Chapter 1 Cell Pathology
Normal cells are in a state of homeostasis (i.e., an equilibrium with their environment). Injury is defined as a set of biochemical and/or morphologic changes that occur when the state of homeostasis is perturbed by adverse influences. Cell injury may be reversible or irreversible.
The differences are mostly quantitative. Reversible injury is usually mild, and, following the removal of the adverse influences, the cell reverts to its normal steady state. If the cell cannot recover, the injury is considered to be irreversible.
Hypoxia is a relative deficiency of oxygen recognizable as a disproportion between the need for oxygen and its availability. It may result from a reduced supply or increased demand that cannot be satisfied. Complete block in the oxygen supply is called anoxia.
Oxygen is essential for aerobic respiration. Hypoxia prevents normal oxidative phosphorylation, thus reducing the capacity of mitochondria to generate adenosine triphosphate (ATP). Without ATP, the cell cannot maintain its vital functions. Hypoxic cells swell. This change is called hydropic or vacuolar change and is typically reversible.
The cell volume depends on the proper functioning of the plasma membrane, which remains semipermeable only if properly energized with ATP. ATP provides fuel for the Na/K ATPase, which acts as a pump, keeping the high concentration of sodium in the intercellular fluid and the high concentration of potassium inside the cell. If this ATPase malfunctions because of an energy deficiency, an uncontrolled influx of sodium and water from the extracellular space occurs. A consequent net increase of the total fluid content in the cytoplasm results in cell swelling. The intracellular concentration of potassium declines because potassium leaks out of the cell.
Water accumulates in the hyaloplasm but also in the invaginations of the plasma membrane (hypoxic vacuoles), mitochondria, and the cisterns of rough endoplasmic reticulum (RER), causing their malfunction. Swollen mitochondria produce less energy, and the detachment of ribosomes from membranes of dilated RER results in reduced protein synthesis (Fig. 1-1).
Figure 1-1 Hydropic change. Vacuoles containing water form from the invaginations of the surface plasma membrane (hypoxic vacuoles [HV]). Water also accumulates in the cisterns of the rough endoplasmic reticulum (RER), which become dilatated, and mitochondria (M), which become swollen.
(From Damjanov I: Pathology Secrets, 2nd ed. Philadelphia, Mosby, 2005, p. 11.)
Cell injury is accompanied by an increased concentration of free calcium ions in the hyaloplasm (cytosol). These calcium ions are derived from the extracellular fluid, from the mitochondrial compartment, and from the cisterns of RER. Ionized calcium amplifies the adverse effects of hypoxia by activating several enzymes:
Cell injury is accompanied by the lowering of intracellular pH from the normal neutral to the acidic range. For example, the inhibition of oxidative phosphorylation promotes anaerobic glycolysis, which is accompanied by accumulation of lactic acid in the cytoplasm. Phosphates released from phospholipids and ATP contribute further to the acidification of the cytoplasm. Acidic milieu inhibits the activity of most enzymes except those in the lysosomes, which function most efficiently in the acid pH. The release of acid hydrolases from the lysosomes may further contribute to cell injury.
The transition from reversible to irreversible cell injury is gradual and occurs when the adaptive mechanisms have been exhausted. A theoretical “point of no return” separating the reversible from irreversible injury cannot be precisely defined even under tightly controlled experimental conditions.
Initially, the differences between the reversible and irreversible cell injury are only quantitative. For example, the hypoxic vacuoles become more numerous and larger. The mitochondria are swollen, and many are even ruptured. However, many of these changes are still reversible, and it is only when the plasma membrane ruptures and the nuclear changes ensue that one can be certain that an injury is irreversible and the cell is dead.
Figure 1-3 Mitochondrial changes in cell injury. A, Normal mitochondrion has a double membrane and cristae. B, Swollen mitochondrion. The water accumulates in the internal space and between the inner and the outer mitochondrial membrane. C, Rupture of the mitochondrion. This may be associated with calcification of the remnant membranes. D, Myelin figure forms from whorls of mitochondrial membranes. E, Calcification of mitochondrial remnants.
(From Damjanov I: Pathology Secrets, 2nd ed. Philadelphia, Mosby, 2005, p. 12.)
Myelin figures are cytoplasmic bodies seen in damaged cells by electron microscopy. They are composed of concentric whorls of membranes derived from damaged cytoplasmic organelles, such as mitochondria, or RER. Myelin figures are prominent in neurons in Tay-Sachs disease and other inborn errors of metabolism damaging the cytoplasmic membranes. Like other remnants of damaged organelles, myelin figures are taken up into autophagosomes.
Figure 1-4 Irreversible cell injury involves nuclear changes and rupture of the plasma membrane. Nuclear changes include condensation of chromatin (pyknosis), lysis of chromatin (karyolysis), and fragmentation of the chromatin (karyorrhexis).
(From Damjanov I: Pathology Secrets, 2nd ed. Philadelphia, Mosby, 2005, p. 13.)