Cell fate and death

What is cell injury?

Structural and functional damage to a cell caused by stress or injurious stimuli; may be lethal (cell death) or sublethal (potentially reversible).

What is lethal cell injury?

Cell injury that results in cell death.

What is sublethal cell injury?

Cell injury that does not initially cause cell death and may either be reversible or progress to irreversible injury and death.

Why is understanding reversible injury clinically important?

Early intervention may restore normal function before irreversible cell death occurs, e.g. rapid reperfusion after myocardial ischaemia.

What are the 8 major causes of cell injury?

Oxygen deprivation, chemical agents, infectious agents, immunological reactions, genetic defects, nutritional imbalances, physical agents and ageing.

What is ischaemia?

Reduced blood supply to tissue causing oxygen deprivation.

What is hypoxia?

Reduced oxygen availability to cells.

What is myocardial infarction?

Death of cardiac muscle due to ischaemia.

What causes most myocardial infarctions?

Atherosclerotic narrowing of coronary arteries with superimposed thrombus formation causing acute occlusion.

What determines the cellular response to injury?

Type of injury, duration of injury and severity of injury.

How does duration of injury affect outcome?

A mild injury may be reversible if brief but become irreversible if prolonged.

How does severity of injury affect outcome?

More severe injury is more likely to be irreversible and lead to cell death.

How does cell type influence response to injury?

Different cells have different metabolic demands and regenerative capacities.

Why are neurons particularly vulnerable to injury?

They have high metabolic requirements and limited regenerative capacity.

Why is cartilage relatively resistant to hypoxia?

It has low metabolic requirements and can survive prolonged oxygen deprivation.

What tissues have a good regenerative capacity?

Bone marrow and liver.

Why does the liver regenerate well?

Hepatocytes retain the ability to proliferate following injury.

Why do the heart and brain regenerate poorly?

Cardiac myocytes and neurons have very limited capacity for proliferation.

What four intracellular systems are particularly vulnerable to injury?

Cell membrane integrity, ATP generation, protein synthesis and integrity of the genetic apparatus.

Why is cell membrane integrity so important?

It keeps essential components inside the cell and prevents unwanted entry of substances.

Why does ATP depletion injure cells?

Energy-dependent processes fail including membrane maintenance and protein synthesis.

How does DNA damage contribute to cell injury?

It disrupts normal protein production and cellular function.

What did Goldin emphasise about the four injury mechanisms?

They interact extensively and are difficult to separate into primary and secondary processes.

What occurs first: loss of function, cell death or morphological change?

Loss of cellular function occurs first, then cell death, then morphological changes become visible.

Why may someone die from ventricular fibrillation without pathological changes being seen at post-mortem?

Function fails before structural changes develop.

What is cellular adaptation?

A response allowing cells to survive stress by altering size, number or phenotype.

What is the difference between physiological and pathological stress on cells?

Physiological stress occurs in normal healthy conditions whereas pathological stress occurs as part of disease.

Give a physiological cause of cardiac hypertrophy.

Prolonged strenuous exercise.

Give two pathological causes of cardiac hypertrophy.

Hypertension and aortic stenosis.

Why does the left ventricle become thickened in hypertension?

Increased workload causes hypertrophy of individual cardiac myocytes.

What is the normal weight of an adult male heart according to the lecture?

Approximately 300 g.

How heavy may a hypertrophied heart become?

Approximately 400-500 g.

What did Goldin describe as a useful diagnostic checklist when considering causes of disease in any organ?

Oxygen deprivation, chemicals, infections, immunological reactions, genetic defects, nutritional disorders, physical agents and ageing.

What virus did Goldin specifically mention as a cause of myocarditis?

Coxsackie virus.

Why can bone marrow compensate after blood loss?

Bone marrow cells retain the ability to proliferate.

What experimental example did Goldin use for liver regeneration?

A rat can undergo removal of most of the liver and the liver can regenerate.

What determines whether a cell undergoes adaptation or death?

The nature, duration and severity of the stress or injury.

Why is the heart a poor regenerative organ?

Adult cardiac myocytes have minimal proliferative capacity.

Define atrophy.

Shrinkage in the size of a cell or organ due to loss of cell substance.

What happens to cell size in atrophy?

Cells become smaller.

What happens to organ size in atrophy?

The organ becomes smaller because it contains smaller cells.

What causes muscle atrophy following denervation?

Loss of trophic stimulation from the nerve supply.

What brain change is seen in advanced dementia?

Cerebral atrophy with widened sulci and reduced brain substance.

How can cerebral atrophy be recognised grossly?

Widened sulci and increased space around the brain.

Define hypertrophy.

Increase in cell size producing an increase in organ size.

What causes hypertrophy?

Increased functional demand or hormonal stimulation.

Can hypertrophy be physiological?

Yes.

Can hypertrophy be pathological?

Yes.

What is a physiological example of hypertrophy in the heart?

Athletic exercise producing increased cardiac workload.

What is a pathological example of cardiac hypertrophy?

Hypertension or aortic stenosis.

Why does cardiac hypertrophy occur rather than hyperplasia?

Adult cardiac myocytes do not normally proliferate.

What physiological example of hypertrophy did Goldin emphasise?

Pregnancy-associated enlargement of the uterus.

How does the gravid uterus enlarge?

Smooth muscle cells increase in size due to hormonal stimulation.

What hormone drives uterine hypertrophy?

Oestrogen.

Define hyperplasia.

Increase in the number of cells within an organ or tissue.

Can hyperplasia be physiological?

Yes.

Can hyperplasia be pathological?

Yes.

What are the two types of physiological hyperplasia?

Hormonal and compensatory.

What is the classic physiological hyperplasia example from the lecture?

Proliferative endometrium during the oestrogenic phase of the menstrual cycle.

How does oestrogen affect the endometrium?

It stimulates proliferation of endometrial glands.

What is compensatory hyperplasia?

Increased cell numbers to compensate for loss of tissue or increased demand.

What example of compensatory hyperplasia was given?

Enlargement of the remaining kidney after nephrectomy.

What usually causes pathological hyperplasia?

Excessive hormonal or growth factor stimulation.

Why can prolonged hyperplasia be dangerous?

It may provide the seedbed for cancer development.

What histological feature demonstrates active hyperplasia?

Increased numbers of mitotic figures.

Define metaplasia.

A reversible change in which one adult differentiated cell type is replaced by another adult differentiated cell type.

What is the key word in the definition of metaplasia?

Reversible.

Why is reversibility clinically important?

Removing the stimulus may allow tissue to revert to normal.

Is metaplasia itself malignant?

No.

Why is metaplasia clinically important?

It can form the basis upon which malignancy develops.

What happens to smoking-induced squamous metaplasia if smoking stops?

It may gradually reverse over many years.

How long might smoking-related respiratory metaplasia take to reverse after smoking cessation?

Potentially many years, often 10-15 years.

What is the physiological metaplasia example discussed in the lecture?

The cervix.

What normally lines the ectocervix?

Stratified squamous epithelium.

What normally lines the endocervix?

Columnar glandular epithelium.

Why can endocervical columnar epithelium become exposed on the ectocervix?

Cervical expansion, especially during pregnancy.

What happens to exposed endocervical columnar epithelium?

It undergoes squamous metaplasia.

What drives cervical squamous metaplasia?

Exposure to the acidic vaginal environment.

Why does columnar epithelium on the ectocervix undergo squamous metaplasia?

It is exposed to the acidic vaginal environment.

What is exposed on the ectocervix during cervical ectropion?

Endocervical columnar epithelium.

Why is cervical metaplasia reversible?

When the cervix returns to normal, the epithelium can revert to columnar phenotype.

In the cervix, what happens when metaplastic squamous epithelium later returns into the endocervical canal?

It can revert back to columnar epithelium.

What is Barrett's oesophagus?

Replacement of oesophageal squamous epithelium with columnar glandular epithelium due to chronic acid reflux.

What is the technically correct term for Barrett's oesophagus according to Goldin?

Columnar-lined oesophagus.

Who was Barrett?

The surgeon who first described the condition.

What normally lines the oesophagus?

Stratified squamous epithelium.

Why does Barrett's oesophagus develop?

Squamous epithelium is poorly adapted to chronic acid exposure.

What type of epithelium replaces the normal oesophageal epithelium in Barrett's?

Columnar glandular epithelium.

What special cell type is commonly seen in Barrett's oesophagus?

Goblet cells.

What does the term "columnar-lined oesophagus" emphasise better than "Barrett's oesophagus"?

It directly describes the histological change present.

Why is squamous epithelium poorly suited to chronic acid exposure?

It is tough but not specialised for acid resistance.

Why is obesity linked to Barrett's oesophagus?

Obesity increases acid reflux.

Why is Barrett's oesophagus important clinically?

It predisposes to dysplasia and adenocarcinoma.

Why do patients with Barrett's develop adenocarcinoma rather than squamous carcinoma?

The metaplastic tissue is glandular rather than squamous.

What is the sequence from reflux to cancer in Barrett's oesophagus?

Acid reflux → metaplasia → dysplasia → adenocarcinoma.

Why has oesophageal adenocarcinoma increased in Western countries?

Increased obesity has increased acid reflux and Barrett's oesophagus.

What type of oesophageal cancer is expected in a normal oesophagus?

Squamous cell carcinoma.

What type of oesophageal cancer develops from Barrett's oesophagus?

Adenocarcinoma.

Define dysplasia.

Precancerous epithelial change showing cytological and genetic features of malignancy but without invasion.

What is the key distinction between dysplasia and cancer?

Dysplasia lacks invasion through the basement membrane.