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From what I know, the main function of red blood cells (RBCs) is hemoglobin transport. So, why do we need cells packed with hemoglobin: why can't it travel freely in the bloodstream?

My own thoughts were:

1) Having hemoglobin packed into cells means it can be released where it's most needed. For example, when we are exercising, our muscles need more oxygen, so more erythrocytes release their oxygen in the muscle tissue.

2) The diameter of a capillary is much bigger than a single protein molecule's diameter, but comparable to a cell's diameter. So, when cells are traveling through a capillary, all of them are close to its walls. However, when free molecules are traveling through it, some of them are close to the walls, while the others are in the "middle". I figured, those in the "middle" can't exchange oxygen with the surrounding tissues. So, red blood cells make gas exchange more effective.

Do you think any of this makes sense? Why in reality do RBCs exist?

Any insight or book recommendations would be very appreciated:)

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    $\begingroup$ #1 doesn't make sense. Whether in cells or not in cells, O2 binding to Hg depends on O2 concentration in solution. #2 doesn't make sense, but you are close to the interesting idea "having objects with diameter close to the blood vessel has unique and desirable hydrodynamic properties", but I would suspect it's more that capillaries evolved to track particle size, not the other way around. A useful insight would be to look at closely related animals with and without RBCs. Also, consider nucleated bird RBCs. $\endgroup$ – Superbest Oct 18 '14 at 22:08
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    $\begingroup$ If you want a good look at why free hemoglobin is a bad idea, read an article about transfusion reactions (hemolysis) and the organs it damages. $\endgroup$ – anongoodnurse Oct 18 '14 at 22:33
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Hemoglobin molecules used to manufacture these products are not contained by a red cell membrane, and when released into the vasculature, these molecules rapidly scavenge nitric oxide.This can result in systemic vasoconstriction, decreased blood flow, increased release of proinflammatory mediators and potent vasoconstrictors, and a loss of platelet inactivation,17- 20 creating conditions that may lead to vascular thrombosis of the heart or other organs. This mechanism has recently been shown in preclinical models to be responsible for injury during hemolytic states, in which hemoglobin is also released into the circulation.21

Unlike naturally occurring hemoglobin, manufactured cell-free hemoglobin-based blood substitutes (HBBSs) can be chemically altered to theoretically minimize such toxicities. It has been postulated that cross-linking, polymerization, or pegylation of hemoglobin will create larger, more stable HBBS molecules, preventing extravasation and thereby leading to a reduction in toxicities related to nitric oxide scavenging. At least 1 manufacturer has also chemically increased the affinity of its HBBS for oxygen (lower P50, the partial pressure of oxygen required for 50% hemoglobin saturation) to decrease arteriole oxygen transfer and thereby potentially eliminate untoward cardiovascular effects.

So cell free hemoglobin is toxic. As you can see this toxicity can be reduced in other ways too, so it seems like there is an evolutionary pressure in the direction of having blood cells, maybe it is simpler this way. To answer the other question, I think there can be free HGB in the blood when blood cells fall apart because of an infection e.g. malaria, etc...

Hemolysis in falciparum malaria results in NO quenching by cell-free hemoglobin, and may exacerbate endothelial dysfunction, adhesion receptor expression and impaired tissue perfusion. Treatments that increase NO bioavailability may have potential as adjunctive therapies in SM

Btw. I agree with rhill45, I think too that it is easier to regulate O2 and CO2 exchange if you have a specialized cell type, so it might have regulation purposes. It can have recycling purposes either, because it is hard to distinguish between old (damaged) and new HGB when they are in a cell-free form. This problem probably can be solved by destroying only glycosylated hemoglobin, but I guess it is much easier to filter out the old RBCs in the spleen...

In the process of maturation, a basophilic pronormoblast is converted from a cell with a large nucleus and a volume of 900 fL to an enucleated disc with a volume of 95 fL. By the reticulocyte stage, the cell has extruded its nucleus, but is still capable of producing hemoglobin.

  • according to wikipedia (without citation).

Other sources claim the same, with the extension that this period lasts only for a short time, because the cell soon loses its mRNA and so it stops producing HGB. So according to these articles RBCs create the HGBs in the early stages of their life. (I did not find a real scientific article about this, but I can accept this theory.)

According to Chris this toxicity is just a protection mechanism, so I dug deeper.

Bacterial virulence is greatly enhanced by freely available iron, such as that in fully-saturated transferrin or free haemoglobin. Following trauma a fall in tissue Eh and pH due to ischaemia, plus the reducing powers of bacteria, can make iron in transferrin freely available and abolish the bactericidal properties of tissue fluids with disastrous results for the host. Hyperbaric oxygen is a possible therapeutic measure that could restore normal bactericidal systems in infected tissues by raising the Eh and pH.

Iron lies at the center of a battle for nutritional resource between higher organisms and their microbial pathogens. The iron status of the human host affects the pathogenicity of numerous infections including malaria, HIV-1, and tuberculosis.

So RBCs protect the iron against microbial pathogens, that's their key role. I think every other related problem, like O2 release regulation, free HGB toxicity, HGB recycling, etc... can be solved with free HGB as well, so most probably iron protection is the evolutionary pressure to store HGB in blood cells instead of letting it be in the blood in a cell free form. It's funny that every single book gets this wrong, and they claim that carrying oxygen is the most important role of this cell type, while they aren't mention anything about iron protection... :-)

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    $\begingroup$ One point of free hemoglobin in the blood being toxic is the fact this happens when red blood cells get damaged, which is obviously not a good thing. So this is a protective mechanism as well. $\endgroup$ – Chris Oct 18 '14 at 21:20
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    $\begingroup$ Hmm interesting theory. RBCs might be protecting the Fe from infectious microbes. I heard a theory that by infections the human body clears up Fe from blood, because microbes need Fe for multiplication, creating metalloproteins etc... I never investigated... :-) $\endgroup$ – inf3rno Oct 18 '14 at 21:36
  • $\begingroup$ @Chris thanks, this iron theory seems like really true. $\endgroup$ – inf3rno Oct 18 '14 at 21:48
  • $\begingroup$ Oh wow, thank you for your response. The 'iron protection' reason is a beautiful explanation :) I wonder if there are any other proteins with iron incorporated and whether they are protected as well, I'll try to look into it $\endgroup$ – Eva Oct 19 '14 at 6:09
  • $\begingroup$ @Eva Ofc. there are, e.g. transferrin, but by infection they are cleared from the blood (hepcidin regulates their level), but HGB cannot be removed, because it is the oxygen carrier, so you would drown in the lack of HGB... $\endgroup$ – inf3rno Oct 19 '14 at 12:29
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This is a well worded question. There are more reasons than the following but the most apparent is hemoglobin production and its transport. The erythrocyte is a cell whose structure is optimal for its function-the production and transport of hemoglobin.

It lacks a nucleus and organelles so that it can devote almost 100% of its energy to hemoglobin production. It has this bi-concave disk shape to increase its surface area thus increasing the exposure of hemoglobin to oxygen and CO2.

It's a small and flexible cell allowing them to easily maneuver the capillaries (where they work).

Because it's anuclear it has a short lifespan but they are rapidly produced and regulated by erythropoietin.

In order for tissues to receive oxygen and rid themselves of carbon dioxide there needs to be an orderly transfer and movement of hemoglobin from the tissues to the lungs and back-and-forth. Without this cycling of hemoglobin on the erythrocyte the protein would move more in the body through diffusive means. This would not promote the required segregation of oxyhemoglobin in the tissues and carbaminohemaglobin in the lungs.

Check out any edition of Anatomy and Physiology by Marieb. All editions have an entire chapter related to the subject

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    $\begingroup$ Thank you for your answer! I didn't know that hemoglobin is synthesized in RBCs, it makes more sense now. However, I still have a question: how do red blood cells help segregation? When gas exchange happens, is hemoglobin free in the tissue or still actually inside a cell? $\endgroup$ – Eva Oct 18 '14 at 17:41
  • $\begingroup$ Cause the hg is on the rbc, wherever the rbc is the hg is. Only the rbc can effectively be circulated, if was just swishing around the body too much hg would diffuse where it not needed in respect to oxyhemoglobin and carbonMinohemoglobin $\endgroup$ – rhill45 Oct 18 '14 at 18:27
  • $\begingroup$ Do you have any references for this? It seems unlikely to me that a red blood cell can produce haemoglobin without DNA or RNA (once it's degraded). $\endgroup$ – canadianer Oct 18 '14 at 18:27
  • $\begingroup$ It's not an easy concept because you have to think of the requirements of the whole organism additionally the requirements of specific regions of the body tissues versus Lungs. $\endgroup$ – rhill45 Oct 18 '14 at 18:28
  • $\begingroup$ Your claim about diffusion is interesting but, again, do you have a reference? $\endgroup$ – canadianer Oct 18 '14 at 18:29
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This is not an answer to the question, but tangent comments that might be useful for how you look at the problem (and too long for a comment). First, for a question like this it is useful to look at other solutions to the same problem. For instance, the second most common molecule for oxygen transport is Hemocyanin, and this is not bound to cells but is directly suspended in hemolymph (arthropod/mollusc "blood"). So specialized cell types for oxygen transport is not a necessity for effecient oxygen transport in rather advanced organsism. So your question; "why do we need cells packed with hemoglobin: why can't it travel freely in the bloodstream?", while being true for humans and other vertebrates, is not true for oxygen transport in all "complex" animals.

Second, while there seems to be good reasons for why hemoglobin is bound in RBC, you should at least entertain the idea that the cause of RBC-bound hemoglobin in vertebrates is an evolutionary contingency (i.e. a random historical event). Evolution is always constrained by previous evolutionary history, and the reason that all vertebrates (+ a number of other organsisms) share RBC-bound hemoglobin may simply be that they share a common ancestor. This does not mean that it lacks advantages, but it also means that it might be misleading to search for the reason for RBC-bound hemoglobin in a particular species. For some background on evolutionary contingencies and many useful references in the intro, as well as an interesting experiment to test for contingencies, you can have a look at Blount et al. (2008) (part of Lenski's Long-term Experimental Evolution project).

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I remember going to a chemistry lecture which mentioned this (the lecture was on blood transfusion in general).

The main reasons are:

1) Hemoglobin is toxic to the human body: Hb in RBCs is a tetramer, but in the plasma it breaks into two dimers --> toxicity in the kidneys. Hb needs modification by cross-linking or recombination. Wikipedia states that this is Acute Tubular Necrosis.

2) Hb in plamsa decreases osmotic pressure

3) Hemoglobin removes the NO from the vessel walls causing vasoconstriction, shrinkage of the vessels. --> this was the main focus of the chemistry lecture; there was a lot of talk about free radicals and stuff but I've unfortunately forgotten the details

I've also searched a bit on the web and some people (one yahoo answers) confirm rhill45's answer.

I think searching failed blood transfusion products (people have tried transfusing Hb directly) will be of great help.

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    $\begingroup$ Could you please add some references to support your response! $\endgroup$ – Bez Nov 15 '14 at 16:35
  • $\begingroup$ for 1) and 2) chm.bris.ac.uk/motm/mpg/whymod.htm for 3) I got the info. from a chemistry lecture I attended, so it's just personal notes $\endgroup$ – M Choy Feb 17 '15 at 12:55
  • $\begingroup$ See one of my references. It writes the exact same thing that Hg binds to NO. Removing NO from blood is a problem because NO is a gasotransmitter causing vasodilatation. So having less of it causes vasoconstriction. en.wikipedia.org/wiki/Gaseous_signaling_molecules#Nitric_oxide $\endgroup$ – inf3rno May 10 at 20:04

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