Haemoglobin and red cells (3) Flashcards
The erythrocyte:
a very specialised RB cell and has perfect function
Oxygen flow:
- Oxygen is absorbed in the high pO2 in lung and transported to tissues bound to haemoglobin
- Needs for oxygen are not the same everywhere, some areas need more than others
- In the middle is the lungs, where the red cells pick up oxygen
- Circulation may require different oxygen levels
- Most of the power in the gut as it does require lots of oxygen Must get there safely, to the places and give oxygen depending on needs
Shape of RBC:
Biconcave shape optimises O2 uptake and delivery
Cytoskeleton function:
The structure supports circulation and safety
Structure/function of haemoglobin:
- Delivers O2 where it is needed
- Oxygen must be released according to need in this case little to arms and brain, lots to the legs. How does haemoglobin do this?
- Haemoglobin has to bind oxygen in the lungs and then has to release it progressively
What do we mean by simplicity?
The red cell has given up:
- Nucleus – more room in the cell for haemoglobin and doesn’t get in the way of the biconcave shape
- Mitochondria – the red cell gets its oxygen from simple sugars and absorption, it is relatively inefficient (uses glycolysis)
- Ribosomes – pointless as it cannot transcribe any mRNA as there is no nucleus, cannot commit to apoptosis, lack of protect as proteins cannot repair any damage
Why would a RBC give its organelles up?
- Efficient and stable – nothing unnecessary
- Room for haemoglobin – no proteins, cannot replicate
- Unattractive to infecting organisms – pointless to invade as there’s nothing to attack
Is RBC giving up its organelles a problem?
- No nucleus: No capacity for to making mRNA
- No Mitochondria no TCA cycle – limits the capacity to generate ATP or reducing power - vulnerable
- No Ribosomes no translation of mRNA no protein synthesis
- highly efficient and adaptable
- but very vulnerable
Two parts to cytoskeleton (PM):
- The membrane links that are the vertical proteins – membrane anchors
- Linked by the horizontal proteins on the membrane cytoskeleton
Bi-concave disc is the optimal shape:
- High surface area to volume ratio
- Allows oxygen to diffuse in and co2 to diffuse out with a short diffusion rate/ pathway
- When in the capillary we want a relaxed biconcave shape
- Want them closely packed together
- In arteries you want to move very fast so do not want the relaxed state
Optimal flow:
The structure can adopt an alternative “torpedo” shape in high flow conditions
Basically becomes compressed and more oval
Optimal flexibility:
The structure can flex to allow cells to pass through small branched vessels in tissues
Basically becomes like a peanut shape
The membrane and damage repair:
The lack of ability to make new proteins limits repair capacity for the cells cannot undergo apoptosis so temporary fixing is needed to prevent toxicity – the membrane structure is self-repairing to limit immediate damage.
This must not happen – haemoglobin released into circulation is highly toxic, the cytoskeleton structure allows a fix to prevent Hb “leakage”.
Damage by fibrin strands in the circulation caused by local clotting activation:
- slicing damage
- repair and vacuole formation
- vacuole pops but RBC is sealed
- further sealed fragments may be formed
Inherited abnormal cytoskeleton or antibody may cause diffuse membrane loss:
- Membrane is damaged diffusely
- small sealed blebs of membrane are lost
- the cell shrinks gradually becoming a rigid sphere
- the rigid damaged ‘sphereocyte’ is lost in the spleen
- biconcave shape is replaced by a sphere
Sigmoid dissociation curve:
An s-shaped curve that has no oxygen to begin with so no saturation, then gradually becomes a straight line which is optimal, then curves off which means all Hb is saturated and can no longer carry oxygen
Function of Hb:
- the oxygen-binding chemical elements: the haem
- the surrounding protein elements: globin
- (protein sheath to keep the iron safe and in place)
Haem:
Porphyrin structure holds iron in a flat two dimensional structure:
Two interaction sites remain above and below the plane:
- One fixes the molecule to the globin protein
- One is available to bind oxygen
- Iron binds 6 electrons
- Porphyrin only binds 4 electrons – one binds to the globin molecule and the other is able to bind to oxygen
- Each haem has 4 binding domains
The function of globin:
- Binding to protein keeps haem contained (not free) & therefore safe
- Iron is a free radical producer that must be kept tight in the proteins to ensure no damage occurs
- To produce the sigmoid Oxygen-binding curve
Leaving the lung:
4 oxygen molecules bound: “relaxed form”: holds on to oxygen tightly until the oxygen in tissues begins to drop then the first oxygen is released
- Cooperation between chains means that each influences the other. After release of the first oxygen the structure becomes increasingly “tight” and each subsequent release becomes easier.
- One oxygen molecule bound: “tight form”: gives up oxygen easily
- Relaxed form binds very tightly to oxygen
- As you get to a tissue the first oxygen is dropped off
- As soon as this happens the chains get tighter and closer together, holding oxygen less closely, this makes releasing the oxygen a lot easier
The tight and relaxed form are influenced by:
- pH
- CO2
- Metabolic products
Present mainly in active tissues and promote the tight form more
Physiological Hb variation during development:
- Foetal development, embryonic and foetal haemoglobin’s
- During development the embryo, then foetus make a succession of alternative haemoglobin’s
- The best studied is foetal haemoglobin – this form does not bind 2,3 DPG and therefore has higher affinity for haemoglobin
- This allows the foetal haemoglobin (HbF) to compete with the mothers haemoglobin for Oxygen – transferring the oxygen from the mother to the developing foetus
RBC and Self-defence:
- the iron-rich haemoglobin is inhospitable to bacteria
- exploited by malaria
- immune system does not recognise a damaged cell, only the haemaglobin proteins that are released which can be very toxic
MALARIA:
- The malaria parasite introduced by mosqitoes is able to live inside red cells, protected from the immune system and metabolising their haemoglobin for energy, replicating then affecting other red cells.
- Parasite of flies and fish
- Red blood cell becomes pale and gets bigger
Summary of RBC diseases:
- Haemoglobin S [Sickle cells (up to 15% gene frequency)]
- Beta thalassaemia (gene up to 17%)
- Deficiency of glucose 6 phosphate dehydrogenase (G6PD) (gene up to 5-25%)
- Haemoglobin C [gene frequency up to 24%] – protects you against malaria but also makes you very ill
G6PD deficiency:
- G6PD is a red cell enzyme that generates reducing power (NADPH) that protects the haemoglobin from oxidative damage. The simple metabolism of the red cell means it depends on this enzyme.
- Deficiency of the G6PD means that when oxidative stress is high the haemoglobin is damaged and the red cell destroyed
- It is believed that during malarial infection oxidative stress in red cells is high and so malarial infected red cells are destroyed providing some protection
G6PD deficiency prevalence:
The gene is prevalent in Africa, some Arab states and in some Mediterranean areas and can cause death after some foodstuffs or medications increase oxidation
