Death And Destruction

Cell damage, cell death and apoptosis
15.9.06

Cellular injury: causes
• Hypoxia.
• Not the same as ischaemia.
• Physical agencies:
-trauma;
-burns/severe cold;
-radiation;
-electric shock;
-barotrauma.
• Infectious agents:
-cytopathic;
-toxins;
-immune-mediated.
• Other immune reactions:
-autoimmune;
-anaphylactic.
• Nutritional deficiencies/excesses.
• Genetic.

Chemical injury
• Direct eg. acids, alkalis.
-Mercury compounds, cyanide.
• Via toxic metabolites eg. paracetemol.

Cellular injury
• Most vulnerable points:
-mitochondria;
-membranes;
-protein synthesis;
-nuclear DNA.
• Mechanisms.
• Complex, but can be summarised as:
-free radicals;
-ATP deficit;
-mitochondrial damage;
-leaky membranes;
-loss of Ca2+ control.

Free radicals
• Free electron in outer orbit.
• End-point of many processes.
• Highly reactive, chain reaction.
• Generated by:
-respiration ie. metabolism;
-polymorphs;
-transition metal reactions.
• Unpaired electron in outer orbit.
• Very active and propagate.
• Eg. OH•, O2-•, NO2•, NO3-•.
• Implicated in:
-irradiation;
-inflammation;
-chemical and drug injury;
-carcinogenesis;
-ageing;
-paradigm: paraquet.

Cellular injury - outcome
• Minor - recovery.
• Major - apoptosis, necrosis.

Reversible injury
• ATP falls.
• Sodium pump fails.
• Cell swells.
• Anaerobic respiration uses up glycogen.
• If causes uncorrected, leads to…

Irreversible injury
• Severe swelling and disruption of organelles, particularly mitochondria.
• Lysosomes become leaky and enzymes damage cell.
• Can be detected in blood.

Apoptosis
• Dropping off (like leaves) - active process.
• Seen in:
-cell shedding (normal);
-atrophy;
-involution;
-embryogenesis;
-cell injury (insufficient to cause necrosis);
-tumours.
• Programmed cell death.
• Cell dismantled into apoptotic bodies.
• Phagocitised.
• No inflammatory reaction.

Phases of apoptosis
• Signal:
-TNF;
-nuclear cortisol receptors;
-p53-mediated after DNA damage.
• Control:
-fas-fas ligand (CD95 receptor);
-bcl-2 (mitochondrial function);
-increased mitochondrial permeability;
-opposed by bax.
• Effector:
-proteolysis - caspases.
• Removed by phagocytes.

Heart - reperfusion injury
• Free radicals quite low during ischaemia.
• Torrent produced on reperfusion.
• Mainly reactive oxygen species.
• Neutrophils involved (attracted by cytokines).