Pathology 3: cells in trouble Flashcards
Define the 5 reversible cell adaptations which occur in response to a change in environment and give an example of each adaptation.
1. Hypertrophy = an increase in cell size (eg. myocardial hypertrophy in response to sustained high blood pressure)
2. Hyperplasia = an increase in cell number (eg. endometrial hyperplasia due to prolonged stimulation of the endometrium by the hormone oestrogen)
3. Metaplasia = a change from one differentiated (mature) cell type to another mature cell type which is better able to withstand the adverse environment (eg. intestinal metaplasia of the oesophagus (Barretts oesophagus))
4. Dysplasia = disordered cell growth caused by a carcinogen (eg. cervical dysplasia caused by human papilloma virus infection)
5. Atrophy = a reduction in cell size (eg. if a muscle loses its nerve supply it will undergo denervation atrophy)
Left ventricular hypertrophy on x-ray…
What is the significance for a patient with squamous metaplasia of the bronchus?
- Cigarette smoking causes squamous metaplasia of the bronchus (normally lined by pseudostratified columnar epithelium), which can progress to dysplasia, which can later progress to invasive squamous cell carcinoma of the bronchus
What is the significance for the patient with endometrial hyperplasia?
- Prolonged stimulation of the endometrium (the womb lining) by the hormone oestrogen can cause an increase in cell number and gland number (hyperplasia)
- this increases the risk of the development of a gland-forming cancer of the endometrium (endometrial adenocarcinoma)
What are the 3 possible outcomes for a cell which is irreversibly damaged?
- Necrosis.
- Apoptosis.
- Necroptosis.
What is necrosis?
- Necrosis = an unregulated form of cell death where cell membranes are damaged causing lysosomal enzymes to be released and the cell contents to leak resulting in an inflammatory reaction.
- note: necrosis is always pathological.
List 6 pathological types of necrosis and an example of the diseases in which these occur.
1. Coagulative necrosis - myocardial ischaemia (necrosis due to lack of blood supply).
**2. Liquefactive necrosis **- stroke (ischaemic necrosis in the brain).
3. Gangrenous necrosis - peripheral vascular disease.
4. Caseous necrosis - tuberculosis.
5. Fat necrosis - pancreatitis.
6. Fibrinoid necrosis - vasculitis.
What molecular features characterise necrosis?
- Mitochondria are damaged: depleting ATP
- Influx of calcium: activates enzymes (eg. proteases)
- Free radicals (unpaired electrons) accumulate: damage proteins, lipids, and nucleic acids
- Increased membrane permeability: affects plasma membranes, lysosomal membranes and mitochondrial membranes
- Intracellular proteins which leak out of necrotic cells (eg. Troponin is released into the blood stream in the context of myocardial necrosis and can be measured to confirm a myocardial infarction (heart attack))
What is apoptosis?
- Apoptosis = programmed cell death (can be either physiological or pathological)
- Caused by protein or DNA damage
- There is no loss of membrane integrity and no inflammatory reaction
What exposures/diseases are associated with apoptosis and disrupted apoptosis?
- Radiation, hypoxia and cytotoxic drugs can damage DNA and if repair mechanisms fail apoptosis is induced to prevent malignancy
- p53 is a tumour suppressor gene which normally stops cells dividing if DNA is damaged and if the damage is too great apoptosis is triggered (p53 mutations predispose to cancer)
- Misfolded proteins can accumulate in the endoplasmic reticulum (ER) causing ER stress and subsequent apoptosis
- Viral infections (eg. HIV can cause apoptosis directly or by a host immune reaction (via cytotoxic T-cells))
- T-cells can also cause apoptosis in tumours and in transplants during cellular rejection
- Apoptosis causes atrophy in the setting of duct obstruction (eg. pancreas, salivary gland and kidney)
List the two apoptosis pathways.
- Intrinsic (mitochondrial) pathway.
- Extrinsic (death receptor) pathway.
Explain how the intrinsic apoptosis pathway works.
- Triggered by cell injury, DNA damage or decreased hormone stimulation
- there is inactivation of a molecule called BCL-2 which is an anti-apoptotic molecule normally
- this inactivation allows cytochrome C to leak from the inner mitochondrial matrix into the cytoplasm of the cell to activate caspases
- (caspases are proteases which can breakdown cell proteins)
Explain how the extrinsic apoptosis pathway works.
- Can be activated by FAS ligand binding to the FAS death receptor on a target cell, activating caspases
- this is the mechanism by which lymphocytes which respond to self can be eliminated
- this pathway can also be triggered by TNF binding to the TNF receptor on a target cell
- (some viruses and normal cells can produce a molecule called FLIP which can block apoptosis)
Once a cell dies by apoptosis, what happens then?
- Phosphatidylserine flips from the inner to the outer aspect of the cell membrane and this is recognised by macrophage receptors
- Macrophages phagocytose the apoptotic bodies and the dead cells disappear within minutes
- note: this is a very efficient process
List the 4 mechanisms which can cause abnormal accumulations to occur within cells and give one example of a disease associated with each mechanism.
1. Abnormal metabolism: eg. fat accumulating in liver cells in alcoholic liver disease
2. Lack of an enzyme: eg. lysosomal storage diseases
3. Defect in protein folding or transport: eg. nephrotic syndrome causes excess protein loss through the kidneys and causes protein accumulation in kidney cells
4. Ingestion of indigestible material: eg. carbon accumulation in pneumoconiosis (a lung disease seen in coal miners)
