Irreversible cell injury

Objective

At the end of this PDF, student will be able to

•         Explain the sequence of changes occurring during irreversible cell injury

•         Explain the morphology of  irreversible cell injury

•         Describe the pathogenesis of irreversible cell injury due to hypoxia and ischemia

Irreversible cell injury

Pathogenesis of irreversible cell injury

•       Ischemia & hypoxia persists for long time, results in irreversible changes in structure & function of cell

Irreversible cell injury differs from reversible cell injury

•       Inability of cell to reverse the mitochondrial changes

•       Disturbance in cell membrane  structure & function

Sequence of events in irreversible cell injury

Mitochondrial dysfunction

•       Continued hypoxia

•       Large influx of Ca²⁺  –  taken up by mitochondria  – mitochondrial dysfunction

•          Formation of vacuole

•         Deposition  of amorphous Ca²⁺  in mitochondrial matrix  

Membrane damage

•       O₂ deprivation  –  Ca²⁺  from mitochndria & ER shifts to cytosole

•       ↑Ca²⁺ activates phospholipases & proteases

•       Phospholipases –  breakdown phospholipids in cell membrane

•       Accumulation of lipid break down product – Injury to cell

•       Leakage of proteins, co-enzymes, RNA and other vital cell constituents

•       Free radicals of O₂ –  superoxide, hydrogen peroxide & hydroxyl

•       Injury –  lipid peroxidation, DNA, RNA destruction

Liberation of hydrolytic enzymes

•       Damage to lysosomal membranes-  liberates hydrolytic

•       enzymes – digestion of cellular components

•       Nuclear changes – cell death

•       Cellular contents digested by lysosome hydrolases

•       Dead cells replaced by myelin figues (large phospholipid masses)

Serum estimation of liberated intracellular enzymes

•       Liberated enzymes leak across the abnormally permeable cell membrane in to serum

•       Estimation of these enzyme levels in serum  –  extent of cell death

E.g. In MI, serum estimation of SGOT, LDH, Creatinine kinase and cardiac troponins – guides for assessing extent of death of cardiac muscles

Morphology of irreversible cell injury

Cell death occurs as local or focal changes

•       Autolysis

•       Necrosis

•       Apoptosis and changes that follow like gangrene and pathological calcification

Autolysis

•       Self digestion

•       Disintegration of cell by its own hydrolytic enzyme

•       Rapid in tissues rich in hydrolytic enzymes  – pancreas, gastric mucosa

•       Intermediate in liver, kidney and heart

•       Slow in fibrous tissues

•       May or may not be associated with inflammation

Necrosis

•       Focal death of living tissue

•       Progressive degeneration by various enzymes

•       Often associated with inflammation

•       Result of 2 concurrent process

–      Cell digestion by lytic enzymes

–      Denaturation of proteins

Types of necrosis

•       Coagulative necrosis – Most commom, due to sudden cessation of blood supply

•       Liquefaction necrosis – follows ischemic injury, bacterial or fungal infection; Common in brain

•       Caseous necrosis  –  combination of coagulative & liquefaction necrosis ; in centre of tuberculous infection

•       Fat necrosis – focal area associated with fat destruction

•       Fibrinoid necrosis – appearance of fibrin like materials; in peptic ulcer & immunologic injury

Gangrene

•       Form of coagulative necrosis

•       Characterized by inflammation

•       Provoked by virulent bacteria resulting in massive tissue necrosis

3 types of gangrene

Ø  Wet gangrene

Ø  Dry gangrene

Ø  Gas gangrene

Dry gangrene

•        Usually occur in limbs

•        Originates from toe or fingers

•        Affected by improper blood supply due to ischemia

•         Microbial contamination follows

•        Spreads from origin upward until it reaches the point of blood supply

Wet gangrene

•         Occurs in moist tissues and organs as mouth, bowel, lungs, cervix, etc.,

•         Occur during vein blockage rather than arterial blockage

Gas gangrene

•       Special form of wet gangrene

•       Formed by gas forming clostridia  –     G +ve  bacteria

•       Gains entry into open wounds

•       Produces toxins that causes necrosis and edema

Pathological calcification

•       Deposition of calcium in tissues other than bone and enamel

      e.g. Kidney stones

Two types

• Dystrophic calcification- Deposition of calcium in dead and degenerated tissue
• Metastatic calcification – In normal living tissues with deranged calcium metabolism

Apoptosis

•       Co-ordinated, internally programmed cell death

•       Physiological process –  unwanted cells are eliminated

Changes occurring during apoptosis

–      Shrinkage of cells

–      Formation of membrane bound apoptotic body

–      Condensation of chromatin

–      Phagocytosis of apoptotic bodies by macrophages

–      Proteolysis of cytoskeleto proteins

Necrosis vs. Apoptosis

Summary

•       Hypoxia and ischemia causes cell injury

•       If hypoxia and ischemia persists for a long time, it results in irreversible cell injury

•       It is associated with mitochondrial dysfunction, membrane damage, liberation of hydrolytic enzymes

•       Irreversible cell injury brings about certain morphological changes like autolysis, gangrene, necrosis, apoptosis