Module 2

Question 1

Name the 7 causes or agents of cell injury - provide examples.

Answer 1

1) Physical Agents
- Ex. Trauma, radiation, temperature extremes, change in pressure, etc.

2) Chemical Agents
- Air pollutants, CO, pesticides, poisons, toxins, drugs, etc.

3) Biological Agents
- Micro-organisms - viruses, bacteria; biological toxins

4) Nutritional or Metabolic Alterations
- Nutrient deficiencies ischemia, hypoxia)

5) Immune Reactions
- Allergens, autoimmune diseases

6) Genetic Defects
- Sickle cell disease, Down Syndrome

7) Cellular Aging
- Loss of intrinsic repair mechanisms, repeated healing and repair following external injuries

Question 2

How do cells survive?

Answer 2

By reacting and adapting to changing internal and external environments.

Question 3

How is cell injury recognized?

Answer 3

When the environmental changes exceed the capacity of the cell to maintain homeostasis.

Question 4

What type of response can stress or a damaging stimulus result for a cell?

Answer 4

A mild, completely reversible response to a long-term adaptive change in cell growth to a irreversible damage and cell death

Question 5

What is the point of no return?

Answer 5

When reversible injury becomes irreversible

Question 6

In terms of injury, what does the cells response depend on?

Answer 6

• Severity of stimulus
• Time frame (acute/chronic)
• Individual cell type & its characteristics

Question 7

What 4 parts of a cell are vulnerable to injury?

Answer 7

1) Cell membranes - critical for ionic and osmotic homeostasis
2) Mitochondria - generation of energy via ATP
3) Protein synthesis
4) Cellular DNA

Question 8

Define atrophy.
- Give an example.

What plays a key role?

Is it physical or pathological?

Answer 8

Atrophy: Reduced demand leads to atrophy of organs (if you don’t use it you lose it) - it is defined by a decrease in mass due to shrinkage in cell size
- Ex. Ischemia: Diminished blood supply allows for a new steady state where a smaller cell is able to survive

Degradation of cellular proteins - two systems:

• Lysosomes - Digestive enzymes that degrade molecules outside (endocytosis) or inside (autophagy)
• Ubiquitin-Proteasome - Cytosolic and nuclear proteins are targeted for degradation by conjugation to a 76-amino acid protein and degraded within a larger proteolytic complex

It can be both:

• Physiological - Occurs in normal aging (i.e. shrinkage and loss of brain cells)
• Pathological - Disuse atrophy of skeletal muscle in immobilized limbs or denervation atrophy following loss of nerve input to a muscle

Question 9

What is hypertrophy? Is it physiological or pathological?

Give an example.

Answer 9

It is an increase in the size of existing cells due to the increase in synthesis of cellular protein and structural components/organelles responsible for producing them.
- It can be both in response to increasing functional demand or specific hormonal stimulation

Ex. Hypertrophy of skeletal muscles is a physiological response to weight training

Ex. Pathological response include hypertrophy of cardiac muscle fibers occurs in response to increased workload as a result of systematic hypertension.

Question 10

What is hyperplasia?

Give an example.

Answer 10

An increase in the number of cells caused by cell division.

Ex. Hyperplasia can occur when a portion of tissue is removed

Ex. Excessive stimulation of normal uterus by estrogen may result in endometrial hyperplasia.

Question 11

Can hypertrophy and hyperplasia occur together?

Answer 11

Yes

Ex. Hyperplasia and hypertrophy of the uterine smooth muscle occurs in pregnancy in response to estrogen

Question 12

What is metaplasia?
Provide an example.

What happens if the stimulus is removed?

Answer 12

If the long-term environment becomes unsuitable for certain types of cells, they may change into a different ell type

Ex. Bronchi of a smoker change from ciliated to squamous cells.

If the stimulus is removed, the tissue reverts to the resting state.

Question 13

Name and explain a few intracellular accumulations

Answer 13

1) Lipofuscin: Stores the products of turnover as endogenous pigments such as, degraded phospholipids as the golden brown granules of the “Wear and Tear” pigment which increases with age particularly in the brain, heart, and lungs
2) Melanin: An insoluble brown-black pigment, found in the skin and in certain brain cells

3) Hemosiderin: Iron rich brown pigment derived form the breakdown of RBC
- Hemosidirosis: Excess iron storage in the skin, pancreas, heart, kidneys, and endocrine glands can damage vital organs

Question 14

What to many inherited disorders of metabolism result in?

Answer 14

Abnormal accumulation of metabolites in cells

Question 15

What is the most common exogenous pigment?

Answer 15

Carbon which is inhaled and deposited in the tracheobronchial lymph nodes and lung tissue

Question 16

What is fatty change (steatosis)?

Answer 16

It is linked to the intracellular accumulation of triglycerides either because of an increased delivery of fat to the cell (i.e. starvation or diabetes), an impairment of the fat metabolism (i.e. liver cells in alcoholism), or decreased synthesis of apolipoproteins for transport out of the cell (i.e. protein malnutrition)

• Small vacuoles of fat appear throughout the cytoplasm or may coalesce to form one large vacuole that displaces the nucleus.
• The liver, where most fats are stored and metabolized, is particularly susceptible to fatty change, but it may also occur in heart, kidney, skeletal muscle and other organs as a result of toxin exposure (e.g. alcohol, carbon tetrachloride), protein malnutrition or starvation, diabetes, obesity and anoxia.

Question 17

What is the most common cause of fatty change in the liver? Is it reversible?

Answer 17

Alcohol abuse

- Yes, if the stimulus is removed

Question 18

What is reversible cell injury?

Answer 18

Mild forms of injury where the functional and morphological changes are reversible if the stimulus is removed - the injury has not progressed to severe membrane of nuclear damage.

Question 19

What is irreversible cell injury?

Answer 19

With continuing damage, cell injury becomes irreversible which differ in their morphology, mechanisms, and cause.

Question 20

What are the characteristics of reversible cell injury?

Answer 20

Cellular/Hydropic Swelling

• increase in cell volume (i.e. large, pale and vacuolated cytoplasm and a normally located nucleus)
• results from impairment of the process that controls ion concentrations
• NA-K pump may be impaired, leading to an increase in Na in the cells, leading to an increase of water in the cell to maintain isosmotic conditions and the cell swells
• mitochondria may swell as well

Question 21

What are the characteristics of irreversible cell injury?

Answer 21

Necrosis: Cell death

• Intense eosinophilia (pinkness)
• Pyknosis: Cell shrinkage
• Karyorrhexsis: pyknotic nucleus fragments)
• Karyolysis: Dissolution of the nucleus

Question 22

What are two types of cell death?

Answer 22

Necrosis and apoptosis

Question 23

Name the 4 types of necrosis:

Answer 23

1) Coagulative: Eosinophilia, pyknosis, karyorrhexis, karyolysis
- Cells appear like ghosts of themselves
- Ex. Ischemia

2) Liquefactive: Rapid loss of tissue architecture digestion of the dead cells
- Most often seen in CNS
- Typical of bacterial damage.

3) Fat: Specific to fat (adipose) tissue
- Released enzymes digest fat that complexes with calcium to form chalky-white deposits
- E.g. pancreatitis; damage to breast tissue.

4) Caseous: soft, friable, ‘cheesy’ material
- Ex. Characteristic of tuberculosis.

Question 24

What does the term gangrenous necrosis refer to?

Answer 24

It is used to refer to coagulative necrosis (most frequently of a limb) when there is superimposed infection with a liquefactive component
- If the necrotic tissue dries out (with no infectious component) it becomes dark black and mummified and is called “dry gangrene”

Question 25

What is apoptosis? How does it differ from necrosis?

Answer 25

It is a morphologic manifestation of programmed cell death and is distinct from necrosis - Apoptosis is an energy-dependent process specifically designed to switch off unneeded or damaged cells and eliminate them - Therefore, apoptosis can occur under either physiologic (e.g. during embryogenesis in shaping of fingers and toes; the physiological involution of thymus during development or endometrium during the menstrual cycle; removal of an infected or damaged cell) or pathologic (e.g. following radiation injury, in some cancers) conditions.

Question 26

How do apoptotic cells initiate their own death? What occurs?

Answer 26

By the activation of proteases (capases and endogenous endonucleases that break down the cell nucleus and cytoskeleton - The cell nucleus collapses, the cell shrinks and is cleaved into membrane-bound clumps enclosing organelles (apoptotic bodies) - The membrane bound material is recognized and quickly engulfed by phagocytic cells.

Question 27

What determines if a cell undergoes apoptosis or necrosis?

Answer 27

The magnitude and type of injurious stimulus can determine whether a cell undergoes apoptosis or necrosis - Severe damaging stimuli tend to result in necrosis and lower-grade stimuli and immune-mediated damage tend to cause apoptosis - A critical factor seems to be how much cellular ATP is available after cell damage (remember apoptosis is an energy-dependent process!) - Where there is severe depletion of ATP the necrotic pathway is followed.

Question 28

What do reactive oxygen species do? How are they formed? What do these molecules possess? What can they initiate?

Answer 28

They are identified as a likely cause of cell injury These highly reactive species can be formed via the action of ionizing radiation (hydrolysis of water produces hydroxyl radicals resulting in DNA damage and apoptosis in rapidly dividing cells); during reperfusion of tissues following a period of ischemia; in the presence of excess oxygen; and normally in inflammatory cells. All of these molecules possess a free electron that makes them highly reactive with a number of key cellular elements. - They can initiate lipid peroxidation leading to a loss of membrane integrity, cross-link essential proteins, damage DNA or form secondary damaging ROS (e.g. lipid peroxide radicals, peroxynitrite).

Question 29

How does the body detoxify from reactive oxygen species?

Answer 29

Because these molecules are also formed during normal metabolism and oxygen respiration, the body has several mechanisms to detoxify these potentially damaging substances including: - spontaneous decay (e.g., superoxide breaks down in the presence of water into oxygen and hydrogen peroxide) - superoxide dismutase (converts superoxide to hydrogen peroxide and oxygen) - catalase (converts hydrogen peroxide to water and oxygen) or glutathione peroxidase (reduction of hydrogen peroxide to water). - Endogenous or exogenous (ingested) antioxidants such as vitamins A, C and E can also offer some protection against these free radical species. When these endogenous systems become overwhelmed damage can occur.

Question 30

How do chemicals cause cell injury? Provide an example.

Answer 30

1) Directly (e.g. heavy metals; chemotherapeutic agents) 2) Indirectly following metabolism to active metabolites. Ex. Carbon tetrachloride (CCl4) is metabolized by the liver cytochrome P450 enzyme complex to a highly reactive trichloromethyl free radical intermediate that begins a cascade of lipid peroxidation and cell membrane damage - This same P450 mixed function oxidase system is responsible for the metabolism of a variety of drugs and chemicals others of which also form active, injurious metabolites.

Question 31

What is the most common type of cell injury? What is it an important cause of?

Answer 31

Ischemia (i.e. reduction or interruption of blood flow) | - An important cause of coagulative necrosis

Question 32

Can schema injure tissue faster than reduced levels of oxygen (hypoxia)? If so, how?

Answer 32

Yes - Since both oxygen and substrates for glycolysis and continued ATP generation disappear - Decreased oxygen compromises respiration in mitochondria damaging the ability to produce ATP - Decreased ATP impairs the ability of the cells to pump ions and water (via Na-K ATPase) with the subsequent accumulation of intracellular sodium and the diffusion of potassium out of the cell. 8 - The net gain of sodium is accompanied by an iso-osmotic gain of water resulting in acute cellular swelling and in the swelling of cellular components with damage and rupture to the cell plasma membranes.  Decreased ATP also results in increased anaerobic glycolysis and the depletion of glycogen stores with a build-up of lactic acid in the cell (and hence a decrease in intracellular pH or a more acidic environment). - Decreased ATP and pH levels cause ribosomes to detach from rough endoplasmic reticulum (RER) with a reduction in protein synthesis.

Question 33

What happens if schema or hypoxia persist too long?

Answer 33

IF ischemia or hypoxia is not relieved, worsening mitochondrial function and increasing membrane permeability cause further deterioration with irreversible cell injury and: - The release of proteolytic enzymes from their normal compartments in the cell which induces widespread damage. - In addition, calcium increases in cells due to pump failure (Ca-ATPase). Increase in intracellular calcium activates many enzyme systems inappropriately leading to further cell damage - Some of the enzyme systems attack cellular skeletal proteins which cause cells to become abnormally fragile; membrane damage is critical to the development of lethal cell injury.