Page 46 - Textbook of Pathology, 6th Edition

30 mitochondria fails first. This is followed by switch to of lysosomal enzymes into the cytoplasm. These biochemical
anaerobic glycolytic pathway for the requirement of energy changes have effects on the ultrastructural components of
(i.e. ATP). This results in rapid depletion of glycogen and the cell (Fig. 3.7):
accumulation of lactic acid lowering the intracellular pH. 1. Calcium influx: Mitochondrial damage. As a result of
Early fall in intracellular pH (i.e. intracellular lactic acidosis) continued hypoxia, a large cytosolic influx of calcium ions
results in clumping of nuclear chromatin. occurs, especially after reperfusion of irreversibly injured cell.
3. Damage to plasma membrane pumps: Hydropic Excess intracellular calcium collects in the mitochondria
swelling and other membrane changes. Lack of ATP disabling its function. Morphologically, mitochondrial
interferes in generation of phospholipids from the cellular changes are vacuoles in the mitochondria and deposits of
SECTION I
fatty acids which are required for continuous repair of amorphous calcium salts in the mitochondrial matrix.
membranes. This results in damage to membrane pumps 2. Activated phospholipases: Membrane damage. Damage
operating for regulation of sodium and calcium as under: to membrane function in general, and plasma membrane in
i) Failure of sodium-potassium pump. Normally, the energy particular, is the most important event in irreversible cell
+
+
(ATP)-dependent sodium pump (Na -K ATPase) operating injury in ischaemia. As a result of sustained ischaemia, there
at the plasma membrane allows active transport of sodium is increased cytosolic influx of calcium in the cell. Increased
out of the cell and diffusion of potassium into the cell. calcium activates endogenous phospholipases. These in turn
Lowered ATP in the cell and consequent increased ATPase degrade membrane phospholipids progressively which are
activity interfere with this membrane-regulated process. This the main constituent of the lipid bilayer membrane. Besides,
results in intracellular accumulation of sodium and diffusion there is also decreased replacement-synthesis of membrane
of potassium out of cell. The accumulation of sodium in the phospholipids due to reduced ATP. Other lytic enzyme
cell leads to increase in intracellular water to maintain iso- which is activated is ATPase which causes further depletion
osmotic conditions (i.e. hydropic swelling occurs, discussed of ATP.
later in the chapter). 3. Intracellular proteases: Cytoskeletal damage. The
normal cytoskeleton of the cell (microfilaments, microtubules
ii) Failure of calcium pump. Membrane damage causes and intermediate filaments) which anchors the cell
disturbance in the calcium ion exchange across the cell membrane is damaged due to degradation by activated
membrane. Excess of calcium moves into the cell (i.e. calcium intracellular proteases or by physical effect of cell swelling
influx), particularly in the mitochondria, causing its swelling
and deposition of phospholipid-rich amorphous densities. producing irreversible cell membrane injury.
Ultrastructural evidence of reversible cell membrane 4. Activated endonucleases: Nuclear damage. The
General Pathology and Basic Techniques
damage is seen in the form of loss of microvilli, nucleoproteins are damaged by the activated lysosomal
intramembranous particles and focal projections of the enzymes such as proteases and endonucleases. Irreversible
cytoplasm (blebs). Myelin figures may be seen lying in the damage to the nucleus can be in three forms:
cytoplasm or present outside the cell, these are derived from i) Pyknosis: Condensation and clumping of nucleus which
membranes (plasma or organellar) enclosing water and becomes dark basophilic.
dissociated lipoproteins between the lamellae of injured ii) Karyorrhexis: Nuclear fragmentation in to small bits
membranes. dispersed in the cytoplasm.
4. Reduced protein synthesis: Dispersed ribosomes. As a iii) Karyolysis: Dissolution of the nucleus.
result of continued hypoxia, membranes of endoplasmic 5. Lysosomal hydrolytic enzymes: Lysosomal damage, cell
reticulum and Golgi apparatus swell up. Ribosomes are death and phagocytosis. The lysosomal membranes are
detached from granular endoplasmic reticulum and damaged and result in escape of lysosomal hydrolytic
polysomes are degraded to monosomes, thus dispersing enzymes. These enzymes are activated due to lack of oxygen
ribosomes in the cytoplasm and inactivating their function. in the cell and acidic pH. These hydrolytic enzymes include:
Similar reduced protein synthesis occurs in Golgi apparatus. hydrolase, RNAase, DNAase, protease, glycosidase, phos-
Up to this point, withdrawal of acute stress that resulted phatase, lipase, amylase, cathepsin etc) which on activation
in reversible cell injury can restore the cell to normal state. bring about enzymatic digestion of cellular components and
hence cell death. The dead cell is eventually replaced by
IRREVERSIBLE CELL INJURY. Persistence of ischaemia or masses of phospholipids called myelin figures which are either
hypoxia results in irreversible damage to the structure and phagocytosed by macrophages or there may be formation of
function of the cell (cell death). The stage at which this point calcium soaps.
of no return or irreversibility is reached from reversible cell Liberated enzymes just mentioned leak across the
injury is unclear but the sequence of events is a continuation abnormally permeable cell membrane into the serum, the
of reversibly injured cell. Two essential phenomena always estimation of which may be used as clinical parameters of
distinguish irreversible from reversible cell injury (Fig. 3.6): cell death. For example, in myocardial infarction, estimation
Inability of the cell to reverse mitochondrial dysfunction of elevated serum glutamic oxaloacetic transaminase (SGOT),
on reperfusion or reoxygenation. lactic dehydrogenase (LDH), isoenzyme of creatine kinase
Disturbance in cell membrane function in general, and in (CK-MB), and more recently cardiac troponins (cTn) are
plasma membrane in particular. useful guides for death of heart muscle. Some of the common
In addition, there is further reduction in ATP, continued enzyme markers of cell death in different forms of cell death
depletion of proteins, reduced intracellular pH, and leakage are given in Table 3.1.