Cellular Responses to Stress and Injury

Question 1

Define cellular adaptation.

What causes cells to adapt?

List the types of cellular adaptation.

Answer 1

• Cellular adaptations are reversible changes in the size, number, phenotype, metabolic activity or functions of cells.
• Cellular adaptation occurs in response to cellular stress, which may arise due to changes in the mechanical, chemical or hormonal environment.
• The types of adaptation are:

1 - Hyperplasia.

2 - Hypertrophy.

3 - Atrophy.

4 - Metaplasia.

Question 2

What is hyperplasia?

What stimulates hyperplasia?

Answer 2

• Hyperplasia is an increase in the number of cells.
• Hyperplasia occurs following either physiological or pathological stimuli that are usually hormonal or chemical in nature.

Question 3

Give one physiological and one pathological example of hyperplasia.

Answer 3

• A pathological example of hyperplasia is benign prostatic hyperplasia (BPH).
• BPH is predominantly stimulated by DHT, and involves hyperplasia of epithelial and stromal cells in the prostate. This produces nodules that compress the urethra, resulting in urinary obstruction.
• A physiological example of hyperplasia is endometrial growth in response to oestrogen secreted during the menstrual cycle.

Question 4

What is hypertrophy?

What stimulates hypertrophy?

Answer 4

• Hypertrophy is an increase in size of cells.

- Hypertrophy occurs following either physiological or pathological stimuli that are usually mechanical in nature.

Question 5

Give one physiological and one pathological example of hypertrophy.

Answer 5

• A pathological example of hypertrophy is left ventricular hypertrophy. This occurs in response to hypertension, which produces mechanical pressure against the ventricular wall. Whilst initially beneficial, excessive wall thickening eventually causes the heart to stiffen, resulting in impaired diastolic filling.
• A physiological example of hypertrophy is the increase in size of myocytes during weight lifting. This occurs due to increased production of contractile proteins in the cells in response to mechanical stimulation.

Question 6

What is atrophy?

What stimulates atrophy?

Answer 6

• Atrophy is a decrease in size and / or number of cells.

- Atrophy occurs following a range of either physiological or pathological stimuli.

Question 7

Give one physiological and one pathological example of atrophy.

Answer 7

• A pathological example of atrophy is atrophy of musculature in Duchenne’s musculature dystrophy.
• A physiological example of atrophy is the post-pubertal atrophy of the thymus gland.

Question 8

What is hypoplasia?

Answer 8

Hypoplasia is the failure of a tissue or organ to reach normal size during development (e.g. hypoplastic limbs related to thalidomide).

*Not the opposite of hyperplasia!

Question 9

What is metaplasia?

What stimulates metaplasia?

Answer 9

• Metaplasia is (potentially reversible) replacement of one differentiated cell type by that of another, resulting in loss of normal cell function and increased risk of malignancy.
• Metaplasia occurs in response to an unfavourable environment for the original cell type, resulting in a reprogramming of local tissue stem cells or colonisation by other differentiated cells from adjacent sites.
• Not a change in the phenotype of an already differentiated cell!

Question 10

List 3 causes of metaplasia, the site at which the metaplasia occurs, as well as the original and metaplastic cell types.

Answer 10

1 - Cigarette smoking.

• Metaplasia occurs in the bronchus.
• The original phenotype is pseudostratified ciliated columnar epithelium.
• The metaplastic phenotype is squamous epithelium.

2 - Acid reflux.

• Metaplasia occurs in the lower oesophagus (Barrett’s oesophagus).
• The original phenotype is squamous epithelium.
• The metaplastic phenotype is columnar (gastric) epithelium.

3 - H. pylori infection.

• Metaplasia occurs in the stomach.
• The original phenotype is columnar (gastric) epithelium.
• The metaplastic phenotype is intestinal (enterocyte-like) epithelium.

Question 11

Which malignancy may arise from Barrett’s oesophagus?

Answer 11

Barrett’s oesophagus may give rise to an adenocarcinoma.

Question 12

What may cause cell injury?

List 4 biochemical mechanisms of cell injury.

Answer 12

• Cell injury may occur due to direct damage to cells or due to a failure to adapt.
• Biochemical mechanisms of cell injury involve:

1 - ATP depletion, resulting in:

• Failure of Na/K ATPase, leading to increased cytoplasmic Na+ and subsequent cell swelling.
• Increased anaerobic glycolysis, leading to a decrease in pH causing impaired enzymatic action and chromatin clumping.
• Detachment of ribosomes from the rough ER, leading to decreased protein synthesis.

2 - Mitochondrial damage, resulting in:

• ATP depletion.
• Release of cytochrome c and other mediators of apoptosis.

3 - Increased intracellular Ca2+, resulting in:

• Activation of phospholipases, leading to membrane damage.
• Activation of proteases, leading to breakdown of cellular proteins.
• Activation of endonucleases, leading to chromatin fragmentation.
• Activation of ATPases, leading to ATP depletion (see 1).

4 - Increased ROS production, resulting in:

• Oxidation of plasma membranes, proteins and DNA.

Question 13

List 2 histological indications of early, reversible cell injury.

Answer 13

Histological indications of early, reversible cell injury include:

1 - Cell swelling due to entry of sodium and water.

2 - Reduction in cytoplasmic RNA due to reduced transcription, causing a red appearance upon H&E staining known as eosinophilia (as haematoxylin has reduced genetic material to bind to).

Question 14

List the 2 primary types of cell death.

What drives each type?

Answer 14

Types of cell death include:

1 - Necrosis.

• Necrosis is driven by external injury.

2 - Apoptosis.

• Apoptosis is driven by internally programmed cell death.

Question 15

List 9 differences between necrosis and apoptosis.

Answer 15

Differences between necrosis and apoptosis include:

1 - Necrosis is energy independent whereas apoptosis is energy-dependent and tightly regulated.

2 - Necrosis involves loss of integrity of the plasma membrane whereas apoptosis does not.

3 - Necrosis causes amorphous densities in mitochondria, whereas apoptosis does not.

4 - Apoptosis involves condensation of chromatin whereas necrosis does not.

5 - Necrosis causes pyknosis (shrinkage), karyorrhexis (fragmentation) and karyolysis (disappearance) of the nucleus, whereas apoptosis causes nuclear fragments known as apoptotic bodies.

6 - Necrosis involves cell swelling whereas apoptosis involves cell shrinkage.

7 - Necrosis involves groups of cells whereas apoptosis involves single cells.

8 - The tissue response to necrosis is acute inflammation whereas the tissue response to apoptosis is phagocytosis.

9 - Necrosis only occurs pathologically whereas apoptosis can be either physiological or pathological.

Question 16

List the signalling events in apoptosis.

Answer 16

Apoptosis is divided into two pathways, each resulting in the activation of caspases:

1 - Intrinsic (mitochondrial) pathway.

• Cell injury is detected by the BCL2 family of sensor proteins.
• BCL2 stimulate the mitochondria to produce cytochrome c.
• Cytochrome c activates caspases.

2 - Extrinsic (death-receptor) pathway.

• External receptors such as Fas and TNF receptors are stimulated by external signals.
• These receptors stimulate adaptor proteins to activate caspases.
• Caspases (activated by both pathways) lead to nuclear fragmentation (by endonuclease activation) and breakdown of the cytoskeleton.

Question 17

List the different types, causes and characteristics of necrosis.

Answer 17

1 - Coagulative necrosis.

• The architecture of the dead tissue is still visible.
• Nuclei fragment and dissolve away, leaving only the cell outline.
• Coagulative necrosis is often see following ischaemic injury.

2 - Liquefactive necrosis.

• The architecture of the dead tissue is lost.
• Fibrin meshwork is present in between cellular material.
• Nuclei are still visible.
• Liquefactive necrosis is often seen in bacterial infection.

3 - Caseous necrosis.

• Occurs at the centre of granulomas as eosinophilic material.
• Has a macroscopic appearance reminiscent of cottage cheese.
• Caseous necrosis is often seen in TB.

4 - Fibrinoid necrosis.

• Occurs in the smooth muscle wall of blood vessels.
• Smooth muscle and connective tissue in the vessel wall is replaced with fibrin, which has a string-like appearance.
• Caused by leakage of fibrin proteins from a damaged vessel lumen, as in vasculitis.

5 - Fat necrosis.

• Occurs at any site containing adipocytes.
• Adipocytes become damaged and burst, releasing their fat content.
• Damaged adipocytes induce an inflammatory response.
• Macrophages are recruited, which show a foamy / bubbly cytoplasm due to phagocytosis of fats.
• Occurs most dramatically in acute pancreatitis where adipocyte damage results from leakage of pancreatic lipases.

Question 18

List 2 causes of cell death beyond necrosis and apoptosis.

How do they differ from necrosis and apoptosis?

Answer 18

Causes of cell death beyond necrosis and apoptosis include:

1 - Necroptosis.

• This is a caspase-independent pathway that morphologically resembles necrosis, however, like apoptosis, it is triggered by the extrinsic death receptor pathway (e.g. TNF receptor).

2 - Pyroptosis.

• This is a caspase-dependent cell death caused by intracellular microbial products which, unlike apoptosis, is associated with IL-1 production, inflammation and fever via the inflammasome complex.

Question 19

Give a clinical example of necrosis.

How does it present?

What is the pathophysiology?

How is diagnosis of this condition confirmed?

Answer 19

• A clinical example of necrosis is toxic epidermal necrolysis.
• It presents as full thickness necrosis of the skin and mucous membranes affecting >30% of the body.
• It is caused by cytotoxic lymphocytes attacking the epidermis, usually as part of an acute drug reaction.
• Diagnosis is confirmed by demonstrating full thickness epidermal necrosis on a skin biopsy, which shows a coagulative pattern.