Amos Rodger MWAKIGONJA, MD, MMed, PhD, FCPath ECSA Senior Lecturer CELL INJURY Amos Rodger MWAKIGONJA, MD, MMed, PhD, FCPath ECSA Senior Lecturer

Lecture objectives Define cell injury Explain causes and classification Recognize the morphology of cell injury and distinguish between reversible & irreversible injury

outline: Definition Classification Causes Morphology Mechanisms Responses to cell injury/ cellular adaptations

definition Cell injury refers to a sequence of events in a cell which follow when either Excessive physiologic stress or Pathologic stimuli It may be due to a variety of stresses a cell encounters in its Internal External environment surpass the limits of adaptive response or when adaptation to such stimuli is not possible.

classification Cell injury can be reversible or Irreversible if the stimulus persists or if it is Severe enough from the outset.

causes Exogenous causes (external environment) e.g. Physical agents Endogenous causes (internal environment) e.g. metabolic factors, etc. Congenital or Acquired

list of the causes Physical agents: Mechanical trauma Temperature extremes Sudden changes in atmospheric pressure Radiation Electric shock

Chemical agents and drugs: Innumerable chemicals inflict cell injury e.g. glucose, salt, oxygen, poisons like arsenic, cyanide, mercury, etc., pollutants, insecticides, herbicides, carbon monoxide, asbestos, alcohol, narcotics and therapeutic drugs. Infectious agents: Microbes parasites

Immunologic reactions: Double edged sword Defensive functions primarily but can be Injurious e.g. anaphylaxis and autoimmunity. Genetic derangements: germline or somatic Gross malformations e.g. Downs syndrome Subtle alterations at DNA level e.g. SCA Nutritional imbalances: Deficiencies e.g. PEM, avitaminosis Excesses e.g. hyperlipidemia (atherosclerosis), hypervitaminosis

morphology Morphology of reversible injury: Light microscopy: Cellular swelling due to inability to maintain homeostasis Fatty change in cells involved in and dependent on fat metabolism e.g. hepatocytes and myocardial cells; Intra-cytoplasmic lipid vacuoles Appearing in hypoxic and toxic injury

Vacuolar degeneration Ultrastructural changes- Hydropic change Vacuolar degeneration Ultrastructural changes- Plasma membrane alterations-blebbing, blunting, microvilli distortion, myelin figures, loosening of intercellular attachments Mitochondrial changes Dilation of endoplasmic reticulum Nuclear alterations Gross: organ pallor, turgor and increased weight

Morphology of irreversible cell injury (Necrosis): Light microscopy: Membrane rupture Dispersal of organelles Breakdown of lysosomes Nuclear changes- Karyolysis (DNA breakdown) Pyknosis (nuclear shrinkage) Karyorrhexis (nuclear fragmentation) Gross tissue changes: coagulative (denaturation), liquifactive (enzymatic digestion), caseous and fat necrosis.

Mechanisms (Pathogenesis) of cell injury Depends on: 1. Type, duration & severity of stress 2. Type, status & adaptability of target cell 3. Underlying intracellular phenomena-reversal mechanisms 4. Morphologic consequences

Pathogenesis (continued) For some injurious agents the biochemical platforms of attack is well defined, viz: Glycolysis Citric acid cycle and Oxidative phosphorylation in mitochondrial inner membranes.

Common biochemical pathways of cell injury: ATP depletion-ATP is produced by Oxidative phosphorylation and Glycolysis Oxygen & oxygen-derived free radicals (reactive oxygen species) Loss of calcium homeostasis (intracellular calcium accumulation) defects in selective membrane permiability-xteristic of all forms of cell injury.

Responses to cell injury Lysosomal catabolism-residual bodies, lipofuscin pigment granules, Induction (hypertrophy of smooth endoplasmic reticulum) Mitochondrial alterations-number, size, shape e.g. in cell hypertrophy and atrophy.

IRREVERSIBLE CELL INJURY This results in cell death and there are two types: Necrosis Infarction Apoptosis

IRREVERSIBLE CELL INJURY Types of necrosis Liquifactive Coagulative Caseous Traumatic fat necrosis, etc.

Patterns of Necrosis In Tissues or Organs As a result of cell death the tissues or organs display certain macroscopic changes: Coagulative necrosis: the outline of the dead cells are maintained and the tissue is somewhat firm. Example: myocardial infarction  Liquifactive necrosis: the dead cells undergo disintegration and affected tissue is liquified. Example: cerebral infarction.

Patterns of Necrosis In Tissues or Organs Caseous necrosis: a form of coagulative necrosis (cheese-like). Example: tuberculosis lesions. Fat necrosis: enzymatic digestion of fat. Example: necrosis of fat by pancreatic enzymes. Gangrenous necrosis: Necrosis (secondary to ischemia) usually with superimposed infection. Example: necrosis of distal limbs, usually foot and toes in diabetes.