LO: Describe the cellular response to stress and harmful stimuli

LO: Explain the adaptations of cell growth and differentiation and their importance to clinical practice

LO: Define the following terms and explain their clinical importance, giving examples of each; hypertrophy, hyperplasia, metaplasia and atrophy

Hypertrophy

• Hyper - high, trophy - nourishment (size)
• Increase in size of cells, increase in size of organ
• Relates to increased workload
• Muscle has limited division so undergoes hypertrophy in response to increased workload
• Physiological - uterus in pregnancy
• Pathological - myocardium in hypertension or valvular heart disease

Hyperplasia

• Hyper - high, plasia - place down (formation)
  
• Increase in number of cells in organ/tissue in response to stimulus
• Only takes place if cells are capable of dividing
• Hypertrophy and hyperplasia can occur together

Pathological hyperplasia

• Excessive action of hormones/growth factors
• Growth factors - increase output of new cells from stem cells
• Endometrial hyperplasia - abnormal bleeding due to prolonged stimulation of the endometrium by oestrogen
• Prostatic hyperplasia - due to androgen
• Regresses if stimulus is removed

Metaplasia

• Reversible change where one differentiated cell type is replaced by another cell type
• Adaptive response where replacement is better able to withstand adverse environment
• Caused by stem cell reprogramming
• If stimulus persists, can cause dysplasia

Atrophy

• Reduction in the size of an organ/tissue due to decrease in cell size and number
• Decrease in cell size, decrease in tissue size
• Ubiquitin-proteasome pathway activated
• Autophagy activated

Pathological atrophy

• Disuse atrophy - bed rest
• Denervation atrophy
• Diminished blood supply
• Inadequate nutrition
• Loss of endocrine stimulation
• Pressure atrophy

LO: Explain ischaemic/hypoxic injury, reperfusion injury and toxic/chemical injury and give examples of diseases associated with each process

Ischaemia

• Ischa - restrict/block
• emia - blood
• Blood is restricted so less blood gets to tissue so less oxygen to cells
• Less aerobic respiration
• Less ATP
• Na⁺/K⁺ pump not maintained
• Na⁺ enters and remains inside cell
• $\psi$ (water potential) decreases in cell
• Water moves into cell by osmosis
• Cell is lysed (bursts) - necrosis

Hypoxia

• Hypo - low
• Oxia - O₂
• Can occur even when blood flow is normal

flowchart LR
	A[Less oxygen] --> B[Less aerobic respiration]
	B --> C[Less ATP]

Types of necrosis

Type	Associations
Coagulative (Structurally same)	Ischaemia
Liquefactive (Liquid)	Bacterial infection
Gangrenous (Both coagulative and liquefactive)	Ischaemia
Caseous (Cheese)	Tuberculosis
Fat	Pancreatitis
Fibrinoid	Vasculitis

LO: Explain the process of apoptosis and describe the differences between apoptosis and necrosis

Necrosis

• Accidental/unregulated cell death
• Damage to membranes - lysosomes
• Leakage of cell contents - inflammation
• Ischaemia, toxins, infections, trauma
• Always pathological
• Mitochondria damage, opens Mitochondrial Permeability Transition Pore (MPTP) and less ATP
• Influx of calcium - opens MPTP
• Accumulation of free radicals - damage to DNA/proteins
  Free radicals take electrons from healthy cells' atoms

flowchart TD
	A[Healthy cell] --Reversible injury--> B[Increased cell size, Membrane blebs, Swelling of ER and mitochondria]
	B --Recovery--> A
	B --Progressive injury--> C[Breakdown of plasma membrane, Leakage of contents, inflammation]

Apoptosis

• Regulated programmed cell death caused by protein/DNA damage, loss of hormone stimulation or by membrane receptor activation
• No loss of membrane integrity - no inflammatory reaction
• Intrinsic and extrinsic
• Cell shrinks, nucleus fragments, membrane remain intact and membrane bound small apoptotic bodies form

flowchart TD
	A[Healthy cell] --> B[Reduced cell size, Membrane blebs]
	B --> C[Cellular fragmentation, nuclear fragmentation, apoptotic bodies]
	C --> D[Phagocytosis of apoptotic cells and fragments]

When

• Hormone withdrawal
• Elimination of inflammatory cells
• Radiation
• Hypoxia
• Cytotoxic drugs
• DNA damage
• Protein misfolding
• Viral infection
• Organ rejection and tumours
• Duct obstruction

Intrinsic

• Triggered by cell injury, DNA damage or decreased hormonal stimulation
• Inactivation of BCL2 causes cytochrome C to leak from mitochondria
• Activation of caspases
  Caspases are enzymes that break down proteins (proteases)

Extrinsic

• Triggered by FAS ligand binding to FAS death receptor on target cell
• TNF binding to TNF receptor alternatively
• Activation of caspases

Removal of apoptotic cells

• Phosphatidylserine flips from the inner to outer aspect of cell membrane - recognised by macrophage receptors
• Secrete soluble factors which recruit macrophages
• Coated in thrombospondin or bind C1q which attracts macrophages
• Very efficient - disappear in minutes