Lecture #2: Mechanism of Cell Damage

A cell is the basic structural, functional, and biological unit of all known living organisms. A cell is the smallest unit of life that can replicate independently, and cells are often called the “building blocks of life.” When a cell is exposed to an injurious agent, the possible results are:

a.       The cell may adapt to the situation or

b.      The cell may acquire a reversible injury

c.       The cell may obtain an irreversible injury and may die. The cell may die via one of two ways: either by necrosis or by apoptosis.

Types of cellular adaptation

 

A.     Hypertrophy

 

Hypertrophy is increase in the size of cells. Increase workload leads to increased protein synthesis and increased size and number of intracellular organelles which, in turn, leads to increased cell size. The increased cell size leads to increased size of the organ.

Example: cardiomegaly

 

B.     Hyperplasia

 

Hyperplasia is an increase in the number of cells. It can lead to an increase in size of the organ. It is usually caused by hormonal stimulation. It can be physiological as in enlargement of the breast during pregnancy or it can be pathological as in endometrial hyperplasia.

 

C.      Atrophy

 

Atrophy is a decrease in the size of the cell. This can lead to decreased size of the organ. The atrophic cell shows autophagic vacuoles which contain cellular debris from degraded organelles.

 

Atrophy can be caused by: (1) Disuse (2) Undernutrition (3) Decreased endocrine stimulation (4) Denervation (5) Old age

 

D.     Metaplasia

 

Metaplasia is the reversible replacement of one differentiated cell type with another mature differentiated cell type. The change from one type of cell to another may generally be a part of normal maturation process or caused by some sort of abnormal stimulus.

In simplistic terms, it is as if the original cells are not robust enough to withstand the new environment and so they change into another type more suited to the new environment. If the stimulus that caused metaplasia is removed or ceases, tissues return to their normal pattern of differentiation.

 

Types of Cell Damage

 

A.     Fatty Change

 

Cell has been damaged and is unable to adequately metabolize fat. Small vacuoles of fat accumulate and become dispersed within cytoplasm. Mild fatty change may have no effect on cell function; however more severe fatty change can impair cellular function. In the liver, the enlargement of hepatocytes due to fatty change may compress adjacent bile canaliculi leading to cholestasis. Depending on the cause and severity of the lipid accumulation, fatty change is generally reversible.

       

B.     Cellular Swelling

Cellular swelling may occur due to cellular hypoxia, which damages the sodium–potassium membrane pump; it is reversible when the cause is eliminated. Cellular swelling is the first manifestation of almost all forms of injury to cells. When it affects many cells in an organ, it causes some pallor, increased turgor, and increase in weight of the organ. On microscopic examination, small clear vacuoles may be seen within the cytoplasm; these represent distended and pinched – off segments of the endoplasmic reticulum. This pattern of non – lethal injury is sometimes called hydropic change or vacuolar degeneration. The ultrastructural changes of reversible cell injury include: (1) Blebbing (2) Blunting (3) Distortion of microvilli (4) Loosening of intercellular attachments (5) Mitochondrial changes (6) Dilatation of the endoplasmic reticulum.

C.      Necrosis

Necrosis is characterized by cytoplasmic swelling, irreversible damage to the plasma membrane and organelle breakdown leading to cell death. Necrosis does not occur in dead organisms. In dead organisms, autolysis and heterolysis take place.

Stages of Cellular Necrosis:

a.       Pyknosis – is the irreversible condensation of chromatin in the nucleus of a cell undergoing necrosis or apoptosis.

b.      Karyorrhexis – is the destructive fragmentation of the nucleus of a dying cell.

c.       Karyolysis – is the complete dissolution of the chromatin of a dying cell due to the enzymatic degradation by endonucleases.

Types of Necrosis:

a.       Coagulative Necrosis – is a result of sudden interruption of blood supply to an organ especially to the heart causing ischemia or infarction. It can also be induced by high local temperature such as the effect of high intensity focused ultrasound as applied to cancerous cells.

b.      Liquefactive Necrosis – is a result of a transformation of the tissue into a liquid viscous mass. Often it is associated with focal bacterial or fungal infections. In liquefactive necrosis, the affected cell is completely digested by hydrolytic enzymes, resulting in a soft, circumscribed lesion consisting of pus and the fluid remains of necrotic tissue. Dead leukocytes will remain as creamy yellow pus. After the removal of cell debris by white blood cells, a fluid filled pace is left. It is generally associated with abscess formation and is commonly found in the central nervous system.  

c.       Fat Necrosis – the enzyme lipase releases fatty acids from triglycerides. The fatty acids then complex with calcium to form soaps. These soaps appear as white chalky deposits. It is usually associated with trauma of the pancreas or acute pancreatitis. It can also occur in the breast, the salivary glands and neonates after a traumatic delivery.

d.      Caseous Necrosis – is a form of cell death in which the tissue maintains a cheese–like appearance. The dead tissue appears as a soft and white proteinaceous dead cell mass. Frequently, it is encountered in the foci of tuberculosis infection. It can also be caused by syphilis and certain fungi.

e.       Gangrenous Necrosis – is a type of necrosis caused by a critically insufficient blood supply. This potentially life–threatening condition may occur after an injury or infection, or in people suffering from any chronic health problem affecting blood circulation. The primary cause of gangrene is reduced blood supply to the affected tissues, which results in cell death. Diabetes and long–term smoking increase the risk of suffering from gangrene.

(1)  Dry Gangrene is a form of coagulative necrosis that develops in ischemic tissue, where the blood supply is inadequate to keep tissue viable.

(2)  Wet Gangrene is characterized by thriving bacteria and has a poor prognosis (compared to dry gangrene) due to sepsis resulting from the free communication between infected fluid and circulatory fluid. In Wet Gangrene, the tissue is infected by saprogenic microorganisms (Clostridium perfringens and Bacillus fusiformis) which cause tissue to swell and emit a fetid smell. The affected part is saturated with stagnant blood, which promotes the rapid growth of bacteria. The toxic products formed by bacteria are absorbed, causing systemic manifestation of sepsis and finally death. The affected part is edematous, soft, putrid, rotten and dark.

(3)  Gas Gangrene is a bacterial infection that produces gas within tissues. It is mostly caused by alpha toxin producing Clostridium perfringens. Infection spreads rapidly as the gases produced by bacteria expand and infiltrate healthy tissue in the vicinity. Because of its ability to quickly spread to surrounding tissues, gas gangrene should be treated as a medical emergency. Gas gangrene can cause necrosis, gas production and sepsis. Progression to toxemia and shock is often very rapid.

(4)  Necrotizing Fascitis is an infection of the deeper layer of skin and subcutaneous tissues caused by organisms that normally reside on the individual’s skin. They destroy the tissue that makes up the skin and muscle by releasing toxins (virulence factor) which include streptococcal pyogenic exotoxins.

D.     Apoptosis

Apoptosis is a process of programmed cell death that occurs in multicellular organisms. Apoptosis usually occurs as a physiologic process for removal of cells during embryogenesis, menstruation, etc.

Excessive apoptosis causes atrophy, whereas an insufficient amount results in uncontrolled cell proliferation, such as cancer. Some factors like Fas receptors and caspases promote apoptosis while some members of the Bcl–2 family of proteins inhibit apoptosis.

Pathologic Calcification

Calcification of soft tissue (arteries, cartilage, heart valves, etc.) can be caused by Vitamin K2 deficiency or by poor calcium absorption due to high Calcium / Vitamin D ratio. This can occur with or without a mineral imbalance.

Intake of excessive Vitamin D can cause Vitamin D poisoning and excessive intake of Calcium from the intestine, when accompanied by a deficiency of Vitamin K (perhaps induced by an anticoagulant) can result in calcification of arteries and other soft tissue. Such metastatic soft tissue calcification is mainly in tissues containing “calcium catchers” such as elastic fibres or sour mucopolysaccharides. These tissues especially include the lungs (pumice lung) and the aorta.

A.      Dystropic Calcification is caused by abnormalities or degeneration of tissues resulting in mineral deposition, though blood levels of calcium remain normal. These differences in pathology also mean that metastatic calcification is often found in many tissues throughout a person or animal, whereas dystrophic calcification is localized.  

B.      Metastatic Calcification is deposition of calcium salts in otherwise normal tissue, because of elevated serum levels of calcium, which can occur because of deranged metabolism as well as increased absorption or decreased excretion of calcium and related minerals, as seen in hyperthyroidism.