This chapter is most relevant to Section F1(i) from the 2017 CICM Primary Syllabus, which expects the exam candidates to be able to "describe the function and structure of the ...alveolus". A minimalist college comment to Question 15 from the first paper of 2016 reveals that the college expected some basic anatomical details and descriptions of how they influence alveolar function, but not any sort of extensive functional discussions, nor detailed diagrams, nor any mention of surfactant. A lot more detail was fortunately made available in the comments for Question 4 from the first paper of 2023, which was good, because only 14% of the candidates passed that question.
Structure and Function Relationships of the Alveoli
Alveolar macrostructure: large number of (mostly spherical) air spaces connected by septa
- Large surface area, to facilitate diffusion.
- The interconnected network of walls allows mechanical stress to be shared across a larger area of lung parenchyma (this is alveolar interdependence)
- Spherical in full distension, but folding along pleats with deflation to maintain surface area
Alveolar blood-gas barrier: a thin trilamellar membrane composed of three layers:
- Capillary endothelial cell
- Basal lamina
- Alveolar Type 1 cell
Short diffusion distance: 0.2-2 µm for the blood-gas interface
- Flexibility (facilitated by collagen and elastin fibres in the basement membrane)
- High permeability to gases, but low permeability to water, achieved by the lipid bilayer of the alveolar cell membrane
Elastic basement membrane, containing the septal interstitial fibre network:
- Axial collagen fibres
(from the hila along the bronchi and alveolar ducts)
- Peripheral fibres (from the visceral pleura via interlobular septa)
- Septal fibres (along the alveolar septa).
- Increases the elastic recoil of the distended lung
- Increases the resistance to atelectasis
Type I alveolar cells: thin cells with extended cytoplasmic plates which cover a large surface arrea
- Barrier function (very poor permeability to water-soluble substances)
- Gas exchange function (very high permeability to gases)
Type II alveolar cells:
- Secrete surfactant (which decreases the surface tension of the fluid on the alveolar walls, preveing their collapse)
- Act as stem cells to replenish Type I alveolar cells, which cannot replicate
Pores of Kohn: defects in alveolar septal walls
- Their main function is to allow collateral ventilation between alveoli
- This is another mechanism of matching ventilation and perfusion
Of the published literature the single best resource is probably Knudsen & Ochs (2018), which covers everything you could possibly need to know about this topic. This article has more information than the official CICM recommended resources, is better structured, and is free.
If one were to design the gas exchange surfaces of the lungs from scratch, one would have to satisfy several engineering specifications. In order to work properly, these structures need to have the following characteristics:
That last point is probably relatively important. One would not want one's respiratory epithelium to leak fluid all over their gas exchange surfaces. Even though the blood-gas barrier is composed of capillary endothelial cells as well as pneumocytes, that barrier function appears to be largely the province of Type I alveolar cells.
Alveoli are the basic unit of the gas exchange surface. In summary, the following things can be said about the alveolar shape and structure:
Like most things in medicine, our direct observations of alveolar shape come from cruel animal experiments. For example, Klingele & Staub (1970) got a hold of some cat lungs and ventilated them (just the lower lobes) with known increments of transpulmonary pressure. Then, we froze each lobe by inundating it for 2 min with liquid propane cooled to - 180 C in liquid nitrogen and transferred it to a cryostat at -40 C".
So, though they are depicted in most textbooks as little spherical sacks of gas, in reality this only holds true when they are well-inflated. To "borrow" this diagram from Gill et al (1979), one can see that one's alveoli are only vaguely spherical when they are distended, and in a collapsed state they take on a sorry folded-looking shape.
The point of this diagram is to impose upon the reader the significance of lung volume on alveolar shape and surface area changes. These little sacks do not undergo orderly sphere-like inflation as if they were a party balloon (which would have made their surface area predictable and easy to calculate). Instead, they are complex polyhedral shapes, which undergo volume change by folding along pleated septa (where the folds tend to be at the corners between alveoli).
After seeing the diagram above, it probably does not need to be said that alveoli are clearly not individual isolated air sacks but an interconnected honeycomb of cavities where each cavity shares its walls with several others. As such, changes to one alveolus affect the surrounding alveoli. This mechanism is variably known as "radial traction" or "alveolar interdependence". Discussion of this matter and its implications probably belong more in the chapters which relate to lung mechanics, but in brief:
If one were to inflate the usually flattened capillaries of the lung to make them more prominent, one might be able to depict the cells of the lung in this manner:
This diagram was put together from various sources, such as this electron microphotograph. If anybody is ever asked to describe the cellularity of the of alveoli in the form of an unstructured list, it might look a little like this:
Of these cell populations, for this lung-ish chapter the focus will be on Type I and Type II cells. It is sad that Ward & Nicholas' 1984 paper is paywalled by Wiley, because it is an excellent discussion of pneumocytes, but luckily their juiciest most examinable content is reproduced below in a minimally altered state.
Type I cells are incredibly complex topographically. A single cell body may have long flat plate-like extensions which may span across several alveoli branching out from the central nucleated region. Those plates are vanishingly thin and largely devoid of organelles (where would you fit them). Numerous micropinocytotic vesicles are seen in that membrane, but it is otherwise a fairly empty region of cytoplasm - which serves all the better to maintain its thinness, one might suppose. The diagram below contains a diagram of a Type I cell with six cytoplasmic plates and an informative SEM image of isolated Type I cells in culture. That latter picture is from Fuchs et al (2003) and shows them spreading across a plate, forming thin disks with centrally raised blobs containing the nuclei and all the other cellular machinery.
Given this morphological complexity, the mind boggles as to how a cell like this might undergo division. Along which line might it divide? Weibel (1974) expressed disbelief that they even divide at all, and on that basis advanced the hypothesis that they probably don't, and that their population is replenished by Type II cells, which turned out to be accurate (Barkauskas et al, 2013).
One might one day be asked in a viva to explain the function, rather than the structure, of Type I cells. What do these cells even do? Well. Two things: they do gas exchange and they do barrier function.
Gas exchange functions are discussed well enough in the section on the blood-gas barrier below, and without too many spoilers one can summarise that their main way of fulfilling that function is by being thin (200-500 nm in thickness).
Barrier function of the whole blood-gas barrier is mainly the effect of alveolar cells being poorly permeable, whereas the promiscuous pulmonary capillary endothelial cells seem to allow any damn thing into the alveolar interstitium. Capillary endothelial junctions are "maculi adherentes", leaky because they are full of gaps, whereas the alveolar epithelial junctions are "zonuli occludentes" and are tight with all sorts of interlacing ridges and overlapping grooves.
The most useful outcome of this is that your circulating blood volume does not immediately escape your body frothing through your lungs. To use a more scientific tone, experiments (eg. Wangensteen et al, 1969) show that the permeability of the overall blood-gas barrier to water and water-soluble solutes to be very poor. The investigators were somewhat surprised that the diffusion coefficient was relatively similar for all tested substances, including water (in the order of 0.5-2.3 × 10-5 cm2/sec), with permeability properties similar to those of a cell membrane. They came to the conclusion that the barrier was permeable by virtue of small, relatively non-selective leaks, probably some sort of water-filled pores.
This barrier function is not absolutely exclusive, as one can easily conceive of a situation where dissolved blood components might actually be needed inside the alveolus. For example, the alveolar epithelium transports immunoglobulins to the alveolar surface, so they may lay there like landmines waiting for pathogens. Proteins are also slowly absorbed from the alveolar surface and transported back into the blood, a mechanism which is thought to be responsible for some of the resolution of pulmonary oedema.
Type 2 cells are mainly functional rather than structural. They have two main roles: production of surfactant and proliferation to replace Type I cells. Structurally, these are unremarkable cuboidal cells, usually depicted as covered in microvilli (which are so small that they are usually only revealed by electron microscopy). The stolen image below depicts a Type II cell from a rat lung (Evans et al, 1973).
Probably the most prominent structural component of these cells after the nucleus are the lamellar bodies, so called because electron microscopy reveals them to be full of fine alternating layers. These are the vesicles which contain pulmonary surfactant.
Secretion of surfactant is probably one of their most important roles of the Type II cells. The properties of lung surfactant are interesting enought that they merit a chapter all to themselves, also having attracted the attention of college examiners (Question 6 from the second paper of 2012). It will suffice to say here that it keeps the alveoli from collapsing, and so without surfactant, all the other brilliant engineering solutions of the lungs would be pointless, and we should all just go back to gills.
Replenishment of Type I cells occurs as a result of injury or normal wear-and-tear. Type II cells clonally proliferated and transformed into Type I cells over the course of 48-72 hours when Evans et al (1973) blew nitrogen dixoide into the lungs of eleven rats. As they divide, the daughter cells hug the basement membrane and move under the adjacent Type I cell.
Maine & West (2006) published an excellent paper on this topic, which at the time of writing is somehow free from semanticscholar.org. The title of the paper is "Thin and Strong", which actually describes the minimal expected knowledge of its properties for the CICM exam candidate. To elaborate further on its properties would waste valuable cognitive bandwidth, which is of course in keeping with the unwritten mission statement of Deranged Physiology. Therefore, in summary:
According to Maine & West (2006), this design was so successful for the Silurian Dipnoi that the basic elements have remained largely unaltered in all the descendents ever since they dragged themselves out onto land. Presumably, the consistent lethal failure of anything different has defended this structure for millions of years. The authors describe these as Baupläne ("frozen cores") as "such constructions are probably the only feasible and practical solutions to exacting functional requirements".
The pulmonary capillaries and alveolar endothelial cells are essentially suspended in mid-air on a loosely woven hammock of fibroelastic tissue. This is the alveolar interstitial tissue, consisting of protein fibers and basal laminae for the endothelial and epithelial cells.
There is also a potential interstitial space bounded by the aforementioned basal laminae, which contains a network of collagen and elastin fibres. There are some fibroblasts lurking in there, of which a number have contractile properties. This potential space is not uniformly present in all alveolar walls, of which the thinnest have a joint basal lamina for both alveolar epithelial and vascular endothelial cells. About half of the total surface area is as thin as this, and the rest has a potential space to accumulate oedema fluid.
The collagen and elastin fibres stretch across this space in a purposeful manner. Elastic fibres are concentrated around the openings of alveoli like purse strings, and the collagen fibre network extends from the hila and from the visceral pleura. Axial collagen fibres extend from the hila along the bronchi down to the alveolar ducts, peripheral fibres extend inward from the visceral pleura via interlobular septal boundaries, and septal fibres connect the axial and peripheral networks by extending along the alveolar septa. The septal fibres are therefore under some tension when the lung distends, as they are stretched between the other networks. Weibel (2017) explains this much better, and with more helpful diagrams
These are basically holes in the alveolar walls, usually bounded by Type II cells. Their very existence was doubted during the earlier half of the 20th century, and it took electron microscopy (eg. Boatman & Martin, 1963) to confirm that they are actually a real and normal part of lung structure rather than an artifact of specimen processing or early lesions of emphysema. "The free edges are seen not
to be tears since the basement membrane passes intact round from the alveolar wall facing into one alveolus to the wall facing the adjoining alveolus. Furthermore, the basement membrane
is not denuded of epithelium" wrote Cordingley in 1972. In short, these are intentional defects in the alveolar septa.
The electron microscopy image above is from rat lungs investigated by Pastor et al (2006). The pores are the smallest of all the collateral ventilation passages, the others being interbronchiolar Martin’s
channels (30 μm in diameter) and bronchoalveolar Lambert’s channels (120 μm in diameter). Incidentally, "collateral ventilation" is what you call it when the ventilation of alveoli occurs via pathways that bypass normal airways (Terry et al, 2016).
Factoids one may need to learn about these pores for exam purposes include:
In textbooks (eg. the 8th edition of Nunn's), their functional significance is generally said to be "interalveolar air drift" (Reich & Abouav, 1965), or some variation thereupon. Given that they are clogged with lung surfactant, one might expect that the role of the pores of Kohn probably has more to do with cell migration between alveoli than gas exchange, but in fact these pores are not completely pointless as mediators of ventilation.
This hypothesis stands up to the test of comparative biology. For example, collateral circulation might be viewed as an additional mechanism of matching ventilation and perfusion; thus wherever such a mechanism is well-developed the reliance on other V/Q matching mechanisms (eg. hypoxic pulmonary vasoconstriction) is diminished. This is in fact exactly what you see in animals. Kuriyama et al (1981) reasoned that "if collateral ventilation helps keep interregional oxygen tensions homogeneous, then in its absence, local ventilation-perfusion balance must rely on arterial constriction", and tested this by looking at the muscularity of pulmonary arteries in animals, by way of measuring their propensity to develop pulmonary hypertension at high altitude. Cattle, with their thick septa and poor collateral ventilation, are highly prone to high altitude pulmonary hypertension, whereas dogs and sheep did not have this problem.