List 6 causes of cell injury and death
- Hypoxia
- Physical agents, including trauma
- Drugs and therapeutic agents
- Microorganisms
- Dietary insufficiency or excess
- Immune mechanisms or genetic abnormalities
Describe the causes and consequences of hypoxia
- Oxygen deprivation to a cell
- Some cells are less tolerant of this, i.e. neurones
- If persistent will cause cell adaptation or death
Explain reversible and irreversible hypoxic injury
- Reversible
- Reduced ATP from oxidative phosphorylation
- This decreases ATP available for Na/ K pump
- As a result, Na accumulates inside the cell
- The cell starts to swell from osmosis (oncosis)
- Anaerobic respiration reduces pH = damage enzymes
- Ribosomes detach from ER = lower protein synthesis
- Irreversible
- Not a clear cut off point
- Profound oncosis
- Loss of membrane integrity = calcium influx
- Necrosis, as calcium triggers many potent enzymes
Explain the mechanisms of reperfusion injury
- Increased production of ROS
- Increased supply of neutrophils and ergo inflammation
- Delivery of complement proteins
What are the three most important biological free radicals?
- OH (hydroxyl)
- O2- (superoxide)
- H2O2 (hydrogen peroxide)
Free radicals attack lipids in cell membranes and cause lipid peroxidation. They can also damage proteins, carbohydrates and nucleic acids.
Describe the body’s defence against free radicals
- Enzymes
a) superoxide dismutase (makes H2O2 - less harmful)
b) catalases and peroxidases - Free radical scavengers
a) vitamins A, C and E
b) glutathione - Storage proteins which sequester radical catalysts
a) Transferrin and ceruloplasmin
What are heat shock proteins?
- Proteins consisting of chaperones, unfoldases and stress proteins
- Triggered by any injury and remain inside the cell
- Increased HSP synthesis following injury
- Recognise incorrectly folded proteins and correct them
- Remove if they can’t be fixed
Define and describe oncosis
- Cell death with swelling
- Blebbing
- Typically as a result of hypoxia and ischaemia
- Three main changes can be seen microscopically
1) Cytoplasmic - reduced pink staining
2) Nuclear - chromatin clumping
3) Abnormal intracellular accumulations
Define and describe necrosis
- Occurs in a living person
- The morphological change after cell death
- Occurs typically 4-24 hours after cell death
- Either coagulative or liquifactive
- Appearance, not a process
Define and describe apoptosis
- Programmed cell death
- Either single or small cluster of cells
- Shrinkage
- Eosinophillic cytoplasms
- Cell budding
- Embryogenesis
What are the types of gangrene? Describe
- Necrosis that is visible to the naked eye
- Dry gangrene = coagulative necrosis
- Wet gangrene = infected. Liquifactive necrosis
- Gas gangrene = infection with anaerobic bacteria
Explain red infarct and where it occurs
- haemorrhagic
- dual blood supply or anastomoses
- poor stromal support
- lungs, intestines
Explain white infarct and where it occurs
- anaemic
- occurs in structures with good stromal support
- occlusion of an end artery
- heart, spleen and kidney
List and explain some abnormal cell accumulations
1) water and electrolytes
2) lipids - e.g. steatosis
3) proteins
4) pigments - exogenous (i.e. soot) or endogenous
5) carbohydrates
Describe dystrophic calcification
- Occurs in areas of dying tissue, atherosclerotic plaques, damaged heart valves and tuberculous lymph nodes
- local calcification
- hypercalcaemia not normally present
Describe metastatic calcification
- systemic calcification
- hypercalcaemia normally present
- increased PTH
- bone tumours
- paget’s disease of bone (increased turnover)
Briefly explain cellular aging
- decline in ability to replicate
- ‘replicative scenesence’
- successively shortening telomeres
- telomerase is found in stem cells and stops this process
Briefly, what are the effects of alcohol on the liver?
- fatty change: steatosis and hepatomegaly
- acute alcoholic hepatitis: focal necrosis, liver tenderness and jaundice. Usually reversible.
- Cirrhosis: hard, shrunken liver. Excess collagen.
What is hypoxaemia?
Arterial content of oxygen is low, i.e. reduced inspired O2 at altitude
What is anaemia?
Decreases ability of haemoglobin to carry oxygen, i.e. reduced RBC or CO2 poisoning
What is ischaemia?
An interruption in blood supply to a tissue, normally as a result of infarction
Histiocytic
Inability to utilise oxygen in cells due to oxidative phosphorylation enzymes
What are the 4 essential targets of cell injury?
- Cell membranes
- Nucleus
- Proteins
- Mitochondria
How is apoptosis initiated?
- Intrinsica) DNA damage or p53 protein (many others)
b) increased mitochondrial permeability
c) releases cytochrome C from mitochondria
d) interacts with APAF1 and caspase 9
e) activates downstream caspases - Extrinsica) TRAIL or Fas ligands
b) bind to death receptors on membrane
c) activation of caspases independent of mitochondria
