Paper - The development of the terminal air passages of the human lung

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Barnard WG. and Day TD. The development of the terminal air passages of the human lung. (1937) J. Pathol. and Bacteriol. :57-73.

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This historic 1937 paper by Barnard and Daydescribes the development of the terminal air passages of the human lung.




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The Development of the Terminal Air Passages of the Human Lung

W. G. Barnard And T. D. Day.

London County Council Central Histological Laboratory, Archway Hospital.

(PLATES XV. AND XVI.)


Maximow and Bloom (1934), in discussing the possibility of an epithelial lining in the alveoli of the lung, stated that a study of the later stages in development would probably throw light on its nature and existence. It is certain that whereas in the early foetal lung the embryonic Anlage of the air passages is completely lined by an obvious epithelium, in the adult such an epithelium can only be indisputably seen in the bronchi and the distal branches of the bronchial tree. It was therefore decided to study embryos from the third month onwards, with a view to tracing the changes in development which lead to such a striking alteration in the histological picture and to the apparent disappearance of the epithelium from the terminal air passages in the adult. '


Material studied. This consisted of lungs from human foetuses. Of these 48 were sufficiently well preserved to warrant histological examination. The lungs were fixed within from half-an-hour to 24 hours of the cessation of the heart beat. It was impossible to obtain the exact age of many of the foetuses so that this had to be deduced from their length and stage of development. In the 1-3 months group (length up to 9 cm.) there were 7, in the 4-5 months group (length over 9 and up to 17 cm.) 9, in the 5-6 months group (length over 17 and up to 27 cm.) 20 and in the 6-7 months group (length over 27 and up to 34 cm.) 10. Lungs from 2 fresh, still-born, 6-month foetuses who had made some attempts to breathe were also examined.


In the earlier months the lungs conist of undifferentiated mesenchyme containing a few capillaries, and bronchi represented by a few scattered tubes. During the third month of foetal life the lung consists of relatively large tubular spaces lined by pseudo-stratified columnar epithelium separated by an abundant mesenchyme (fig. 4). In the latter are a few blood vessels and capillaries. At the fourth month there occurs a differentiation of the epithelium into two kinds. The larger spaces are still lined by pseudo-stratified columnar epithelium; some are surrounded by cartilage and smooth muscle and closely resemble the adult bronchi in structure. Continuous with these are numerous smaller branching tubules which end in almost spherical vesicles. The epithelium lining these small branches and the terminal vesicles is quite distinct in appearance and differs entirely from that lining the foetal bronchi. The cells are approximately cubical, with prominent outlines, and they lie side by side in diagrammatic fashion (fig. 1). In sections of ordinary thickness they show no tendency to be superimposed upon one another. The nucleus is spherical and in sections stained with haematoxylin and eosin, the cytoplasm is for the most part unstained. In sections stained by Best’s method the cytoplasm co\ntains abundant bright red material, presumably glycogen. It is emphasised that epithelium of this type is never found in the adult. According to the plane of the section the vesicles appear as rings of epithelium and also as plaques of cells, a similar appearance to that seen in sections of the vesicles in the thyroid gland. The continuity of the vesicles with the bronchial epithelium was proved by direct observation and also by the fact that fluids injected into the trachea at moderate pressure may be seen in sections to h.ave filled both bronchi and vesicles. The mesenchyme between the epithelial groups is still abundant but there is an increase in the number of differentiated blood vessels which it contains. Around the vesicles it is usually possible to make out a local concentration of concentric spindleshaped cells.


At the end of the fourth and beginning of the fifth month there is an increase in the branching and ramification of the epithelial tubules and their terminal vesicles, with proportional decrease in width of the space between them. Undifferentiated mesenchyme is still abundant but capillaries are far more numerous. The concentric spindle-shaped cells around the vesicles are now mostly seen to be the endothelial cells lining the capillaries (fig. 2).

During the fifth month the capillaries around the vesicles are more prominent and the intimate relationship of the blood vessels and the epithelial vesicles resembles that of a ductless gland. Towards the end of the fifth month, however, a most unusual change in the inter-relationship of the vascular and epithelial elements occurs. The vesicles up to this stage are lined by a single layer of epithelium which separates their lumina from the vascular mesenchyme outside, but from now onwards the capillaries may be seen to encroach more and more upon the epithelium (fig. 2). Some loops penetrate between the epithelial cells to reach the lumina of the vesicles, which are thus changed from simple spherical structures to lobed vesicles and these when artificially expanded resemble adult alveoli.


FIG. 1. Lung from human embryo in the fourth month, showing grouping of capillaries around and immediately beneath the epithelium of the terminal vesicles.

FIG. 2. Lung from embryo in the early fifth month. Here the capillaries have pushed between the epithelial cells and reach the lumina of the vesicles.

FIG. 3. Lung from a. six-month foetus. The capillaries now project into the vesicles, dividing them into irregular spaces corresponding to the adult alveoli.


At the sixth month the branching of the epithelial tubules reaches its maximum. With the increase in their number the spaces between them become diminished and are occupied almost entirely by blood vessels and capillaries (fig. 3). The tendency for the capillaries to penetrate the epithelium becomes more marked and towards the end of the sixth month the epithelium degenerates and desquamates into the lumina of the potential air spaces (fig. 6). As the result of these two processes~—encroachment of capillaries and desquamation of epithelium—the potential air spaces come more and more to be lined by capillaries and no longer by epithelial elements. From this time onward, when breathing has occurred, the terminal air passages take on the adult appearance of irregular spaces communicating with the bronchioles. The walls of these spaces are composed of blood vessels and connective tissue fibrils. Although a few epithelial cells may still be seen in sections of lungs of full—term still births (fig. 5), in infants which have breathed for any length of time no trace of the epithelium can be found.


It is clear that the lung does not change essentially in structure after the stage reached by the end of the sixth month. It is at this time in a condition in which the act of breathing alone will transform it rapidly into a structure in all essentials the same as that of the adult. It was found moreover that by inflating foetal lungs artificially by suction in a closed chamber (artificial thorax), with or without simultaneous perfusion of the pulmonary artery, it was quite impossible to transform the appearance of immature lungs very materially. During and after the sixth month such procedures increased the similarity of the lung structure to that of the adult to varying degrees. It may be remarked parenthetically that this period roughly corresponds to that at which the foetus is capable of an independent existence.


Rose (1928), in his study of the development of the lung, came to the conclusion that the terminal air passages were entirely composed of mesenchymal elements, the most important being vascular endothelium. This view is borne out by the observations recorded above. It has also been possible to show the precise manner in which the state of affairs in the adult lung has come about. The role of the epithelium which lines the primitive air passages appears to be solely that of canalisation. When the maximal degree of canalisation has been attained, the epithelium lining the primitive vesicles degenerates and under normal circumstances does not reappear. In pathological circumstances it is well known that the terminal air passages may again become lined by an obvious epithelium. This change is frequently found to be associated with immobilisation of the affected parts of the lung. The epithelium, however, does not resemble that described above in the foetus but rather that of the adult bronchiole. In some cases it is possible to trace the continuity of the new epithelium with that fining the bronchi. It is suggested that just as the mobility of the lung due to breathing plays a part in displacing the original epithelium from the infant’s lung, immobilisation of the adult lung allows the ingrowth of bronchial epithelium into the static air spaces.

Discussion

It is interesting to note that the earlier observers, e.g. Rainey (1855) and Zenker (1862), did not describe an alveolar epithelial lining. They believed that the capillaries were in direct contact with the alveolar air. Many investigators appear to find it difficult to consider this possibility, but that this direct contact of air and capillaries can occur is clearly seen in birds. Here the walls of the capillaries form the alveoli and we have not seen, nor have We so far been able to discover any description of, an epithelial lining in avian lungs. The first descriptions of alveolar epithelium in human lungs came as the result of injecting silver nitrate in various strengths into the bronchi and cutting thick sections of the lung. Under these conditions an appearance suggesting lining can be made out. Maximow and Bloom (1934) considered the appearance was artificial and pointed out that a similar appearance could be obtained if thick sections were cut and stained by Bielschowski’s method for fibrous tissue. We also have failed to demonstrate it in the least diseased parts of eleven lungs or parts of lungs fixed immediately after removal at operation.

It would appear therefore that these descriptions of the alveolar epithelium are a result of faulty technique. We have carried out a number of experiments in our attempts to demonstrate an alveolar epithelial lining. We have fixed lungs, both in the body and immediately after removal, by fixatives passed down the bronchi or injected into the blood vessels, but have failed to show anything which could be described as an epithelial lining. Our experiments were carried out on lungs from patients of various ages, most of whom had been dead from two to four hours. All had died as a result of accident or from some condition not directly affecting the lungs.

In View of our failure it would be as well to suggest some reasons for the widespread belief in such a lining, which is still held in spite of the fact that the majority of those who hold it have also failed to demonstrate the epithelium. The reason most commonly given for the belief in an alveolar epithelium is that in various chronic inflammations of the lung, spaces can be shown lined by low cuboidal cells and it is argued from this that these lining cells must have developed in situ. It is impossible in most cases to prove that the spaces are in fact alveoli. Even should they be alveoli it is impossible to exclude downgrowth of epithelium from terminal bronchioles. The one thing which appears certain is that when these spaces are observed they are no longer functional alveoli. It appears to us as reasonable to base the normal histology of the kidney on organs the seat of chronic nephritis or to work out the normal distribution of bile ducts from fibrotic livers as to attempt to prove an epithelial alveolar lining from observations based on fibrotic lungs.


FIG. 5. Lung from a full term still-born foetus.


PLATE XVI

FIG. 4. Lung from a twelve - week foetus. The pseudo-stratified columnar epithelium in the bronchi and the abundant undifferentiated mesenchyrne are shown. The problem consists in tracing the changes responsible for transforming the appearance as shown here to that shown below.


FIG. 6. Lung from a six—month foetus. The lung was fixed within half-an-hour of cessation of the heart beat. The desquamated degenerate epithelial cells are clearly shown in the centre of the picture.


In a series of interesting experiments, Young (1928) showed that by chemical stimulation the endothelium of the pleura could become cubical, columnar and even stratified squamous—appearances which made it indistinguishable from epithelium. In the course of these experiments he found that the alveoli immediately beneath the endothelium became lined by cubical epithelium. He stresses the ability of the endothelium to assume all the characters of epithelium, but when he mentions the changes in the alveoli he suggests that these prove that the alveoli must be lined by epithelium. Cappell (1929, p. 677), in his research on reticulo-endothelium, accepts Young’s view and although he says that the cuboidal cells of the alveoli behave exactly as the Kupffer cells of the liver, yet he too suggests that they must be epithelial. These experiments, particularly those of Young, have been advanced as evidence to support the view that there is a lining epithelium in the alveoli. We submit that the evidence no more supports that view than it does the view that the pleura is covered by epithelium and not endothelium and yet, as far as we know, no such View has been advanced.

As has been shown by Young, endothelial cells can assume characters indistinguishable from epithelium and this power is also shown in malignant growths of the cells lining the peritoneum and pleura and in inflammatory lesions of these membranes. So that if under abnormal conditions alveoli in the lung are lined by epithelium—like cells, this would not in itself prove that they were in fact epithelial or that they were derived from pre-existing epithelial cells.

It is stated by Kolliker (1881), Ogawa (1920) and others that the alveoli are lined by non-nucleated epithelial squames. If they were so lined it would be pertinent to ask what happens to the squames when they are shed. It would be even more important to know how they are renewed. The total surface area of the lung alveoli is about 90 square metres (Halliburton, 1917) and it seems inconceivable that all these squames should be constantly shed and renewed without leaving the least trace of their presence or activity. In serial sections of fixed fresh lung tissue we have been unable to find them. Their renewal could only take place by lateral outgrowths from the epithelium in the terminal respiratory bronchioles. We have been unable to find evidence of this and if it occurs it would be unlike the renewal of epithelium anywhere else in the body.

It is possible that considerations of function lie behind the reluctance to abandon the idea of an epithelial lining. The possibility that under exceptional conditions oxygen is secreted into the blood has not been disproved and so a secretory epithelium has been postulated. A specialised capillary endothelium might be as effective as epithelium if secretion is necessary, and for simple diffusion of gases the thinner the wall separating the red cells from the alveolar air the better. When studying sections it is often difficult to remember that in life the lung alveoli are in constant movement. They expand and collapse about fifteen times a minute. In no other part of the body is there an epithelial lining contracting and expanding in this manner.* There is a too general tendency to regard the lung as a glandular organ, whereas in fact it is primarily a vascular organ and a part of the cardio-vascular system. The bronchi and their appendages are only necessary to allow the passage of air from the outside to the alveoli and to regulate the temperature and condition of that air which will come into intimate contact with the capillaries. The majority of the investigators of the histological structure of the lungs have paid so much attention to the epithelial structures that they appear to have largely ignored the vascular elements. We suggest that it would have been unnecessary to postulate acontinuous epithelial lining in normal lung had due allowance been made for the capillaries, their endothelium and the necessary though scanty reticulum which holds them together.

Summary

Based on the examination of the lungs of 48 human foetuses, the development of the terminal air passages is described and it is shown that their epithelial lining begins to disappear towards the end of the fifth month of embryonic life and does not reappear.

References

CAPPELL, D. F. . . . . . 1929. this Journal, xxxii. 675.

HALLIBURTON, W. D. . . . 1917. Handbook of physiology, 13th ed., London.

K6LLII{ER, A. . . . . . 1881. Verhandl. der Physikal.-Med. Gesellschaft, Wvlirzburg, Vol. xv., p. xii.

The absence of movement may well play an important part in the production of lined spaces in diseased lungs or in lungs following experiments.

MAXIMOW, A. A., AND BLOOM, 1934. W. OGAWA, C. 1920. RAINEY, G. 1855. ROSE, S. B. 1928. YOUNG, J. S. 1928. ZENKER, F. A. 1862.

A text-book of histology, 2nd ed., Philadelphia and London, pp. 456 and 463.

Amer. J. Anaz., xxvii. 333.

Brit. and Foreign Med.-Ohir. Rev., xvi. 491.

Arch. Path., vi. 36.

this Journal, xxxi. 265.

Beitrage zur normalen und pathoIogischen Anatomie der Lunge, Dresden.


Cite this page: Hill, M.A. (2018, December 11) Embryology Paper - The development of the terminal air passages of the human lung. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Paper_-_The_development_of_the_terminal_air_passages_of_the_human_lung

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