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I have decided to take early retirement in September 2020. During the many years online I have received wonderful feedback from many readers, researchers and students interested in human embryology. I especially thank my research collaborators and contributors to the site. The good news is Embryology will remain online and I will continue my association with UNSW Australia. I look forward to updating and including the many exciting new discoveries in Embryology!

Addison WHF. and How HW. On the prenatal and neonatal lung. Amer. J Anat. 15(2): 199-214.

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This historic 1913 paper by Addison and How describes respiratory development prenatal and neonatal period


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On The Prenatal and Neonatal Lung

William H. F. Addison And Harold W. How

The Anatomical Laboratory of the University of Pennsylvania

Eight Figures


Introduction

Of the various changes occurring in the lung at birth, we have studied especially the increase in size of the spaces within the respiratory lobules, and the change in the character of the contents of these spaces. Whenever this portion of the lung's history is considered, the statement is made that, with the first pulmonary inspirations after birth, the spaces become distended, but we have found no data expressing the amount of this distention. As to the question of the existence of fluid contents in the spaces of the prenatal lung, it is seldom mentioned in current literature, although it would seem to be of importance, especially in connection with the beginning of breathing.


In making comparisons, we have used material from experimentally controlled animals, in order to obtain specimens of prenatal and neonatal lungs, which would be comparable in all respects. This was done by using animals of the same litter, of which some had breathed, and others had not breathed.

Literature

Measurements made on the minute parts of the lung have been recorded by a comparatively small number of investigators. Friedrich Merkel, in Bardeleben's Handbuch ('02), reproduces from Rossignol ('46) a table of sizes of lung alveoli at different ages. The first item in the list gives the mean size of alveoli of newborn children which have not breathed, or have breathed only a few hours. It is exactly between these two classes of individuals that we have sought to study the differences. Kolliker made numerous lung measurements but apparently none directly contrasting the two conditions seen in the prenatal and postnatal lung. ^Miller's ('95) table of sizes of the various air-passages in dogs is from material of one stage only. Concerning the phenomenon of expansion from a more general point of view, there are many observations. For instance, the fact that all parts of the neonatal lung do not expand equally has been recorded a number of times. Dohrn ('91) says that at least two days are required to unfold the lungs completely. Jalan de la Croix ('83), found in the lung of a child which lived seven days groups of alveoli which persisted airless. In dealing with the lung of children which have survived only a few days after birth, there is the possibility, however, of the organ being prematiu'e or pathological, and either of these conditions would affect its expansion. The question of the contents of the spaces in the fetal lung has for the most part been referred to only incidentally, by observers interested in premature respiratory movements. The experiments recorded by Preyer ('85) in his "Specielle physiologie des embryo," are the most definite we have found, and these will be referred to later.


A complicating factor in studying the appearance of the normal fetal lung is the possible occurrence of intrauterine respiratory movements. These have been described in the study of living human fetuses by a whole series of clinical observers (for instance, Ferroni '99) and have even been recorded by means of tracings. The current opinion as expressed by Howell ('11) is that the mammalian fetus under normal conditions makes no respiratory movements while in utero. Ballantyne ('02) in his Antenatal pathology and hygiene" accepts the results of the clinicians, but says it is doubtful if such movements are strong enough to draw liquor amnii into the lungs. It would also seem from our experiments that if these movements are really similar to respiratory movements, the}^ are not to be compared in point of intensity with the postnatal efforts, and do not affect the structure of the lung to any extent.


Method of Preservation of Material

In order to preserve, as nearly as possible, the normal relations of the lung to surrounding structures, and to prevent its collapse, all animals were injected with 5 or 10 per cent formalin, either through one of the umbilical vessels, or through the aorta, without opening the thoracic cavity. After the lungs had hardened in situ, portions were removed, embedded in paraffin or celloidin and sectioned.

Contexts of the Spaces \Mthix the Fetal Lung

When a living fetus, near full-term, is exposed within the uterus, with the amniotic sac still unruptured, it can readily be stimulated to make respiratory movements. The angles of the mouth begin to twitch, and are drawn slightly upwards, the abdomen enlarges, evidently due to the descent of the diaphragm, and almost simultaneously the nostrils dilate, and the mouth slightly opens in a yawning manner. The result is the drawing into the respiratory tract of the amniotic fluid. We found that the mere manipulation necessary to expose the fetus is sufficient to bring about these movements, if the animal is very near the end of gestation. A surer method is to clamp the umbilical cord, but neither method will act if the animal is not sufficiently advanced in its development. Several have previously recorded the above or similar observations. Winslow is quoted by Preyer as having written in 1787, Liquorem amniirespirare videntur." Leclard ('15) clamped the neck of a still living fetus, and on opening the trachea found there a fluid analogous to amniotic fluid. When a colored fluid had been injected previously into the amniotic fluid that in the bronchi was likewise colored. Preyer ('85, p. 148) repeated and verified Leclard's experiment with a guinea-pig near the end of gestation. He found that the fuchsin which he injected into the amniotic sac not only colored the lips, tongue, palate and all the pharynx, but also the lungs and the inside of the stomach. Geyl ('80) added to the experiment in the following manner. With all aseptic precautions, he injected aniline blue into the amniotic sacs of seven fetuses of a rabbit, which was nearly three weeks pregnant. Three days later the seven young were born, three dead and four alive. The three former had their lungs colored blue, as had also one of the latter. While there is no doubt that liquid is present within the lungs after these inspirations of amniotic fluid, none of the observers have directed their attention especially towards seeing the contents before such inspirations had taken place. One can easily deduce that liquid is present all the time during the development of the fetal lung, but in order to obtain, if possible, direct evidence several simple experiments were performed. The first series was with large sheep fetuses, obtained from an abattoir, with membranes and uterus intact. In two cases the following procedure was followed. The uterus was opened, and the fetus, 35 cm. in length, exposed within the unruptured amniotic sac. By means of a needle carefully passed through the amnion, a strong ligature was drawn through the tissues of the neck of the fetus, behind the trachea, and out of the amnion again at the point of entrance. With the head of the fetus covered by the amniotic fluid, the ligature was tied tightly and the trachea constricted. Our special aims were to prevent liquid escaping from the amniotic sac and air from entering it. The trachea and lungs were carefully dissected out, without injuring the visceral pleura, and placed in a large jar of water, from which all air-bubbles had been previously removed. After they had been allowed to sink to the bottom of the jar they were agitated in order to remove adherent air. Different parts of the lung were then cut with scissors and crushed. A yellowish-red fluid escaped from the crushed masses of tissue and diffused through the water but no bubbles were seen to escape.


In a third sheep fetus the trachea was ligated at its upper and lower ends and then dissected out. The closed segment of trachea was carefully cleaned and dried, before being opened over a dry glass plate. It was found to contain a faintly yellowish slightly viscid fluid, which was pressed out on the plate. When this fluid was tested with acetic acid there was a reaction showing the presence of mucin. The bronchi contained a similar fluid, and when the lungs were compressed this fluid was forced out.


In order to secure histological material for a study of the normal appearance of these lungs, another fetus of approximately the same size was injected through the umbilical vein with 10 per cent formalin. Later the thorax was opened and after the relations of the lung were observed, pieces of the lung were taken for histological sections. The appearance as evidenced by characters to be described later, was that of a lung which had not made premature respiratory movements.


The second series of experiments were repetitions of the foregoing, performed on a litter of living dog fetuses lying within the uterine horns of the mother. The parent animal was anesthetized and the young carefully exposed one at a time without unnecessary manipulation. In order to prevent the entrance of amniotic fluid, due to premature respiratory movements, the trachea of each fetus used was clamped with an artery forceps as soon as it was exposed and before the amnion was ruptured. As a result of this stimulation the animal at once began to make violent efforts to breathe, but if the trachea was well clamped these were ineffectual and the animal soon died of asphyxiation. The lungs were removed as described for the sheep fetuses, and experiments carried out in a parallel way. The results were similar to those of the first series, so it may be concluded that normally in the fetal trachea, bronchi and lungs there exists a liquid which resembles the amniotic fluid in appearance. The question arises as to what becomes of this liquid when breathing begins. From observations on fetuses removed from the uterus, the first act in breathing is always inspiration. As the lung enlarges, due to the contraction of the diaphragm and other respiratory muscles part of the liquid in the upper parts of the tract is drawn downwards and part remains distributed along the walls of the air-passages. When the fetus inspires amniotic fluid before its removal from the sac, it is always much handicapped. It does not breathe so strongly, and its efforts become weaker, and farther apart until they cease altogether. If in these circumstances, as we tried with young dogs, the animal be held with head downwards, and the thorax compressed at short intervals, the difficulty in breathing is often relieved, and the animal improves and lives. As is known from both clinical medicine and expierimental studies, the lung has a marked capacity for the absorption of liquids, and the quantity of fluid present in normal birth is readily disposed of.

Material for Breathing And Non-Breathing Lung

In order to secure examples of the breathing and non-breathing lung which would be strictly comparable, we used pregnant dogs near the end of the gestation period. By the manner described in experiment on the contents of the prenatal lung, some of the fetuses were removed and not allowed to breathe. Others were removed from the membranes as quickly as possible, before any attempt at breathing had been made. After the umbilical cord was tied and severed, they were laid in a warm place. They soon showed signs of activity, crying and crawling about. These were etherized at the end of an hour, and injected with formalin. Fetal material was also obtained by etherizing the parent animal after several fetuses had been taken out and allowing the remainder of the young to die before removing them. For comparison with the new-born, pups two days old were used, and these were injected with formalin through the abdominal aorta.

Study of Prenatal Lung

The appearance of sections from the fetal lung obtained in the above described manner is shown in figures 1 and 2, The texture of the organ is quite gland-like, with the mesenchyme framework present in large amount. The spaces are variable in size and shape on account of the structures being cut in different planes of section, but the distribution of the spaces is fairly uniform. In order to study the relative area occupied by lung tissue and the intervening open spaces, drawings were made with the Edinger drawing apparatus, on cross-ruled millimeter paper. Various magnifications were used, varying from 60 to 220. The results of a series of such drawings showed that the percentage of area occupied by lung tissue was 70 to 80 per cent and by the intervening spaces 20 to 30 per cent. In view of this condition it does not seem correct to call the fetal lung 'solid,' as do some of the present-day text-books of physiology and pathology. On the other hand, it is very easy to increase the size of the spaces artificially. In J. AI. Flint's paper on the development of the lungs ('06), he has an illustration of the lung of a fetal pig 27 cm. long, which is a stage shortly before birth. For the purpose of preservation the lung was injected intra-tracheally with the fixing fluid and this fact is responsible for the appearance of the lung in section. The appearance resembles very closely that of a lung which has breathed, as one can see by comparing it with his next figure, no. 29, that of a two-day-old pig. This is because the spaces were distended by the injection of the fixing fluid and indeed, as we found with sheep fetuses, relatively little force is required to distend the fetal lungs when introducing fluid through the trachea. In consequence of this distention the lining cells of the respiratory lobules are artificially stretched and flattened and no longer show the normal condition.



Fig. 1 Fetal lung of dog. at end of gestation. X 62.

Fig. 2 Fetal lung of dog, at end of gestation, with the granular reticular substance in the spaces, and two of the free mononuclear cells. X 280.


When the spaces are examined they are seen not to be entirely empty, but to contain here and there light pink-staining irregular masses of a finely granular substance. This is apparently a precipitate derived from the liquid existing within the spaces, and was clearly seen at the period just before birth in all well-preserved fetal lungs not only of dog, but also of cat, rat and man. The origin of the mucin constituent of the fluid is at least partly from the goblet cells of the trachea, for in sections of the latter we found them numerous and characteristically stained. Mention may also be made of conspicuous large rounded cells lying free within the spaces. They are distributed rather evenly but not in large numbers, and usually occur singly. They measure 11 to 14 At in diameter, and have a single nucleus which is eccentrically placed. The nucleus may be round, oval or indented, and varies from 6 to 7 /x in its greatest dimension. If flattened in shape, the width is 3 to 4 ix. These cells in the dog have a distinctly granular cytoplasm, which stains well with eosin. They probably belong to the same variety of cells as those present in the air-spaces of the normal breathing lung which take part in removing carbon particles and other foreign matter from the alveoli. In the fetal lung they may have the similar function of removing cellular debris, from the liquid-filled spaces. They also resemble the 'heart-failure cells' of the lung which are seen in certain pathological conditions. Several views are held as to the nature of these phagocytic cells in the breathing lung, but the study of these very similar appearing cells in the fetal lung, leads one to agree with Kolliker ('02 vol. 3, p. 310), that they are a form of 'Wanderzellen,' and not desquamated epithelium.

Neonatal Lung One Hour Old

When the respiratory muscles first begin to act at the beginning of neonatal life, the thoracic cavity is enlarged. In consequence of the relation between thorax and pleural sacs the lung is likewise enlarged and inspiration is the result. With the increase in size of the lungs to occupy a larger volume, the framework of the organ is stretched and put on a tension, while the spaces become larger. This is easily apparent when one compares figures 4 and 3, showing the lung of a dog which had breathed one hour, and a fetal lung respectively. By examining sections across the entire lung and sections from different regions, it can be seen that expansion does not take place equally in all parts of the lung, nor in any particular area do all the alveoli and airsacs increase alike. As a result it was not easy to arrive at a quantitative estimation of the area of lung-tissue and of the air passages, as seen in the sections. In regions, which had not been much inflated, and did not appear much more open in character than fetal lung, the framework still occupied 60 per cent of the total area. But in regions where the respiratory channels were more dilated, it occupied only 40 per cent or in restricted areas even less. Thus there is a variation in the ratio, but in general it may be said that the tissue occupies 40 to 60 per cent of the area of the cross-section. The fact that the lung does not expand at once after birth was seen also in newborn albino rats. These were obtained from The Wistar Institute of Anatomy with the aid of Dr. Stotsenburg. These young were taken immediately after birth, before they were dry and before they had begun to feed. Examination of their lung (fig. 6) shows that some areas have been inflated very little, in contrast with other parts, which are quite expanded.


A careful examination shows that the granular reticular substance may still be found usually lying in contact with the walls of the air-spaces. Its presence here indicates how the fetal liquid is disposed of when breathing commences. When the lung expands and the fluid in trachea and bronchi is drawn downward, part of the fluid remains adherent to the inside of the walls. In many sections it appears that more of the granular precipitate is seen in the peripheral portions of the lobes, immediately under the pleura, as if more of the liquid had found its way to the ends of the lobules.



Fig. 3 Lung of albino rat, one-half hour after birth, showing partial expansion. X 25.



The large mononuclear cells which were seen scattered about in the fetal lung are now difficult to find, although they may still be seen by searching. In comparing the prenatal and neonatal lungs of kittens and other litters of dog, this same condition was noted.

Lung of Two-Day-Old Dog

The structure of the lung at this stage resembles, in general, the mature lung. Reference to figure 5 shows the texture to be very open in character. By means of outline drawings on crossruled millimeter paper the framework is found to be only 20 to 30 per cent of the entire area, the open spaces constituting the remainder 70 to 80 per cent. As the lung enlarges with the further growth of the animal, the spaces still further increase. As it is generally expressed, the growth of the lungs does not keep pace with the growth of the thorax, as a whole, and consequently the framework of the lungs becomes more and more stretched, and the spaces are thereby also enlarged.

In the study of the lungs of these prenatal and postnatal animals other points are seen. The behavior of the lungs when the thorax is opened is different in animals which have breathed, and those which have not breathed. In the former the lung retracts quickly into the dorsal parts of the thoracic cavity, while in the latter little change takes place. The best method for comparing the positions of the lungs within the chest cavity, in these two conditions, is to inject the blood vessels with formalin without opening the thorax. It is true that the formalin causes a swelling of the tissues of the organs, but the relations are well preserved. When one opens the thorax under these conditions, the fetal lung is found not to extend so far forward and not to cover as much of the heart as the postnatal lung, but in general the relations are very similar. The differences are the result of the increase in size of the lungs due to inspiration, while the size of the other organs remains the same.


The fetal lung is opaque, and dense-looking, being often compared in consistency with the thymus. Its color is dull grayish-red. The breathing lung has a translucent pinkish color due to the greatly increased flow of blood, and to the presence of air. It floats upon water in contrast to the non-breathing lung, and this is utilized as a medico-legal test. When the breathing lung is moved between thumb and finger, the characteristic crepitations are elicited.


In sections the postnatal lung shows congested blood-vessels, in striking contrast with the fetal lung, which shows but little blood. It w^ould seem from examples of lung, which we obtained from still-born animals, that the increased flow of blood begins immediately, when the thoracic cavity is enlarged under the action of the muscles. These examples were from kittens, which were born at full-term. Tvvo of them were found with the fetal membranes intact, and had never breathed air, while one of the litter had breathed freely. In the lungs of the non-breathing animals, the spaces were distended slightly more than in the normal fetal lung and the blood-vessels were much congested. The animals had evidently tried to begin to breathe air, but had only succeeded in inspiring the liquor amnii. It would appear that, as soon as the negative pressure commences, more of the blood stream is deflected into the pulmonary arteries, less going through the ductus arteriosus, and this occurs irrespective of what is being drawn into the lung spaces.

Appearance of Lung of Prematurely Born Animal

An important factor in the expansion of the lung is the stage of development of the fetus at birth, that is, whether it is prematurely born or not. In a kitten born one week before the remainder of the litter, we had an opportunity of seeing this condition. This kitten had the appearance of a healthy normal annual, although somewhat undersized. It crawled about and cried vigorously when disturbed but lived only about twelve hours. Sections from the lung of this animal showed evidence of the struggle to start and maintain respiration. The general appearance is given in the outline drawing, figure 7. The bronchi are all much distended, but only a few of the respiratory spaces have been affected. Those which have been distended, however, are often over-expanded, as may be seen by comparison with figure 8, from a kitten of the same litter, born at normal time, and which had breathed twelve hours. The remainder of the lung is denser than the ordinary fetal lung, and has apparently been compressed by the over-distention of a few of the spaces. Evidently respiration was begun before the lungs were sufficiently developed to assume their noraial function. A point of interest seen in examining the sections is that the alveoli which are situated directly on the bronchioles are distinctly distended. No doubt it was these alveoli which played a large part in aerating the blood of the animal during the period that it survived, and indeed it must be these which function first at the beginning of normal respiration.


We here wish to express our thanks to Professor Piersol for helpful advice and criticism and to Mr. E. F. Faber for assistance with certain of the drawings.

Summary

  1. During prenatal life the future respiratory passages are filled with a liquid. With the first inspirations in air, the thoracic cavity is enlarged by the action of the respiratory muscles, the lung is thereby enlarged, and the Uquid in the trachea and bronchi is drawn down into the lung, and is distributed along the walls of the alveolar and other spaces.
  2. In microscopic sections of lung taken from fetal animals, there is seen a finely granular substance (a precipitate from the fluid present) widely scattered through the spaces; and large mononuclear cells, probably phagocytic in function are found uniformly distributed in small numbers.
  3. In sections of lung of neonatal animals the finely granular substance is still found, usually close to the walls of the airspaces and fewer mononuclear cells are seen.
  4. Before breathing, the lining epithelial cells of the alveoli are irregularly cuboidal with rounded nuclei; but after breathing, with the increased area of the walls of the alveoli, the nuclei are spaced farther apart, the cytoplasm is drawn out and the cells are very thin and flat. After breathing has begun, the mesenchjone appears denser, with its nuclei more compacted, and the bloodvessels are distended and more conspicuous.
  5. Measurements on cross-ruled millimeter paper show that the lung tissue in sections of fetal lung of dog constitute 70 to 80 per cent of the entire area; in sections of lung of dog which has breathed one hour, 40 to 60 per cent; and in sections of lung of dog which has breathed two days, 20 to 30 per cent.


Literature Cited

Ballantyne, J. W. 1902 Antenatal pathology and hygiene. William Wood, New York.

DE LA Croix, J. 1883 Die Entwickelung des Lungenepithels beim menschlichen Foetus und der einfluss der Atmung auf dasselbe. Archiv fur mikros. Anatomic, Bd. 22.

DoHRN 1891 tjber den Alechanismus der Respiration des Neugeborenen. Abstract in Archiv fiir Kinderheilkunde, Bd. 13.

Ferroni, E. 1899 Osservazioni e ricerche sui movimenti ritmici fetali intra uterini. Annali di Ostetricia e Ginecologia, T. 21.

Flint JM. The development of the lungs. (1906) Amer. J Anat. 6: 1-138.

Geyl, a. 1880 Die Aetiologie der sogenannten 'puerperalen Infection' des Fotus und des neugeborenen. Archiv fur Gynakologie. Bd. 15.

Howell, W. H. 1911 . Text-book of physiology; 4th Edition. W. B. Saunders, Philadelphia.

KoLLiKER, A. 1902 Handbuch der Gewebelehre des Menschen. Bd. 3, p. 310. Edited by V. von Ebner.

Lecl.\rd 1815 Abstract in Intelligenzblatt of Deutsches Archiv fiir die Phy siologie, Bd. 1, p. 154, under heading 'Untersuchungen, welche zu beweisen scheinen, dass der Fotus das Schafwasser athmet.'

Merkel, F. 1902 'Atmungsorgane,' in Bardeleben's Handbuch der Anatomie des Menschen.

Miller, W. S. 1893 The structure of the lung. Jour. Morph., vol. 8.

Preyer, W. 1885 Specielle physiologie des embryo. Leipzig.


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