: initiation and execution
• Clinical correlates: decreased apoptosis (malignancy, autoimmune diseases), increased apoptosis (neurodegenerative diseases, death of virus-infected cells).

Autophagy

• Definition: A process in which a cell eats its own contents.
• Can be physiological or pathological
• Examples of physiological autophagy: aging, exercise, atrophy
• Examples of pathological autophagy: cancer, neurodegenerative diseases, infectious diseases, inflammatory bowel diseases
• Maintains cellular integrity under stress conditions.

Intracellular Accumulations

• Accumulations of abnormal amounts of substances within a cell (cytoplasm, nucleus, organelles).
• May be reversible or progressive, leading to cell injury and death.
• Types: Lipids (e.g. steatosis, cholesterol and cholesterol esters), Proteins (e.g. amyloid), Glycogen (diabetic mellitus, glycogen storage diseases)

Pigments

• Coloured substances.
• Some are normal constituents of cells.
• Others are abnormal.
• May be exogenous (e.g. carbon/coal dust, tattooing) or endogenous (e.g. lipofuscin, melanin, hemosiderin).

Pathologic Calcification

• Abnormal tissue deposition of calcium salts along with smaller amounts of other mineral salts.
• Two types:
  • Dystrophic: occurs locally in diseased or necrotic tissues (e.g. advanced atherosclerosis, aging/damaged heart valves, normal serum calcium and calcium metabolism).
  • Metastatic: occurs in normal tissues with increased PTH secretion, hypercalcemia, altered calcium metabolism, Vitamin D-related disorders and renal failure.

This quiz explores the fundamental concepts of cell injury and death, covering both reversible and irreversible changes. Key topics include necrosis and apoptosis, the mechanisms involved, and clinical significance. Distinguishing between types of cell injury allows for a deeper understanding of cellular processes and pathology.