Irreversible cell injury – B. Pharma 2nd Semester Pathophysiology notes pdf

Irreversible cell injury

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

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

Necrosis

Apoptosis

Evoked by non-physiological disturbances (immune reaction, microbes,
hypoxia, ischemia & other poisons)

Non physiological process

Induced by stimuli like lack of growth factor, change in hormonal
environment

Significant inflammatory response

No inflammatory response

Affects group of cells

Affects individual cells

Loss of membrane integrity

Membrane blebbing, no loss of integrity

Begins with swelling of cytoplasm & mitochondria

Begins with shrinking of cytoplasm & condensation of nucleus

Ends with total cell lysis

Ends with fragmentation of cells in to smaller bodies

No vesicle formation, complete lysis

Formation of membrane bound vesicles, apoptotic body

Disintegration

Mitochondria becomes leaky due to pore formation

Passive process, no requirement of ATP

Energy dependent active process

Post lytic DNA process

Prelytic DNA fragmentation

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

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