The primary role of the lungs is to ensure gas exchange between the external environment, and the blood within the circulatory system.

This happens thanks to a series of branching tubes called airways, which conduct the air down into small thin-walled sacs called alveoli, which are wrapped in an intricate network of tiny blood vessels called pulmonary capillaries.

And the alveolo-capillary membrane, where the layer of alveolar cells lining the alveoli meets the endothelial cells that make up the pulmonary capillary, is where gas exchange occurs.

Now, before we delve into diffusion, perfusion and their limits, remember that gas exchange across the alveolo-capillary membrane happens according to Fick’s law.

Fick’s law states that the net rate of diffusion - V of any particular gas across the alveolar-capillary membrane, is proportional to the pressure gradient across the wall; which is the difference between the partial pressure of the gas in the alveolar sacs, or PA, and the partial pressure of the gas in the blood, or Pa, and also proportional to the surface area of the wall, or A, but inversely proportional to the wall’s thickness - T. And this is all times the diffusion constant - D, which varies from gas to gas. V=(PA-Pa)ADT So, diffusion-limited gas exchange means that a gas like oxygen or carbon dioxide can diffuse across the alveolo-capillary membrane as long as the partial pressure gradient is maintained.

On the other hand, perfusion-limited gas exchange means that if the pressure gradient is not maintained, and the concentration of gases on the two sides of the alveolo-capillary membrane becomes the same, further gas exchange is only possible by increasing blood flow, or perfusion, in the pulmonary capillary.

To understand these concepts, let’s look at a section of an alveolar sac, with a pulmonary capillary running along its surface.

The capillary carries mixed venous blood, which is low in oxygen and high in carbon dioxide. As blood passes along the alveolar capillary wall along the length of the capillary, it exchanges some gas molecules with the interior of the alveolar sac.

Let’s look at perfusion-limited gas exchange first. In this case, the total amount of gas that diffuses into the blood depends on the amount of blood flowing through the pulmonary capillaries around the alveoli.

The best example to illustrate this is by using Nitrous oxide, or N2O gas. So imagine we’re inflating the alveolar sac with nitrous oxide, and that its partial alveolar pressure, noted as PAN2O is constant.

At the beginning of the alveolar-capillary contact, the partial pressure of nitrous oxide in the pulmonary capillary blood, or PaN2O, is zero, because this gas doesn't initially exist in the blood.

According to Fick’s law, this pressure gradient makes nitrous oxide molecules from the alveolar sac rapidly diffuse into the pulmonary capillary.

Within the blood, nitrous oxide molecules don't bind to hemoglobin or other blood components, so all the gas molecules are free in the blood, which makes the partial pressure of nitrous oxide in the pulmonary capillary blood rise quickly.

In fact, this happens so fast that by the first one-fifth of the capillary length, the equilibrium between the partial pressures on both sides of the alveolo-capillary membrane is already attained.

At this point, the partial pressure gradient falls to zero, so nitrous oxide diffusion stops. In this situation, the only way to increase the net diffusion is to increase blood flow through the pulmonary capillary.

Increased blood flow rushes nitrous-oxide rich blood through the capillary, and brings in new blood with no or less nitrous oxide in it, restoring the partial pressure gradient.

Another example of perfusion limited gas exchange can be illustrated by oxygen, but only under normal circumstances - so this doesn’t apply during strenuous exercise, or in the case of lung disorders like fibrosis or emphysema.

Just your regular, run of the mill oxygen diffusion. Alright, so at the beginning of the alveolar-capillary contact, the partial pressure of oxygen in the alveoli, or PAO2, is higher than that which comes within mixed venous blood in the pulmonary capillaries, which is noted as PaO2.

This creates a partial pressure gradient, which makes oxygen diffuse into the blood. As the process continues, the partial pressure of oxygen in the pulmonary capillary blood rises, but not as quick as with nitrous oxide.

This is because, unlike nitrous oxide, newly diffused oxygen molecules bind to hemoglobin in red blood cells, so first, all hemoglobin molecules have to become saturated with oxygen, before free oxygen molecules appear in the blood and PaO2 increases.

This pushes the point of equilibrium between PAO2 and PaO2 at around one-third of the capillary length, a bit further compared to one fifth in N2O.

From here onwards, unless the rate of blood flow increases to bring in more of oxygen-hungry blood, no more net diffusion of O2 can occur.

Video - Diffusion-limited and perfusion-limited gas exchange

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