Paper - The lung of a human foetus of 170 mm C.R. length
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See also by the same author: Palmer DW. Early Developmental Stages of the Human Lung. (1936) Ohio J. Science. 36(2): 69-79.
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The Lung Of A Human Foetus Of 170 mm C. R. Length
Dwight M. Palmer
Department of Anatomy, Ohio State University
TWO PLATES (TWO FIGURES) (1936)
As Businco (’33) has recently remarked, the discussion of the nature of the pulmonary alveolar wall continues as if endowed with some form of perpetual motion. Moreover the discussion will probably continue until a plan of structure is established deﬁnitely enough to satisfy the embryologist, histologist, physiologist and the pathologist. It cannot be denied that this is one of the most important problems that microscopic anatomy presents. Furthermore the solution of the problem will form a basis for the statement of physiological and pathological considerations of far-reaching implications. Thus the problem of Whether the pulmonary alveolus is lined by epithelium of endodermal origin or by a macrophage system of mesenchymal origin is still considered to be open by a suﬂicient number of workers to merit the consideration of more research. As an example of this attitude we may quote from Bloom (’34) writing in Maximow’s Textbook of Histology, as follows: “the nature of these cells (cells lining the alveoli) is by no means settled.”
There have been several modiﬁcations of the two general contentions (endodermal versus mesenchymal origin) concerning the lining of the respiratory portion of the tracheo bronchial tree (peripheral portion of respiratory bronchioles,
alveolar ducts, alveolar sacs and alveoli). In brieﬂy reviewing the research on the human lung it seems necessary to mention the following workers. In 1881 Kéilliker stated that he had found the respiratory portion of the lung to be lined with two types of cells: groups of small nucleated cells lying in the capillary network and large, thin apparently non-nucleated epithelial plates which were chieﬂy distributed over the alveolar capillaries but which also extended over the capillary meshes. This has been accepted as the classic anatomical description since that time. Some workers have conceived that these two elements are not separate but that they are parts of a single structure. Miller (’28) in a recent summary of his knowledge of the lung states “the epithelium lining the alveolar walls is made up of thin, ﬂattened, nucleated squames, which are closely applied to the alveolar Wall, and that it is a continuous epithelium.” More recently Businco and Giunti (’30) have maintained that only one cell type is present in the alveolar epithelium and that it is an element ‘sui generis’ for which the name ‘pneumocyte’ is suggested. The latter cell is described as a large element whose nucleus is collected with that of its sister cells to form nests in the intercapillary fossae. The plate-like cytoplasmic expansions of these cells spread out and either completely or incompletely cover the free surfaces of the alveolar capillaries. They state that the problem of the nature of the pneumocyte whether epithelial or mesenchymal is very diﬂicult and perhaps impossible of solution, since certain criteria (embryological, physiological, pathological) give claim to an epithelial origin, others (morphological, physio-pathological, colloid—ﬁxing) point toward a mesenchymal origin. Dogliotti and Amprino (’32) state that with present technical methods the majority of the alveolar capillaries present a nude aspect to the alveolar lumen, although nests of small nucleated epithelial cells are found in the intercapillary fossae.
Much of the support of the conﬂicting view which holds that the respiratory portion of the lung is mesenchymal in origin and that it is an extensive macrophage system in structure and function has come from without the anatomical ﬁeld, strictly speaking. This view as stated by Policard (’26) is that the respiratory portion of the lung might be compared to a vast raw sore or open wound. Lang (’26) has shown that the alveolar phagocytes arise from the ‘epithelial’ lining cells of the alveolar walls. Fried (’34) has pointed out that the alveolar cells are actively phagocytic in contrast to the passive phagocytosis exhibited by other epithelial cells as those in the liver and kidney. He produces physiological and pathological evidence to show that the lining cells of the respiratory portion of the lung are very likely not epithelial but mesenchymal in origin and that they represent an essential part of the macrophage system.
This problem has been approached from many angles and all the techniques of anatomical research have been employed. The author has used the method of building up a series of human foetal lungs and attempting to follow the course of the development of the lung through this series. Only selected material has been used in the series and no type of injection has been employed either through the air tubular system or through the pulmonary vessels. Since the supposed ﬂattening of the epithelium of the terminal divisions of the tracheobronchial tree, as postulated by the classic theory of lung embryology, has been subjected to so much criticism, it seems probable that any form of injection might distort the cytological picture of the pulmonary tissue. It may be repeated for emphasis that the most careful selection of material is necessary. Some of the accounts and particularly some of the photomicrographs found in the literature on this subject have some resemblance to the change seen in post-mortem cellular degeneration.
The method of human embryology has been employed by many workers, among whom at least the following deserve mention. Bender ('25) conﬁrmed in a series of human foetuses the observations that Kﬁlliker had made on the lung of an adult man. He stated that the alveolar lining shows alterations from a typical low columnar bronchial epithelium in the latter half of pregnancy. Concerning lungs from this period, he states that the epithelial lining cells gradually flatten out to assume the characteristics of respiratory epithelium. Cassaniga (’30) has also described the origin of the non-nucleated plates in the walls of the alveoli, in the lungs of premature foetuses and of foetuses at term. Siracusa (’31) and Seeman (’31) both believe that part of the epithelial lining of the terminal divisions of the tracheo-bronchial tree is lost during the latter part of prenatal life, leaving nests of cells epithelial in origin, in the intercapillary fossae. Dogliotti and Amprino (’32) have described the lipoidal reaction that appears in some of the alveolar epithelial cells as early as the latter part of the ﬁfth month of prenatal life and also the gradual pushing inward of the alveolar capillaries, encroaching on the small lumina of the terminal divisions of the tracheo-bronchial tree. Some of these alveolar capillary loops appear nude in the wall of the alveoli. These authors deﬁnitely state that with the methods now available that most of the alveolar capillaries appear nude on their alveolar surfaces, while a lesser part are covered by expansions of the nucleated epithelial cells lying in the intercapillary fossae.
Rose (’28) has described the finer structure of seven human foetal lungs. Four of these foetuses measured less than 140 cm. in length (type of ‘length’ not given but probably crownheel). All writers agree that the tracheo-bronchial tree in these stages (up to 140 cm. in length, be it C. H. or even C. R.) is entirely epithelial. Two of the other three foetuses were so far advanced in development that it seems the critical stages had already transpired. The remaining specimen was that of a human foetus “14 cm. in length and about 15 weeks of age.” In this case Rose describes “numerous whirls of cells with elliptical nuclei arranged around an immature alveolar lumen.” The photomicrograph shown is not convincing. The conclusion drawn is that the lung is of dualistic origin.
The author (’34, ’36) has described the lungs of human embryos and foetuses that range in size from a total embryo length of 11 mm. to a crown-rump length of 152 m. From these studies it was concluded that the tracheo-bronchial tree has a continuous . epithelial lining of endodermal origin through all stages up to and including the 152 mm. C. R. stage. In these accounts the number of generations of tubular divisions that grow out from the original tracheal anlage is given, according to an original method for enumerating these divisions. Brieﬂy this method is as follows: The primary bronchus arising from the trachea is designated as generation 1. It is traced until its ﬁrst branch is encountered which is designated as generation 2 and this is in turn followed to its ﬁrst branch. This last mentioned branch is designated as generation 3 and it is traced to its ﬁrst branch called generation 4. The tracing is continued in this manner until the terminal blind-end tubule is reached. If a bifurcation giving rise to equal-sized branches is found, the one having the more orad distribution is chosen for study.
Using this method of enumeration, there were at the 152 mm. C.R. stage, seventeen generations of tubules present. Of these the ﬁrst thirteen generations were lined by a pseudostratiﬁed columnar epithelium, continuous with the trachea. The last four generations were lined by a simple cuboidal epithelium. This cuboidal lining was intact throughout. It appears that these latter generations are immature pulmonary alveoli.
According to charts given in embryology textbooks this 152 mm. C. R. length foetus was in the nineteenth week of prenatal life when expelled (approximately, as the age of a foetus can be computed in more than one way and with varying results). The author has examined several apparently normal human foetuses of slightly larger 0. R. length and is convinced that the 150 to 200 mm. C. R. length interval (approximately from 20 to 23 weeks of prenatal life) includes the developmental period in which changes occur in the growing lung that must be correctly diagnosed if we are to learn the true nature of its ﬁner structure. Therefore a foetus has been selected for study in which these changes are just beginning to be noticeable.
Material and Methods
The foetus, a male, was dead when delivered and was soon afterwards placed in 10 per cent formalin solution. After a few days the pleural sacs were opened and the foetus was placed in fresh formalin solution. Following complete ﬁxation the foetus was examined carefully. No defects or abnormalities were noted. Measurements of the ﬁxed foetus were:
Crown rump (sitting height) 170 mm. Crown heel (standing height) 256 mm. Atlas rump 122 mm.
According to charts for the determination of the age of foetuses these measurements place this specimen in the twenty-ﬁrst week of prenatal life.
The right lung was removed from the body and measured. This lung measured 18 mm. from the apex to the center of the base. The base measured 35 mm. in its longest postero-lateral to antero-medial diameter and 19 mm. in its widest transverse diameter.
The oblique interlobar ﬁssure was complete, but the transverse interlobar ﬁssure was incomplete in the medial 5 mm. of its extent. The pleura was glistening and transparent. Beneath the pleura the lung surface presented many square, pentangular or rounded areas of 1 mm. or less in diameter and a few larger square or polygonal areas of 2 or 3 mm. in diameter. The entire lung was dehydrated and embedded in paraiﬁn. Serial sections were prepared of the upper and part of the middle lobes. Part of these sections were stained with hematoxylin and eosin and part with weak silver carbonate solution (lithium), by a modiﬁcation of Foot’s method for staining the connective tissues.
Wax reconstructions were made by the use of an Edinger projection apparatus. Reconstructions were made of the origin and branchings of the tubules in several portions of the lung.
In addition, several microscopic ﬁelds of sub-pleural lung tissue that did not contain any large pulmonary vessels or large bronchi were projected upon sheets of heavy paper and the tubular areas were outlined. These were carefully cut out and the remaining paper of the microscopic ﬁeld was weighed. The latter method was used to obtain the ratio in volume between the ﬁner tracheo-bronchial tree ramiﬁcations and the stroma.
A. The Trachembronchial Tree
1. Number of generations. This ﬁgure was determined in the area of the bronchus to the right superior lobe (bronchus RD1——-the ﬁrst right dorsal bronchus). Having designated the latter as generation 1, the maximum number of generations found by the method given above was seventeen in this area. This is the number that was found in this same area in a human foetus of 152 mm. C. R. length.
.2. Description of generations. Generations 1 to 5. The epithelium is what is called pseudo—stratiﬁed columnar with cilia. A careful examination shows it to be of the type characteristic of the trachea. and larger bronchi and consisting of four cell types: basal, intermediate, ciliated columnar and goblet cells. Bronchial glands and cartilage plates are present.
Generations 6 and 7. The epithelium is pseudo—stratiﬁed in generation 6 presenting basal and ciliated columnar cells. In generation 7 most of the basal cells have disappeared. There are no bronchial glands present, the last of these being present in the. ﬁfth generation. Cartilage platelets and nodules are found in the walls of these two generations but not in any of the succeeding generations.
Generations 8 to 11. The epithelium is simple columnar with cilia in generation 8. In generations 9 and 10 the epithelium is of lower height, with cilia. Scattered amongst the ciliated low columnar epithelial cells of generation 11 there are cuboidal cells with practically non-staining cytoplasm and large vesicular nuclei.
Generation 12. In this generation the more orad portion is like generation 11 while the more peripheral portion is a lightstaining simple cuboidal epithelium.
Generations 13 to 17. These terminal generations, which may be considered as the immature respiratory portion of tlie lung, are partially lined with a light-staining simple cuboidal epithelium. By the use of wax reconstructions and by projection studies it was determined that generation 13 presents an intact cuboidal epithelium. This statement also appears to be true for the tubules of generation 17 which are blind epithelial-lined end pouches at this stage. It is in the walls of generations 14, 15, 16 that very distinctive changes are occurring. In contrast to the intact epithelial lining of all the terminal generations of the tracheo-bronchial trees of younger foetuses it appears that at the 170 mm. C. R. length the epithelial lining is no longer intact. In many areas a capillary loop from the stroma has pushed in against the cuboidal cells of the alveolar lining and now bulges into the alveolar lumen. The mechanism of the appearance of the capillary loop into relation to the immature alveolar lumen seems to be an opening up of the blood channel with a coincident pushing in of the loop against the bases of the cuboidal cells of the alveolar wall. Many examples can be found showing that two things are happening to the cuboidal cells. In some instances the cytoplasm of these cells is being thinned to cover the capillary loop. In a majority of cases however the surface of the capillary facing into the immature alveolar lumen does not appear with the best technical means at the author ’s command (magniﬁcation at X 2000) to be covered by epithelial cells or by any part of epithelial cells. In these numerous instances it appears from the sharply deﬁned lateral margins of the cuboidal cells next to the intruding capillary that the loop has pushed between the epithelial cells and thus its alveolar aspect is nude of epithelium. The pushing into the alveoli of the vascular loops is not in any sense an occasional feature of a microscopical ﬁeld. In fact this striking phenomenon characterizes the microscopical picture of the tracheo-bronchial tree of this foetus. (This same feature has been demonstrated in sections of the lungs of other foetuses of about this same age. By the time of the 187 mm. C.R. stage the nude intruding capillaries are very prominent.)
In any given tubule of these generations that was followed through serial sections more than one example of the intrusion of the capillary loop was demonstrated. Often the pl1enome— non occurs at three or four points in the wall of one tubule. The points of intrusion may be as close as four euboidal epithelial cells from another intrusion. These intervening cuboidal epithelial cells do not show any degenerative changes. The area of the capillary that is in relation to the lumen of the tubule without an interposed epithelial sheet is not large, the average diameter of the exposed area being that of four to six red blood cells.
There aI'e no evidences of death of the epithelium i11 any part of the tracheo—bronchial tree lining. Between the areas of the intruding capillary loops the epithelium shows no evidence of thinning.
Thus the twenty-ﬁrst a11d twenty-second weeks (approximately) of prenatal life are marked in the developing lung by signiﬁcant changes occurring in the fourteenth, ﬁfteenth and sixteenth generations of the tracheo—bronchial tree. For the ﬁrst time in the development of the lung, points of local discontinuity appear iii the epithelial lining of the tree. In this manner capillary loops are brought i11to intimate contact with the lumina of these generations.
The volume proportion between the stroma and the tracheobronchial tree ramiﬁcations was determined in several subpleural areas. The average of the results obtained was stroma 66 per cent and bronchial tree ramiﬁcations 34 per cent. By the same method and in similar areas the ratio reported at the 152 mm. C‘. R. stage was stroma 79 per cent and tree ramiﬁcations 21 per cent. It may be noted again that by the method of enumeration of generations employed there appears to be the same number of generations present as at an earlier stage, i.e., seventeen. But when ﬁelds from the lung of the 152—mm foetus are compared with the 170-mm. foetus it is readily apparent that the sections of tubular branchings are more numerous at the 1T0—mm. stage. Furthermore, at the latter stage the outlines of the alveoli as seen in section are more irregular and somewhat smaller, a part of which is due to the intrusion of the capillaries described above. The lumina are far less distinct at the 170-mm. stage than at 152 mm. Considering the peculiarities of the method of enumeration employed, the deduction can be made that between the 152- and 170—mm. stages many new tubular ramiﬁcations have grown from the thirteenth, fourteenth, ﬁfteenth and sixteenth generations present at the 152 mm. C. R-. stage.
B. The Stroma
The most striking change in the stroma between the 152and the 170-mm. stages is the vascularization that is now apparent. The study of secti011s of the lung from embryos a11d foetuses at stages up to the 152 mm. C. R. stage all reveals an avascular stroma. The vascularization is most noticeable in the appearance of the sub-epithelial and luminal capillaries described above. The stroma that might be called inter-alveolar, that is the stroma that is not i11 very close relation to the immature alveoli, is still avascular. The collagenous a11d reticular framework is well developed at the 170—mm. stage. The large bronchi and the large pulmonary vessels are surrounded by collagenous connective tissue. This also is found to a very slight extent just beneath the pleurae. Ramifying from the collagenous framework is an extensive reticular network which surrounds the immature alveoli. Beneath the cuboidal epithelium the reticulum forms a basement membrane a11d reticular ﬁbers surround the capillary loops as they push between the epithelial cells. A few instances could be found i11 which a reticulum ﬁber as it passes around a capillary is itself exposed to the lume11 of the immature alveolus.
- The beginning of the sixth month (28-day mo11th) of prenatal life represents a critical period in the development of the human lung.
- During this time interval blood capillaries of the stroma for the ﬁrst time push through the epithelial lining of the fourteenth, ﬁfteenth and sixteenth generations of the tracheobronchial tree at many small loci and thus present in the lumina of these generations a surface devoid of an epithelial layer.
- Sub-pleural areas of the lung are composed of approximately two-thirds stroma and o11e—third tracl1eo—bronc.hial tree ramiﬁcations, by Volume.
- The stroma is 11ot vascularized except where it is in close relationship to the terminal generations of the tracheobronchial tree.
- By the method of enumeration outlined there are seventeen generations of tubular a11d tubulo-alveolar branchings present. The 13 to 17 generations probably represent the immature respiratory portion of the lung.
I am indebted to Miss Thelma Baird for assistance in the preparation of the serial microscopic sections and of the photomicrographs.
BENDER, K. W. 1925 Uber die Entwicklung der Lungen. Zeitschr. f. Anat. u. Entwic-kl., vol. 75, pp. 638-704.
BLOOM, W. 1934 In a Textbook of Histology, Maximow and Bloom, p. 458, revised 2nd ed. W. B. Saunders Co., Philadelphia.
BUSINCO, A. 1933 La struttura del polmone alla luce delle vecchie e nuove ricerche, Riv. san. siliciana, vol. 21, pp. 1049-1061.
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CASSANIGA, A. 1930 Formazione delle placohe anucleate. Gazz. Med. 1omb., vol. 89, pp. 339-346.
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Palmer DW. Early Developmental Stages of the Human Lung. (1936) Ohio J. Science. 36(2): 69-79.
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SEEMAN, G. 1931 Histobiologic der Lungenalveole. Fischer, Jena.
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VON KGLLIKER, A. 1881 Zur Kenntnis des Baues der Lunge des Men. Verhandl. d. ph_VS.*lTl€d. Gesell. zu Wurzburg N. F. Bd. xvi.
1 Section stained with hematoxylin and eosin. C., capillary presenting a surface nude of epithelium toward the immature alveolar lumen. X 450,
2 Section stained by a modiﬁcation of Foot’s silver carbonate method for staining the connective tissues. C., capillary loop presenting a surface nude of epithelium toward the immature alveolar lumen; 19., euboidal epithelium. R., reticulum forming a basement membrane. )< 880.
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