Cell Pathology

Chapter 1 Cell Pathology



Ivan Damjanov, MD, PhD



CELL INJURY



1 Define cell injury


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.



2 What is the difference between reversible and irreversible cell injury?


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.



3 What could cause cell injury?


The causes of cell injury are classified as exogenous or endogenous. In principle, cell injury can occur due to the following factors:


image Excessive or overly prolonged normal stimuli

image Action of toxins and other adverse influences that could inhibit the vital cell functions (e.g., oxidative phosphorylation or protein synthesis)

image Deficiency of oxygen and/or essential nutrients and metabolites


Key Points: Cell Injury



1. Cell injury can be reversible or irreversible.

2. Hypoxia is the most important cause of cell injury.

3. Irreversible cell injury can be recognized by changes in the appearance of the nucleus and rupture of the cell membrane.


4 Name some exogenous causes of cell injury


Exogenous causes include physical, chemical, and biological factors, such as heat and cold, toxins and drugs, and viruses and bacteria.



5 Name some endogenous causes of cell injury


Endogenous causes include genetic defects, metabolites, hormones, cytokines, and other “bioactive” substances.



6 What is hypoxia?


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.



7 What could cause hypoxia or anoxia?


Hypoxia and anoxia can result from the following:


image Inadequate supply of oxygen (e.g., low concentration of oxygen in air at high altitude)

image Obstruction of airways (e.g., strangulation and drowning)

image Inadequate oxygenation of blood in the lungs (e.g., lung diseases)

image Inadequate oxygen transport in blood (e.g., anemia)

image Inadequate perfusion of blood in the tissues (ischemia resulting from heart failure)

image Inhibition of cellular respiration—that is, blocked utilization of oxygen (e.g., cyanide poisoning of respiratory enzymes)


8 How does hypoxia cause cell injury?


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.



9 How does ATP deficiency cause cell swelling?


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.



10 Where does water accumulate during hydropic change?


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).


image

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.)



11 What is the role of calcium in acute cell injury?


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:


image Lytic ATPase: Degrades ATP and further reduces the energy stores.

image Phospholipases: These enzymes remove phospholipids from the plasma or mitochondrial membranes, further impairing their function.

image Proteases: These enzymes degrade cell membrane or cytoskeletal proteins.

image Endonucleases: These enzymes act on the RNA and DNA.

All of these changes are initially reversible, but if prolonged or intensified they may lead to irreversible cell injury (Fig. 1-2).


image

Figure 1-2 Sources and consequences of increased cytosolic calcium in cell injury. ATP, adenosine triphosphate.


(From Kumar V, Cotran RS, Robbins SL: Robbins and Cotran Pathologic Basis of Disease, 7th ed. Philadelphia, Saunders, 2005, p. 8.)



12 How does the cell compensate for the loss of aerobic respiration?


Breakdown of ATP is accompanied by an increase in adenosine monophosphate (AMP), which activates enzymes involved in anaerobic glycolysis. This leads to depletion of glycogen stored in the cytoplasm.



13 Is the cytoplasm of injured cells acidic or alkaline?


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.



14 How does the reversible cell injury become irreversible?


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.



15 What are the signs of irreversible cell injury?


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.



16 Which mitochondrial changes are irreversible?


Swelling of mitochondria represents a reversible change. Irreversible changes include the following:


image Rupture of double membrane

image Fragmentation

image Myelin figures (concentric curling up of damaged membranes)

image Calcification

Damaged mitochondria are taken up into autophagosomes and digested (Fig. 1-3).


image

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.)



17 What are myelin figures?


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.



18 Which nuclear changes are signs of cell death?


Dead cells show typical nuclear changes (Fig. 1-4):


image Pyknosis: This term is derived from the Greek word pyknos meaning “dense,” and it denotes condensation of chromatin.

image Karyolysis: This change results from the lysis of chromatin due to the action of endonucleases.

image Karyorrhexis: This term is derived from the Greek word rhexis meaning “tearing apart” and denotes fragmentation of nuclear material. Colloquially, it is described as formation of “nuclear dust.”

image

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.)



19 What are the clinical signs of irreversible cell injury?


Irreversible cell injury results in a loss of cell functions. For example:


image Myocardial cell injury: loss of heart contraction

image Motor neuron: muscle paralysis
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Jul 23, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Cell Pathology

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