Talk:Respiratory System Development

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Cite this page: Hill, M.A. (2024, June 21) Embryology Respiratory System Development. Retrieved from


Bronchial tree of the human embryo: Examination based on a mammalian model

Sena Fujii 1 , Taiga Muranaka 1 , Jun Matsubayashi 2 , Shigehito Yamada 1 3 , Akio Yoneyama 4 , Tetsuya Takakuwa 1 Affiliations expand PMID: 37602519 DOI: 10.1111/joa.13946 Abstract

The symmetry of the right and left bronchi, proposed in a previous comparative anatomical study as the basic model of the mammalian bronchial tree, was examined to determine if it applied to the embryonic human bronchial tree. Imaging data of 41 human embryo specimens at Carnegie stages (CS) 16-23 (equivalent to 6-8 weeks after fertilization) belonging to the Kyoto collection were obtained using phase-contrast X-ray computed tomography. Three-dimensional bronchial trees were then reconstructed from these images. Bronchi branching from both main bronchi were labeled as dorsal, ventral, medial, or lateral systems based on the branching position with numbering starting cranially. The length from the tracheal bifurcation to the branching point of the labeled bronchus was measured, and the right-to-left ratio of the same labeled bronchus in both lungs was calculated. In both lungs, the human embryonic bronchial tree showed symmetry with an alternating pattern of dorsal and lateral systems up to segmental bronchus B9 as the basic shape, with a more peripheral variation. This pattern is similar to that described in adult human lungs. Bronchial length increased with the CS in all labeled bronchi, whereas the right-to-left ratio was constant at approximately 1.0. The data demonstrated that the prototype of the human adult bronchial branching structure is formed and maintained in the embryonic stage. The morphology and branching position of all lobar bronchi and B6, B8, B9, and the subsegmental bronchus of B10 may be genetically determined. On the other hand, no common structures between individual embryos were found in the peripheral branches after the subsegmental bronchus of B10, suggesting that branch formation in this region is influenced more by environmental factors than by genetic factors.


Transcriptional control of lung alveolar type 1 cell development and maintenance by NK homeobox 2-1

Gas exchange in the lung relies on passive diffusion of oxygen and carbon dioxide across an extraordinarily thin epithelium that is nearly entirely made of the poorly understood alveolar type 1 (AT1) cell. Our study shows that all AT1 cells express and require NK homeobox 2-1 (Nkx2-1) for their development and maintenance. Nkx2-1 mutant AT1 cells lose their characteristic molecular and cellular features and transform toward a gastrointestinal fate, highlighting remarkable plasticity of an otherwise terminally differentiated cell type. This work establishes NKX2-1 as the first overarching factor in the AT1 cell transcriptional hierarchy and paves the way for unraveling not only the unique biology of AT1 cells but also cell type-specific roles of a lineage transcription factor.

See 2012 review paper Signaling Networks Regulating Development of the Lower Respiratory Tract

New Insight into the Development of the Respiratory Acini in Rabbits: Morphological, Electron Microscopic Studies, and TUNEL Assay

Microsc Microanal. 2019 Feb 14:1-17. doi: 10.1017/S1431927619000059. [Epub ahead of print]

Mokhtar DM1, Hussein MT1, Hussein MM1, Abd-Elhafez EA1, Kamel G1.

Abstract This study investigated the histomorphological features of developing rabbit respiratory acini during the postnatal period. On the 1st day of postnatal life, the epithelium of terminal bronchiole consisted of clear cells which intercalated between few ciliated and abundant non-ciliated (Clara) cells. At this age, the rabbit lung was in the alveolar stage. The terminal bronchioles branched into several alveolar ducts, which opened into atria that communicated to alveolar sacs. All primary and secondary inter-alveolar septa were thick and showed a double-capillary network (immature septa). The primitive alveoli were lined largely by type-I pneumocytes and mature type-II pneumocytes. The type-I pneumocytes displayed an intimate contact with the endothelial cells of the blood capillaries forming the blood-air barrier (0.90 ± 0.03 µm in thickness). On the 3rd day, we observed intense septation and massive formation of new secondary septa giving the alveolar sac a crenate appearance. The mean thickness of the air-blood barrier decreased to reach 0.78 ± 0.14 µm. On the 7th day, the terminal bronchiole epithelium consisted of ciliated and non-ciliated cells. The non-ciliated cells could be identified as Clara cells and serous cells. New secondary septa were formed, meanwhile the inter-alveolar septa become much thinner and the air-blood barrier thickness was 0.66 ± 0.03 µm. On the 14th day, the terminal bronchiole expanded markedly and the pulmonary alveoli were thin-walled. Inter-alveolar septa become much thinner and single capillary layers were observed. In the 1st month, the secondary septa increased in length forming mature cup-shaped alveoli. In the 2nd month, the lung tissue grew massively to involve the terminal respiratory unit. In the 3rd month, the pulmonary parenchyma appeared morphologically mature. All inter-alveolar septa showed a single-capillary layer, and primordia of new septa were also observed. The thickness of the air-blood barrier was much thinner; 0.56 ± 0.16 µm. TUNEL assay after birth revealed that the apoptotic cells were abundant and distributed in the epithelium lining of the pulmonary alveoli and the interstitium of the thick interalveolar septa. On the 7th day, and onward, the incidence of apoptotic cells decreased markedly. This study concluded that the lung development included two phases: the first phase (from birth to the 14th days) corresponds to the period of bulk alveolarization and microvascular maturation. The second phase (from the 14th days to the full maturity) corresponds to the lung growth and late alveolarization.

KEYWORDS: air–blood barrier; alveolarization; alveoli; electron microscopy; pneumocytes PMID: 30761973 DOI: 10.1017/S1431927619000059


How high resolution 3-dimensional imaging changes our understanding of postnatal lung development

Histochem Cell Biol. 2018 Dec;150(6):677-691. doi: 10.1007/s00418-018-1749-7. Epub 2018 Nov 2.

Schittny JC1.

Abstract During the last 10 + years biologically and clinically significant questions about postnatal lung development could be answered due to the application of modern cutting-edge microscopic and quantitative histological techniques. These are in particular synchrotron radiation based X-ray tomographic microscopy (SRXTM), but also 3Helium Magnetic Resonance Imaging, as well as the stereological estimation of the number of alveoli and the length of the free septal edge. First, the most important new finding may be the following: alveolarization of the lung does not cease after the maturation of the alveolar microvasculature but continues until young adulthood and, even more important, maybe reactivated lifelong if needed to rescue structural damages of the lungs. Second, the pulmonary acinus represents the functional unit of the lung. Because the borders of the acini could not be detected in classical histological sections, any investigation of the acini requires 3-dimensional (imaging) methods. Based on SRXTM it was shown that in rat lungs the number of acini stays constant, meaning that their volume increases by a factor of ~ 11 after birth. The latter is very important for acinar ventilation and particle deposition.

KEYWORDS: Angiogenesis; Lung development; Microvascular maturation; Pulmonary acinus; Pulmonary alveolarization PMID: 30390117 PMCID: PMC6267404 DOI: 10.1007/s00418-018-1749-7

Understanding alveolarization to induce lung regeneration

Respir Res. 2018 Aug 6;19(1):148. doi: 10.1186/s12931-018-0837-5.

Rodríguez-Castillo JA1, Pérez DB1, Ntokou A1, Seeger W1,2, Morty RE1,2, Ahlbrecht K3,4.

Abstract BACKGROUND: Gas exchange represents the key physiological function of the lung, and is dependent upon proper formation of the delicate alveolar structure. Malformation or destruction of the alveolar gas-exchange regions are key histopathological hallmarks of diseases such as bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis; all of which are characterized by perturbations to the alveolo-capillary barrier structure. Impaired gas-exchange is the primary initial consequence of these perturbations, resulting in severe clinical symptoms, reduced quality of life, and death. The pronounced morbidity and mortality associated with malformation or destruction of alveoli underscores a pressing need for new therapeutic concepts. The re-induction of alveolarization in diseased lungs is a new and exciting concept in a regenerative medicine approach to manage pulmonary diseases that are characterized by an absence of alveoli.

MAIN TEXT: Mechanisms of alveolarization first need to be understood, to identify pathways and mediators that may be exploited to drive the induction of alveolarization in the diseased lung. With this in mind, a variety of candidate cell-types, pathways, and molecular mediators have recently been identified. Using lineage tracing approaches and lung injury models, new progenitor cells for epithelial and mesenchymal cell types - as well as cell lineages which are able to acquire stem cell properties - have been discovered. However, the underlying mechanisms that orchestrate the complex process of lung alveolar septation remain largely unknown.

CONCLUSION: While important progress has been made, further characterization of the contributing cell-types, the cell type-specific molecular signatures, and the time-dependent chemical and mechanical processes in the developing, adult and diseased lung is needed in order to implement a regenerative therapeutic approach for pulmonary diseases.

KEYWORDS: Alveolarization; Neo-alveolarization; Regeneration PMID: 30081910 PMCID: PMC6090695 DOI: 10.1186/s12931-018-0837-5

Development of the pulmonary pleura with special reference to the lung surface morphology: a study using human fetuses

Anat Cell Biol. 2018 Sep;51(3):150-157. doi: 10.5115/acb.2018.51.3.150. Epub 2018 Sep 28.

Yamamoto M, Wilting J, Abe H, Murakami G, Rodríguez-Vázquez JF & Abe SI. (2018). Development of the pulmonary pleura with special reference to the lung surface morphology: a study using human fetuses. Anat Cell Biol , 51, 150-157. PMID: 30310706 DOI.

Yamamoto M1, Wilting J2, Abe H3, Murakami G1,4, Rodríguez-Vázquez JF5, Abe SI1. Author information Abstract In and after the third trimester, the lung surface is likely to become smooth to facilitate respiratory movements. However, there are no detailed descriptions as to when and how the lung surface becomes regular. According to our observations of 33 fetuses at 9-16 weeks of gestation (crown-rump length [CRL], 39-125 mm), the lung surface, especially its lateral (costal) surface, was comparatively rough due to rapid branching and outward growing of bronchioli at the pseudoglandular phase of lung development. The pulmonary pleura was thin and, beneath the surface mesothelium, no or little mesenchymal tissue was detectable. Veins and lymphatic vessels reached the lung surface until 9 weeks and 16 weeks, respectively. In contrast, in 8 fetuses at 26-34 weeks of gestation (CRL, 210-290 mm), the lung surface was almost smooth because, instead of bronchioli, the developing alveoli faced the external surfaces of the lung. Moreover, the submesothelial tissue became thick due to large numbers of dilated veins connected to deep intersegmental veins. CD34-positive, multilayered fibrous tissue was also evident beneath the mesothelium in these stages. The submesothelial tissue was much thicker at the basal and mediastinal surfaces compared to apical and costal surfaces. Overall, rather than by a mechanical stress from the thoracic wall and diaphragm, a smooth lung surface seemed to be established largely by the thick submesothelial tissue including veins and lymphatic vessels until 26 weeks. KEYWORDS: Human fetus; Lung surface; Mesothelium; Pulmonary pleura; Submesothelial morphology PMID: 30310706 PMCID: PMC6172594 DOI: 10.5115/acb.2018.51.3.150

Human lung development: recent progress and new challenges

Nikolić MZ, Sun D & Rawlins EL. (2018). Human lung development: recent progress and new challenges. Development , 145, . PMID: 30111617 DOI.

Nikolić MZ1,2, Sun D1, Rawlins EL3. Author information Abstract Recent studies have revealed biologically significant differences between human and mouse lung development, and have reported new in vitro systems that allow experimental manipulation of human lung models. At the same time, emerging clinical data suggest that the origins of some adult lung diseases are found in embryonic development and childhood. The convergence of these research themes has fuelled a resurgence of interest in human lung developmental biology. In this Review, we discuss our current understanding of human lung development, which has been profoundly influenced by studies in mice and, more recently, by experiments using in vitro human lung developmental models and RNA sequencing of human foetal lung tissue. Together, these approaches are helping to shed light on the mechanisms underlying human lung development and disease, and may help pave the way for new therapies. KEYWORDS: Alveolar; Bronchi; ESC; Lung disease; Progenitor; Stem cell; iPSC PMID: 30111617 PMCID: PMC6124546 DOI: 10.1242/dev.163485

Spatial and temporal changes in extracellular elastin and laminin distribution during lung alveolar development

Sci Rep. 2018 May 29;8(1):8334. doi: 10.1038/s41598-018-26673-1.

Luo Y1, Li N1, Chen H1, Fernandez GE1, Warburton D1,2, Moats R1,3, Mecham RP4, Krenitsky D5, Pryhuber GS5, Shi W6,7.

Abstract Lung alveolarization requires precise coordination of cell growth with extracellular matrix (ECM) synthesis and deposition. The role of extracellular matrices in alveogenesis is not fully understood, because prior knowledge is largely extrapolated from two-dimensional structural analysis. Herein, we studied temporospatial changes of two important ECM proteins, laminin and elastin that are tightly associated with alveolar capillary growth and lung elastic recoil respectively, during both mouse and human lung alveolarization. By combining protein immunofluorescence staining with two- and three-dimensional imaging, we found that the laminin network was simplified along with the thinning of septal walls during alveogenesis, and more tightly associated with alveolar endothelial cells in matured lung. In contrast, elastin fibers were initially localized to the saccular openings of nascent alveoli, forming a ring-like structure. Then, throughout alveolar growth, the number of such alveolar mouth ring-like structures increased, while the relative ring size decreased. These rings were interconnected via additional elastin fibers. The apparent patches and dots of elastin at the tips of alveolar septae found in two-dimensional images were cross sections of elastin ring fibers in the three-dimension. Thus, the previous concept that deposition of elastin at alveolar tips drives septal inward growth may potentially be conceptually challenged by our data.

PMID: 29844468 PMCID: PMC5974327 DOI: 10.1038/s41598-018-26673-1

PDGF-A signaling is required for secondary alveolar septation and controls epithelial proliferation in the developing lung

Gouveia L, Betsholtz C & Andrae J. (2018). PDGF-A signaling is required for secondary alveolar septation and controls epithelial proliferation in the developing lung. Development , 145, . PMID: 29636361 DOI.

Gouveia L1, Betsholtz C1,2, Andrae J3. Author information Abstract Platelet-derived growth factor A (PDGF-A) signaling through PDGF receptor α is essential for alveogenesis. Previous studies have shown that Pdgfa-/- mouse lungs have enlarged alveolar airspace with absence of secondary septation, both distinctive features of bronchopulmonary dysplasia. To study how PDGF-A signaling is involved in alveogenesis, we generated lung-specific Pdgfa knockout mice (Pdgfafl/-; Spc-cre) and characterized their phenotype postnatally. Histological differences between mutant mice and littermate controls were visible after the onset of alveogenesis and maintained until adulthood. Additionally, we generated Pdgfafl/-; Spc-cre; PdgfraGFP/+ mice in which Pdgfra+ cells exhibit nuclear GFP expression. In the absence of PDGF-A, the number of PdgfraGFP+ cells was significantly decreased. In addition, proliferation of PdgfraGFP+ cells was reduced. During alveogenesis, PdgfraGFP+ myofibroblasts failed to form the α-smooth muscle actin rings necessary for alveolar secondary septation. These results indicate that PDGF-A signaling is involved in myofibroblast proliferation and migration. In addition, we show an increase in both the number and proliferation of alveolar type II cells in Pdgfafl/-; Spc-cre lungs, suggesting that the increased alveolar airspace is not caused solely by deficient myofibroblast function. KEYWORDS: Alveogenesis; Lung development; PDGF-A; PDGFRα PMID: 29636361 DOI: 10.1242/dev.161976


In utero alcohol effects on foetal, neonatal and childhood lung disease

Paediatr Respir Rev. 2017 Jan;21:34-37. doi: 10.1016/j.prrv.2016.08.006. Epub 2016 Aug 19.

Gauthier TW1, Brown LA2.


Maternal alcohol use during pregnancy exposes both premature and term newborns to the toxicity of alcohol and its metabolites. Foetal alcohol exposure adversely effects the lung. In contrast to the adult "alcoholic lung" phenotype, an inability to identify the newborn exposed to alcohol in utero has limited our understanding of its effect on adverse pulmonary outcomes. This paper will review advances in biomarker development of in utero alcohol exposure. We will highlight the current understanding of in utero alcohol's toxicity to the developing lung and immune defense. Finally, we will present recent clinical evidence describing foetal alcohol's association with adverse pulmonary outcomes including bronchopulmonary dysplasia, viral infections such as respiratory syncytial virus and allergic asthma/atopy. With research to define alcohol's effect on the lung and translational studies accurately identifying the exposed offspring, the full extent of alcohol's effects on clinical respiratory outcomes of the newborn or child can be determined.

KEYWORDS: Foetal alcohol; immunity; infection; lung; newborn; pregnancy

PMID: 27613232 PMCID: PMC5303127 DOI: 10.1016/j.prrv.2016.08.006

Development of the lung

Cell Tissue Res. 2017 Mar;367(3):427-444. doi: 10.1007/s00441-016-2545-0. Epub 2017 Jan 31.

Schittny JC.


To fulfill the task of gas exchange, the lung possesses a huge inner surface and a tree-like system of conducting airways ventilating the gas exchange area. During lung development, the conducting airways are formed first, followed by the formation and enlargement of the gas exchange area. The latter (alveolarization) continues until young adulthood. During organogenesis, the left and right lungs have their own anlage, an outpouching of the foregut. Each lung bud starts a repetitive process of outgrowth and branching (branching morphogenesis) that forms all of the future airways mainly during the pseudoglandular stage. During the canalicular stage, the differentiation of the epithelia becomes visible and the bronchioalveolar duct junction is formed. The location of this junction stays constant throughout life. Towards the end of the canalicular stage, the first gas exchange may take place and survival of prematurely born babies becomes possible. Ninety percent of the gas exchange surface area will be formed by alveolarization, a process where existing airspaces are subdivided by the formation of new walls (septa). This process requires a double-layered capillary network at the basis of the newly forming septum. However, in parallel to alveolarization, the double-layered capillary network of the immature septa fuses to a single-layered network resulting in an optimized setup for gas exchange. Alveolarization still continues, because, at sites where new septa are lifting off preexisting mature septa, the required second capillary layer will be formed instantly by angiogenesis. The latter confirms a lifelong ability of alveolarization, which is important for any kind of lung regeneration. KEYWORDS: Alveolarization; Branching morphogenesis; Lung development; Microvascular maturation; Pulmonary acinus PMID: 28144783 PMCID: PMC5320013 DOI: 10.1007/s00441-016-2545-0

Schittny JC. (2017). Development of the lung. Cell Tissue Res. , 367, 427-444. PMID: 28144783 DOI.

Table 1 Stages of lung development and their time scale

Period Stage Duration Characteristics Embryonic Embryonic Rabbit: n.d.–E18 Sheep: E17–E30 Mouse: E9.5–E12 Rat: E11–E13 Monkey: n.d. – E55 Human: E26–E49 (4–7 weeksa) Anlage of the two lungs; organogenesis; formation of major airways and pleura. Fetal Pseudoglandular Rabbit: E18–E24 Sheep: E30–E85 Mouse: E12–E16.5 Rat: E13–E18.5 Monkey: E55 – E85 Human: E35–E119 (5–17 weeks) Formation of bronchial tree and large parts of prospective respiratory parenchyma; birth of the acinus even if the acinar epithelia are not yet differentiated. Canalicular Rabbit: E23–E27 Sheep: E80–E120 Mouse: E16.5–E17.5 Rat: E18.5–E20 Monkey: E75–E115 Human: E112–E182 (16–26 weeksa) Formation of the most distal airways leading to completion of branching morphogenesis; first air-blood barrier; appearance of surfactant, acini are detectable due to epithelial differentiation. Saccular or terminal sac Rabbit: E27–E30 Sheep: E110–E140 Mouse: E17.5–P4 Rat: E21–P4 Monkey E105–term Human: E168–E266 (24–38 weeksa) Expansion of (future) airspaces. Postnatal Alveolarization, classical alveolarization (first phase) Rabbit: E30–term (E31) Sheep: E120–term (E145) Mouse: P4 – P21 Rat: P4 – P21 Monkey: E125– <P180b Human: E252 (36 weeks* preterm) – 3 years Formation of secondary septa (septation) resulting in the formation of the alveoli; most of the alveolar septa are still immature and contain a double layered capillary network. Depending on the species alveolarization starts before or after birth. Alveolarization, continued alveolarization (second phase) Rabbit: term (E31) – n.d. Sheep: term (E145) – n.d. Mouse: P14 – young adulthood (∼P36) Rat: P14 – young adulthood (∼P60) Monkey: < P180b– young adulthood (7–8 years) Human: 2 years – young adulthood (17–21 years) Formation of secondary septa (septation) but now lifting off of mature alveolar septa containing a single layered capillary network. Microvascular maturation Rabbit: n.d. Sheep: n.d. Mouse: P4 – young adulthood (∼P36) Rat: P14 – young adulthood (∼P60) Monkey: n.d. Human: ∼term – ∼3–21 years (timing uncertain) Remodeling and maturation of interalveolar septa and of the capillary bed (the double layered capillary network is transformed to a single layered network). In a first approximation it takes place in parallel to alveolarization. The stages are defined mainly by morphological criteria and their beginning and end do not represent sharp borders. In addition, stages are overlapping and regional differences are also common, especially between central and peripheral regions. Furthermore, litter size and nutrition influences the exact timing of development (Bryden et al. 1973; Burri 1999; Miettinen et al. 1997; Schittny et al. 1998, 2008; Ten Have-Opbroek 1991). Based on Schittny and Burri (2008) and Woods and Schittny (2016)

Monkey Rhesus monkey; E embryonic day (days post-coitum); n.d. not determined; P postnatal day

a Weeks post coitum

b Own unpublished observation


The development and plasticity of alveolar type 1 cells

Development. 2016 Jan 1;143(1):54-65. doi: 10.1242/dev.130005. Epub 2015 Nov 19.

Yang J1, Hernandez BJ1, Martinez Alanis D1, Narvaez del Pilar O2, Vila-Ellis L3, Akiyama H4, Evans SE1, Ostrin EJ1, Chen J5.


Alveolar type 1 (AT1) cells cover >95% of the gas exchange surface and are extremely thin to facilitate passive gas diffusion. The development of these highly specialized cells and its coordination with the formation of the honeycomb-like alveolar structure are poorly understood. Using new marker-based stereology and single-cell imaging methods, we show that AT1 cells in the mouse lung form expansive thin cellular extensions via a non-proliferative two-step process while retaining cellular plasticity. In the flattening step, AT1 cells undergo molecular specification and remodel cell junctions while remaining connected to their epithelial neighbors. In the folding step, AT1 cells increase in size by more than 10-fold and undergo cellular morphogenesis that matches capillary and secondary septa formation, resulting in a single AT1 cell spanning multiple alveoli. Furthermore, AT1 cells are an unexpected source of VEGFA and their normal development is required for alveolar angiogenesis. Notably, a majority of AT1 cells proliferate upon ectopic SOX2 expression and undergo stage-dependent cell fate reprogramming. These results provide evidence that AT1 cells have both structural and signaling roles in alveolar maturation and can exit their terminally differentiated non-proliferative state. Our findings suggest that AT1 cells might be a new target in the pathogenesis and treatment of lung diseases associated with premature birth. © 2016. Published by The Company of Biologists Ltd. KEYWORDS: Alveolar angiogenesis; Cell plasticity; Lung development PMID 26586225


FGF-Regulated ETV Transcription Factors Control FGF-SHH Feedback Loop in Lung Branching

Dev Cell. 2015 Nov 9;35(3):322-32. doi: 10.1016/j.devcel.2015.10.006.

Herriges JC1, Verheyden JM1, Zhang Z2, Sui P1, Zhang Y3, Anderson MJ3, Swing DA4, Zhang Y1, Lewandoski M3, Sun X5.


The mammalian lung forms its elaborate tree-like structure following a largely stereotypical branching sequence. While a number of genes have been identified to play essential roles in lung branching, what coordinates the choice between branch growth and new branch formation has not been elucidated. Here we show that loss of FGF-activated transcription factor genes, Etv4 and Etv5 (collectively Etv), led to prolonged branch tip growth and delayed new branch formation. Unexpectedly, this phenotype is more similar to mutants with increased rather than decreased FGF activity. Indeed, an increased Fgf10 expression is observed, and reducing Fgf10 dosage can attenuate the Etv mutant phenotype. Further evidence indicates that ETV inhibits Fgf10 via directly promoting Shh expression. SHH in turn inhibits local Fgf10 expression and redirects growth, thereby initiating new branches. Together, our findings establish ETV as a key node in the FGF-ETV-SHH inhibitory feedback loop that dictates branching periodicity. Copyright © 2015 Elsevier Inc. All rights reserved.

FGF10 and SHH form a feedback loop

  • FGF10 produced in the mesenchyme signals to the distal epithelium to upregulate Shh expression.
  • SHH then feeds back to inhibit Fgf10 expression in the adjacent mesenchyme, splitting the Fgf10 expression domain in two.
  • new FGF10 signaling domains serve as two chemoattractant sources, leading to bifurcation of the epithelial tip.
  • FGF-activated transcription factor genes Etv4 and Etv5 act as intermediates in this feedback loop

PMID 26555052

Mechanically patterning the embryonic airway epithelium

Proc Natl Acad Sci U S A. 2015 Jul 28;112(30):9230-5. doi: 10.1073/pnas.1504102112. Epub 2015 Jul 13.

Varner VD1, Gleghorn JP1, Miller E2, Radisky DC2, Nelson CM3.


Collections of cells must be patterned spatially during embryonic development to generate the intricate architectures of mature tissues. In several cases, including the formation of the branched airways of the lung, reciprocal signaling between an epithelium and its surrounding mesenchyme helps generate these spatial patterns. Several molecular signals are thought to interact via reaction-diffusion kinetics to create distinct biochemical patterns, which act as molecular precursors to actual, physical patterns of biological structure and function. Here, however, we show that purely physical mechanisms can drive spatial patterning within embryonic epithelia. Specifically, we find that a growth-induced physical instability defines the relative locations of branches within the developing murine airway epithelium in the absence of mesenchyme. The dominant wavelength of this instability determines the branching pattern and is controlled by epithelial growth rates. These data suggest that physical mechanisms can create the biological patterns that underlie tissue morphogenesis in the embryo. KEYWORDS: buckling; instability; mechanical stress; morphodynamics; morphogenesis

PMID 26170292

Localized Smooth Muscle Differentiation Is Essential for Epithelial Bifurcation during Branching Morphogenesis of the Mammalian Lung

Dev Cell. 2015 Sep 28;34(6):719-26. doi: 10.1016/j.devcel.2015.08.012. Epub 2015 Sep 18.

Kim HY1, Pang MF1, Varner VD1, Kojima L1, Miller E2, Radisky DC2, Nelson CM3.


The airway epithelium develops into a tree-like structure via branching morphogenesis. Here, we show a critical role for localized differentiation of airway smooth muscle during epithelial bifurcation in the embryonic mouse lung. We found that during terminal bifurcation, changes in the geometry of nascent buds coincided with patterned smooth muscle differentiation. Evaluating spatiotemporal dynamics of α-smooth muscle actin (αSMA) in reporter mice revealed that αSMA-expressing cells appear at the basal surface of the future epithelial cleft prior to bifurcation and then increase in density as they wrap around the bifurcating bud. Disrupting this stereotyped pattern of smooth muscle differentiation prevents terminal bifurcation. Our results reveal stereotyped differentiation of airway smooth muscle adjacent to nascent epithelial buds and suggest that localized smooth muscle wrapping at the cleft site is required for terminal bifurcation during airway branching morphogenesis. Copyright © 2015 Elsevier Inc. All rights reserved.

PMID 26387457

Clonal Dynamics Reveal Two Distinct Populations of Basal Cells in Slow-Turnover Airway Epithelium

Cell Rep. 2015 Jul 7;12(1):90-101. doi: 10.1016/j.celrep.2015.06.011. Epub 2015 Jun 25.

Watson JK1, Rulands S2, Wilkinson AC3, Wuidart A4, Ousset M4, Van Keymeulen A4, Göttgens B3, Blanpain C5, Simons BD2, Rawlins EL6.


Epithelial lineages have been studied at cellular resolution in multiple organs that turn over rapidly. However, many epithelia, including those of the lung, liver, pancreas, and prostate, turn over slowly and may be regulated differently. We investigated the mouse tracheal epithelial lineage at homeostasis by using long-term clonal analysis and mathematical modeling. This pseudostratified epithelium contains basal cells and secretory and multiciliated luminal cells. Our analysis revealed that basal cells are heterogeneous, comprising approximately equal numbers of multipotent stem cells and committed precursors, which persist in the basal layer for 11 days before differentiating to luminal fate. We confirmed the molecular and functional differences within the basal population by using single-cell qRT-PCR and further lineage labeling. Additionally, we show that self-renewal of short-lived secretory cells is a feature of homeostasis. We have thus revealed early luminal commitment of cells that are morphologically indistinguishable from stem cells. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

PMID 26119728

Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors

Development. 2015 Jan 15;142(2):258-67. doi: 10.1242/dev.116855.

Mori M1, Mahoney JE2, Stupnikov MR1, Paez-Cortez JR2, Szymaniak AD3, Varelas X3, Herrick DB4, Schwob J4, Zhang H5, Cardoso WV6.


Basal cells are multipotent airway progenitors that generate distinct epithelial cell phenotypes crucial for homeostasis and repair of the conducting airways. Little is known about how these progenitor cells expand and transition to differentiation to form the pseudostratified airway epithelium in the developing and adult lung. Here, we show by genetic and pharmacological approaches that endogenous activation of Notch3 signaling selectively controls the pool of undifferentiated progenitors of upper airways available for differentiation. This mechanism depends on the availability of Jag1 and Jag2, and is key to generating a population of parabasal cells that later activates Notch1 and Notch2 for secretory-multiciliated cell fate selection. Disruption of this mechanism resulted in aberrant expansion of basal cells and altered pseudostratification. Analysis of human lungs showing similar abnormalities and decreased NOTCH3 expression in subjects with chronic obstructive pulmonary disease suggests an involvement of NOTCH3-dependent events in the pathogenesis of this condition. © 2015. Published by The Company of Biologists Ltd. KEYWORDS: Airway differentiation; Basal cells; COPD; Jagged; Lung regeneration; Notch; Progenitor cells; p63

PMID 25564622


Lung development: orchestrating the generation and regeneration of a complex organ

Development. 2014 Feb;141(3):502-13. doi: 10.1242/dev.098186.

Herriges M1, Morrisey EE.


The respiratory system, which consists of the lungs, trachea and associated vasculature, is essential for terrestrial life. In recent years, extensive progress has been made in defining the temporal progression of lung development, and this has led to exciting discoveries, including the derivation of lung epithelium from pluripotent stem cells and the discovery of developmental pathways that are targets for new therapeutics. These discoveries have also provided new insights into the regenerative capacity of the respiratory system. This Review highlights recent advances in our understanding of lung development and regeneration, which will hopefully lead to better insights into both congenital and acquired lung diseases. KEYWORDS: Branching morphogenesis; Epigenetics; Lung; Regeneration

PMID 24449833

Long noncoding RNAs are spatially correlated with transcription factors and regulate lung development

Genes Dev. 2014 Jun 15;28(12):1363-79. doi: 10.1101/gad.238782.114.

Herriges MJ1, Swarr DT2, Morley MP3, Rathi KS3, Peng T3, Stewart KM3, Morrisey EE4.


Long noncoding RNAs (lncRNAs) are thought to play important roles in regulating gene transcription, but few have well-defined expression patterns or known biological functions during mammalian development. Using a conservative pipeline to identify lncRNAs that have important biological functions, we identified 363 lncRNAs in the lung and foregut endoderm. Importantly, we show that these lncRNAs are spatially correlated with transcription factors across the genome. In-depth expression analyses of lncRNAs with genomic loci adjacent to the critical transcription factors Nkx2.1, Gata6, Foxa2 (forkhead box a2), and Foxf1 mimic the expression patterns of their protein-coding neighbor. Loss-of-function analysis demonstrates that two lncRNAs, LL18/NANCI (Nkx2.1-associated noncoding intergenic RNA) and LL34, play distinct roles in endoderm development by controlling expression of critical developmental transcription factors and pathways, including retinoic acid signaling. In particular, we show that LL18/NANCI acts upstream of Nkx2.1 and downstream from Wnt signaling to regulate lung endoderm gene expression. These studies reveal that lncRNAs play an important role in foregut and lung endoderm development by regulating multiple aspects of gene transcription, often through regulation of transcription factor expression. © 2014 Herriges et al.; Published by Cold Spring Harbor Laboratory Press. KEYWORDS: Nkx2.1; Wnt signaling; development; lncRNA; lung; retinoic acid

PMID 24939938

Alveolar progenitor and stem cells in lung development, renewal and cancer

Nature. 2014 Mar 13;507(7491):190-4. doi: 10.1038/nature12930. Epub 2014 Feb 5.

Desai TJ1, Brownfield DG2, Krasnow MA2.


Alveoli are gas-exchange sacs lined by squamous alveolar type (AT) 1 cells and cuboidal, surfactant-secreting AT2 cells. Classical studies suggested that AT1 arise from AT2 cells, but recent studies propose other sources. Here we use molecular markers, lineage tracing and clonal analysis to map alveolar progenitors throughout the mouse lifespan. We show that, during development, AT1 and AT2 cells arise directly from a bipotent progenitor, whereas after birth new AT1 cells derive from rare, self-renewing, long-lived, mature AT2 cells that produce slowly expanding clonal foci of alveolar renewal. This stem-cell function is broadly activated by AT1 injury, and AT2 self-renewal is selectively induced by EGFR (epidermal growth factor receptor) ligands in vitro and oncogenic Kras(G12D) in vivo, efficiently generating multifocal, clonal adenomas. Thus, there is a switch after birth, when AT2 cells function as stem cells that contribute to alveolar renewal, repair and cancer. We propose that local signals regulate AT2 stem-cell activity: a signal transduced by EGFR-KRAS controls self-renewal and is hijacked during oncogenesis, whereas another signal controls reprogramming to AT1 fate.

PMID 24499815


Lung mesenchymal expression of Sox9 plays a critical role in tracheal development

BMC Biol. 2013 Nov 25;11:117. doi: 10.1186/1741-7007-11-117.

Turcatel G, Rubin N, Menke DB, Martin G, Shi W, Warburton D1.


BACKGROUND: Embryonic lung development is instructed by crosstalk between mesenchyme and epithelia, which results in activation of transcriptional factors, such as Sox9, in a temporospatial manner. Sox9 is expressed in both distal lung epithelium and proximal lung mesenchyme. Here, we investigated the effect of lung mesenchyme-specific inducible deletion of Sox9 during murine lung development. RESULTS: Transgenic mice lacking Sox9 expression were unable to breathe and died at birth, with noticeable tracheal defects. Cartilage rings were missing, and the tracheal lumen was collapsed in the mutant trachea. In situ hybridization showed an altered expression pattern of Tbx4, Tbx5 and Fgf10 genes and marked reduction of Collagen2 expression in the tracheal mesenchyme. The tracheal phenotype was increasingly severe, with longer duration of deletion. Lymphatic vasculature was underdeveloped in the mutant trachea: Prox1, Lyve1, and Vegfr3 were decreased after Sox9 knockout. We also found that compared with normal tracheal epithelium, the mutant tracheal epithelium had an altered morphology with fewer P63-positive cells and more CC10-positive cells, fewer goblet cells, and downregulation of surfactant proteins A and C. CONCLUSION: The appropriate temporospatial expression of Sox9 in lung mesenchyme is necessary for appropriate tracheal cartilage formation, lymphatic vasculature system development, and epithelial differentiation. We uncovered a novel mechanism of lung epithelium differentiation: tracheal cartilage rings instruct the tracheal epithelium to differentiate properly during embryonic development. Thus, besides having a mechanical function, tracheal cartilage also appears to be a local signaling structure in the embryonic lung.

PMID 24274029

Lung epithelial branching program antagonizes alveolar differentiation

Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):18042-51. doi: 10.1073/pnas.1311760110. Epub 2013 Sep 20.

Chang DR, Martinez Alanis D, Miller RK, Ji H, Akiyama H, McCrea PD, Chen J. Author information


Mammalian organs, including the lung and kidney, often adopt a branched structure to achieve high efficiency and capacity of their physiological functions. Formation of a functional lung requires two developmental processes: branching morphogenesis, which builds a tree-like tubular network, and alveolar differentiation, which generates specialized epithelial cells for gas exchange. Much progress has been made to understand each of the two processes individually; however, it is not clear whether the two processes are coordinated and how they are deployed at the correct time and location. Here we show that an epithelial branching morphogenesis program antagonizes alveolar differentiation in the mouse lung. We find a negative correlation between branching morphogenesis and alveolar differentiation temporally, spatially, and evolutionarily. Gain-of-function experiments show that hyperactive small GTPase Kras expands the branching program and also suppresses molecular and cellular differentiation of alveolar cells. Loss-of-function experiments show that SRY-box containing gene 9 (Sox9) functions downstream of Fibroblast growth factor (Fgf)/Kras to promote branching and also suppresses premature initiation of alveolar differentiation. We thus propose that lung epithelial progenitors continuously balance between branching morphogenesis and alveolar differentiation, and such a balance is mediated by dual-function regulators, including Kras and Sox9. The resulting temporal delay of differentiation by the branching program may provide new insights to lung immaturity in preterm neonates and the increase in organ complexity during evolution. Comment in Balancing the developmental niches within the lung. [Proc Natl Acad Sci U S A. 2013]

PMID 24058167

Tracking X-ray microscopy for alveolar dynamics in live intact mice

Sci Rep. 2013 Feb 18;3:1304. doi: 10.1038/srep01304.

Chang S, Kwon N, Weon BM, Kim J, Rhee CK, Choi HS, Kohmura Y, Yamamoto M, Ishikawa T, Je JH. Source 1] X-ray Imaging Center, Pohang University of Science and Technology, San 31, Hyoja-dong, Pohang, 790-784, Korea [2] Department of Materials Science and Engineering, Pohang University of Science and Technology, San 31, Hyoja-dong, Pohang, 790-784, Korea.


Here we report a tracking X-ray microscopy (TrXM) as a novel methodology by using upper right lung apices alveoli in live intact mice. By enabling tracking of individual alveolar movements during respiration, TrXM identifies alveolar dynamics: individual alveoli in the upper lung apices show a small size increment as 4.9 ± 0.4% (mean ± s.e.m.) during respiration while their shapes look almost invariant. TrXM analysis in alveolar dynamics would be significant for better understanding of alveolar-based diseases, for instance, ventilator induced lung injury (VILI) in acute respiratory distress syndrome (ARDS).

PMID 23416838

Localized Fgf10 expression is not required for lung branching morphogenesis but prevents differentiation of epithelial progenitors

Development. 2013 Sep;140(18):3731-42. doi: 10.1242/dev.096560. Epub 2013 Aug 7.

Volckaert T, Campbell A, Dill E, Li C, Minoo P, De Langhe S. Author information


Localized Fgf10 expression in the distal mesenchyme adjacent to sites of lung bud formation has long been thought to drive stereotypic branching morphogenesis even though isolated lung epithelium branches in the presence of non-directional exogenous Fgf10 in Matrigel. Here, we show that lung agenesis in Fgf10 knockout mice can be rescued by ubiquitous overexpression of Fgf10, indicating that precisely localized Fgf10 expression is not required for lung branching morphogenesis in vivo. Fgf10 expression in the mesenchyme itself is regulated by Wnt signaling. Nevertheless, we found that during lung initiation simultaneous overexpression of Fgf10 is not sufficient to rescue the absence of primary lung field specification in embryos overexpressing Dkk1, a secreted inhibitor of Wnt signaling. However, after lung initiation, simultaneous overexpression of Fgf10 in lungs overexpressing Dkk1 is able to rescue defects in branching and proximal-distal differentiation. We also show that Fgf10 prevents the differentiation of distal epithelial progenitors into Sox2-expressing airway epithelial cells in part by activating epithelial β-catenin signaling, which negatively regulates Sox2 expression. As such, these findings support a model in which the main function of Fgf10 during lung development is to regulate proximal-distal differentiation. As the lung buds grow out, proximal epithelial cells become further and further displaced from the distal source of Fgf10 and differentiate into bronchial epithelial cells. Interestingly, our data presented here show that once epithelial cells are committed to the Sox2-positive airway epithelial cell fate, Fgf10 prevents ciliated cell differentiation and promotes basal cell differentiation. KEYWORDS: Basal cells, Branching, Dkk1, Fgf10, Lung development, Mouse, Wnt signaling

PMID 23924632

Species Development of Fetal Lungs

Gestational age (days)
Species Term Embryonic Pseudoglandular Canalicular Saccular
Human 280 < 42 52 - 112 112 - 168 168
Primate 168 < 42 57 - 80 80 - 140 140
Sheep 150 < 40 40 - 80 80 - 120 120
Rabbit 32 < 18 21 - 24 24 - 27 27
Rat 22 < 13 16 - 19 19 - 20 21
Mouse 20 < 9 16 18 19

<pubmed>10852845</pubmed>| PMC1637815 | Environ Health Perspect.

Sheep data -


Multiple roles and interactions of Tbx4 and Tbx5 in development of the respiratory system

PLoS Genet. 2012;8(8):e1002866. doi: 10.1371/journal.pgen.1002866. Epub 2012 Aug 2.

Arora R, Metzger RJ, Papaioannou VE. Author information


Normal development of the respiratory system is essential for survival and is regulated by multiple genes and signaling pathways. Both Tbx4 and Tbx5 are expressed throughout the mesenchyme of the developing lung and trachea; and, although multiple genes are known to be required in the epithelium, only Fgfs have been well studied in the mesenchyme. In this study, we investigated the roles of Tbx4 and Tbx5 in lung and trachea development using conditional mutant alleles and two different Cre recombinase transgenic lines. Loss of Tbx5 leads to a unilateral loss of lung bud specification and absence of tracheal specification in organ culture. Mutants deficient in Tbx4 and Tbx5 show severely reduced lung branching at mid-gestation. Concordant with this defect, the expression of mesenchymal markers Wnt2 and Fgf10, as well as Fgf10 target genes Bmp4 and Spry2, in the epithelium is downregulated. Lung branching undergoes arrest ex vivo when Tbx4 and Tbx5 are both completely lacking. Lung-specific Tbx4 heterozygous;Tbx5 conditional null mice die soon after birth due to respiratory distress. These pups have small lungs and show severe disruptions in tracheal/bronchial cartilage rings. Sox9, a master regulator of cartilage formation, is expressed in the trachea; but mesenchymal cells fail to condense and consequently do not develop cartilage normally at birth. Tbx4;Tbx5 double heterozygous mutants show decreased lung branching and fewer tracheal cartilage rings, suggesting a genetic interaction. Finally, we show that Tbx4 and Tbx5 interact with Fgf10 during the process of lung growth and branching but not during tracheal/bronchial cartilage development.

PMID 22876201

Evidence for adult lung growth in humans

N Engl J Med. 2012 Jul 19;367(3):244-7. doi: 10.1056/NEJMoa1203983.

Butler JP, Loring SH, Patz S, Tsuda A, Yablonskiy DA, Mentzer SJ. Source Division of Sleep Disorders, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Abstract A 33-year-old woman underwent a right-sided pneumonectomy in 1995 for treatment of a lung adenocarcinoma. As expected, there was an abrupt decrease in her vital capacity, but unexpectedly, it increased during the subsequent 15 years. Serial computed tomographic (CT) scans showed progressive enlargement of the remaining left lung and an increase in tissue density. Magnetic resonance imaging (MRI) with the use of hyperpolarized helium-3 gas showed overall acinar-airway dimensions that were consistent with an increase in the alveolar number rather than the enlargement of existing alveoli, but the alveoli in the growing lung were shallower than in normal lungs. This study provides evidence that new lung growth can occur in an adult human.

PMID 22808959

Role of skeletal muscle in lung development

Histol Histopathol. 2012 Jul;27(7):817-26.

Baguma-Nibasheka M, Gugic D, Saraga-Babic M, Kablar B. Source Department of Anatomy and Neurobiology, Dalhousie University Faculty of Medicine, Halifax, Canada.


Skeletal (striated) muscle is one of the four basic tissue types, together with the epithelium, connective and nervous tissues. Lungs, on the other hand, develop from the foregut and among various cell types contain smooth, but not skeletal muscle. Therefore, during earlier stages of development, it is unlikely that skeletal muscle and lung depend on each other. However, during the later stages of development, respiratory muscle, primarily the diaphragm and the intercostal muscles, execute so called fetal breathing-like movements (FBMs), that are essential for lung growth and cell differentiation. In fact, the absence of FBMs results in pulmonary hypoplasia, the most common cause of death in the first week of human neonatal life. Most knowledge on this topic arises from in vivo experiments on larger animals and from various in vitro experiments. In the current era of mouse mutagenesis and functional genomics, it was our goal to develop a mouse model for pulmonary hypoplasia. We employed various genetically engineered mice lacking different groups of respiratory muscles or lacking all the skeletal muscle and established the criteria for pulmonary hypoplasia in mice, and therefore established a mouse model for this disease. We followed up this discovery with systematic subtractive microarray analysis approach and revealed novel functions in lung development and disease for several molecules. We believe that our approach combines elements of both in vivo and in vitro approaches and allows us to study the function of a series of molecules in the context of lung development and disease and, simultaneously, in the context of lung's dependence on skeletal muscle-executed FBMs.

PMID 22648538


Patterning and plasticity in development of the respiratory lineage

Dev Dyn. 2011 Mar;240(3):477-85. doi: 10.1002/dvdy.22504. Epub 2010 Dec 7.

Domyan ET, Sun X.


The mammalian respiratory lineage, consisting of the trachea and lung, originates from the ventral foregut in an early embryo. Reciprocal signaling interactions between the foregut epithelium and its associated mesenchyme guide development of the respiratory endoderm, from a naive sheet of cells to multiple cell types that line a functional organ. This review synthesizes current understanding of the early events in respiratory system development, focusing on three main topics: (1) specification of the respiratory system as a distinct organ of the endoderm, (2) patterning and differentiation of the nascent respiratory epithelium along its proximal-distal axis, and (3) plasticity of the respiratory cells during the process of development. This review also highlights areas in need of further study, including determining how early endoderm cells rapidly switch their responses to the same signaling cues during development, and how the general proximal-distal pattern of the lung is converted to fine-scale organization of multiple cell types along this axis. Copyright © 2010 Wiley-Liss, Inc.

PMID 21337460

The building blocks of mammalian lung development

Dev Dyn. 2011 Mar;240(3):463-76. doi: 10.1002/dvdy.22482. Epub 2010 Nov 18.

Rawlins EL.

Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, United Kingdom.

Abstract Progress has recently been made in identifying progenitor cell populations in the embryonic lung. Some progenitor cell types have been definitively identified by lineage-tracing studies. However, others are not as well characterized and their existence is inferred on the basis of lung morphology, or mutant phenotypes. Here, I focus on lung development after the specification of the initial lung primordium. The evidence for various lung embryonic progenitor cell types is discussed and future experiments are suggested. The regulation of progenitor proliferation in the embryonic lung, and its coordinate control with morphogenesis, is also discussed. In addition, the relationship between embryonic and adult lung progenitors is considered. Developmental Dynamics 240:463-476, 2011. © 2010 Wiley-Liss, Inc.

Copyright © 2010 Wiley-Liss, Inc. PMID: 21337459


Impact of environmental chemicals on lung development

Environ Health Perspect. 2010 Aug;118(8):1155-64. Epub 2010 May 5.

Miller MD, Marty MA. Source Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, California, USA. Abstract BACKGROUND: Disruption of fundamental biologic processes and associated signaling events may result in clinically significant alterations in lung development. OBJECTIVES: We reviewed evidence on the impact of environmental chemicals on lung development and key signaling events in lung morphogenesis, and the relevance of potential outcomes to public health and regulatory science . DATA SOURCES: We evaluated the peer-reviewed literature on developmental lung biology and toxicology, mechanistic studies, and supporting epidemiology. DATA SYNTHESIS: Lung function in infancy predicts pulmonary function throughout life. In utero and early postnatal exposures influence both childhood and adult lung structure and function and may predispose individuals to chronic obstructive lung disease and other disorders. The nutritional and endogenous chemical environment affects development of the lung and can result in altered function in the adult. Studies now suggest that similar adverse impacts may occur in animals and humans after exposure to environmentally relevant doses of certain xenobiotics during critical windows in early life. Potential mechanisms include interference with highly conserved factors in developmental processes such as gene regulation, molecular signaling, and growth factors involved in branching morphogenesis and alveolarization. CONCLUSIONS: Assessment of environmental chemical impacts on the lung requires studies that evaluate specific alterations in structure or function-end points not regularly assessed in standard toxicity tests. Identifying effects on important signaling events may inform protocols of developmental toxicology studies. Such knowledge may enable policies promoting true primary prevention of lung diseases. Evidence of relevant signaling disruption in the absence of adequate developmental toxicology data should influence the size of the uncertainty factors used in risk assessments.

PMID 20444669

Epithelial N-cadherin and nuclear β-catenin are up-regulated during early development of human lung

Kaarteenaho R, Lappi-Blanco E, Lehtonen S.

BMC Dev Biol. 2010 Nov 16;10:113.

PMID 21080917 | PMC2995473 | BMC Dev Biol.

  • Pseudoglandular period (weeks 12 to 16)
    • E-cadherin was strongly expressed in all the epithelial cells of developing bronchi and bronchioles of all sizes including also the smallest structures
    • N-cadherin was also moderately or strongly expressed in the epithelium of bronchi and largest bronchioles whereas it was negative in the smallest developing airways
    • β-catenin displayed strong membrane-bound positivity in bronchi and larger bronchioles, whereas its expression in the small developing airways was mainly strongly nuclear.
  • Canalicular period (weeks 16 to 28)
  • Saccular (weeks 28 to 36) period
  • Alveolar (weeks 36 to 40) period

Regulation of the pulmonary circulation in the fetus and newborn

Physiol Rev. 2010 Oct;90(4):1291-335.

Gao Y, Raj JU.

Department of Physiology and Pathophysiology, Peking University, Health Science Center, Beijing, China. Abstract During the development of the pulmonary vasculature in the fetus, many structural and functional changes occur to prepare the lung for the transition to air breathing. The development of the pulmonary circulation is genetically controlled by an array of mitogenic factors in a temporo-spatial order. With advancing gestation, pulmonary vessels acquire increased vasoreactivity. The fetal pulmonary vasculature is exposed to a low oxygen tension environment that promotes high intrinsic myogenic tone and high vasocontractility. At birth, a dramatic reduction in pulmonary arterial pressure and resistance occurs with an increase in oxygen tension and blood flow. The striking hemodynamic differences in the pulmonary circulation of the fetus and newborn are regulated by various factors and vasoactive agents. Among them, nitric oxide, endothelin-1, and prostaglandin I(2) are mainly derived from endothelial cells and exert their effects via cGMP, cAMP, and Rho kinase signaling pathways. Alterations in these signaling pathways may lead to vascular remodeling, high vasocontractility, and persistent pulmonary hypertension of the newborn.

PMID 20959617

Preparing for the first breath: genetic and cellular mechanisms in lung development

Dev Cell. 2010 Jan 19;18(1):8-23.

Morrisey EE, Hogan BL.

Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Abstract The mammalian respiratory system--the trachea and the lungs--arises from the anterior foregut through a sequence of morphogenetic events involving reciprocal endodermal-mesodermal interactions. The lung itself consists of two highly branched, tree-like systems--the airways and the vasculature--that develop in a coordinated way from the primary bud stage to the generation of millions of alveolar gas exchange units. We are beginning to understand some of the molecular and cellular mechanisms that underlie critical processes such as branching morphogenesis, vascular development, and the differentiation of multipotent progenitor populations. Nevertheless, many gaps remain in our knowledge, the filling of which is essential for understanding respiratory disorders, congenital defects in human neonates, and how the disruption of morphogenetic programs early in lung development can lead to deficiencies that persist throughout life.

PMID 20152174


Wnt2/2b and beta-catenin signaling are necessary and sufficient to specify lung progenitors in the foregut

Dev Cell. 2009 Aug;17(2):290-8.

Goss AM, Tian Y, Tsukiyama T, Cohen ED, Zhou D, Lu MM, Yamaguchi TP, Morrisey EE. Source Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.


Patterning of the primitive foregut promotes appropriate organ specification along its anterior-posterior axis. However, the molecular pathways specifying foregut endoderm progenitors are poorly understood. We show here that Wnt2/2b signaling is required to specify lung endoderm progenitors within the anterior foregut. Embryos lacking Wnt2/2b expression exhibit complete lung agenesis and do not express Nkx2.1, the earliest marker of the lung endoderm. In contrast, other foregut endoderm-derived organs, including the thyroid, liver, and pancreas, are correctly specified. The phenotype observed is recapitulated by an endoderm-restricted deletion of beta-catenin, demonstrating that Wnt2/2b signaling through the canonical Wnt pathway is required to specify lung endoderm progenitors within the foregut. Moreover, activation of canonical Wnt/beta-catenin signaling results in the reprogramming of esophagus and stomach endoderm to a lung endoderm progenitor fate. Together, these data reveal that canonical Wnt2/2b signaling is required for the specification of lung endoderm progenitors in the developing foregut.

PMID: 19686689

Growth of the lung parenchyma early in life

Am J Respir Crit Care Med. 2009 Jan 15;179(2):134-7. Epub 2008 Nov 7.

Balinotti JE, Tiller CJ, Llapur CJ, Jones MH, Kimmel RN, Coates CE, Katz BP, Nguyen JT, Tepper RS. Source Department of Pediatrics, Indiana University Medical Center, James Whitcomb Riley Hospital for Children, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana 46202-5225, USA.


RATIONALE: Early in life, lung growth can occur by alveolarization, an increase in the number of alveoli, as well as expansion. We hypothesized that if lung growth early in life occurred primarily by alveolarization, then the ratio of pulmonary diffusion capacity of carbon monoxide (Dl(CO)) to alveolar volume (V(A)) would remain constant; however, if lung growth occurred primarily by alveolar expansion, then Dl(CO)/V(A) would decline with increasing age, as observed in older children and adolescents. OBJECTIVES: To evaluate the relationship between alveolar volume and pulmonary diffusion capacity early in life. METHODS: In 50 sleeping infants and toddlers, with equal number of males and females between the ages of 3 and 23 months, we measured Dl(CO) and V(A) using single breath-hold maneuvers at elevated lung volumes. MEASUREMENTS AND MAIN RESULTS: Dl(CO) and V(A) increased with increasing age and body length. Males had higher Dl(CO) and V(A) when adjusted for age, but not when adjusted for length. Dl(CO) increased with V(A); there was no gender difference when Dl(CO) was adjusted for V(A). The ratio of Dl(CO)/V(A) remained constant with age and body length. CONCLUSIONS: Our results suggest that surface area for diffusion increases proportionally with alveolar volume in the first 2 years of life. Larger Dl(CO) and V(A) for males than females when adjusted for age, but not when adjusted for length, is primarily related to greater body length in boys. The constant ratio for Dl(CO)/V(A) in infants and toddlers is consistent with lung growth in this age occurring primarily by the addition of alveoli rather than the expansion of alveoli.

PMID 18996997


Evidence and structural mechanism for late lung alveolarization

Am J Physiol Lung Cell Mol Physiol. 2008 Feb;294(2):L246-54. Epub 2007 Nov 21.

Schittny JC, Mund SI, Stampanoni M. Source Institute of Anatomy, University of Bern, Baltzerstrasse 2, Bern, Switzerland.


According to the current view, the formation of new alveolar septa from preexisting ones ceases due to the reduction of a double- to a single-layered capillaries network inside the alveolar septa (microvasculature maturation postnatal days 14-21 in rats). We challenged this view by measuring stereologically the appearance of new alveolar septa and by studying the alveolar capillary network in three-dimensional (3-D) visualizations obtained by high-resolution synchrotron radiation X-ray tomographic microscopy. We observed that new septa are formed at least until young adulthood (rats, days 4-60) and that roughly half of the new septa are lifted off of mature septa containing single-layered capillary networks. At the basis of newly forming septa, we detected a local duplication of the capillary network. We conclude that new alveoli may be formed in principle at any time and at any location inside the lung parenchyma and that lung development continues into young adulthood. We define two phases during developmental alveolarization. Phase one (days 4-21), lifting off of new septa from immature preexisting septa, and phase two (day 14 through young adulthood), formation of septa from mature preexisting septa. Clinically, our results ask for precautions using drugs influencing structural lung development during both phases of alveolarization.

PMID 18032698


Structural aspects of postnatal lung development - alveolar formation and growth

Biol Neonate. 2006;89(4):313-22. Epub 2006 Jun 1.

Burri PH. Source Institute of Anatomy, University of Berne, Berne, Switzerland.


The human lung is born with a fraction of the adult complement of alveoli. The postnatal stages of human lung development comprise an alveolar stage, a stage of microvascular maturation, and very likely a stage of late alveolarization. The characteristic structural features of the alveolar stage are well known; they are very alike in human and rat lungs. The bases for alveolar formation are represented by immature inter-airspace walls with two capillary layers with a central sheet of connective tissue. Interalveolar septa are formed by folding up of one of the two capillary layers. In the alveolar stage, alveolar formation occurs rapidly and is typically very conspicuous in both species; it has therefore been termed 'bulk alveolarization'. During and after alveolarization the septa with double capillary networks are restructured to the mature form with a single network. This happens in the stage of microvascular maturation. After these steps the lung proceeds to a phase of growth during which capillary growth by intussusception plays an important role in supporting gas exchange. In view of reports that alveoli are added after the stage of microvascular maturation, the question arises whether the present concept of alveolar formation needs revision. On the basis of morphological and experimental findings we can state that mature lungs contain all the features needed for 'late alveolarization' by the classical septation process. Because of the high plasticity of the lung tissues, late alveolarization or some forms of compensatory alveolar formation may be considered for the human lung. Copyright (c) 2006 S. Karger AG, Basel.

PMID 16770071


Lung growth and development

Front Biosci. 2003 Jan 1;8:d392-415.

Chinoy MR.

Lung Development Research Program, Department of Surgery, Hershey Medical Center, The Pennsylvania State University, Hershey, PA 17033-0850, USA. Abstract The organogenesis of lung involves several complex mechanisms, including interactions between cells originating from two germ layers--endoderm and mesoderm. Regulation of lung branching morphogenesis with reference to its architecture, growth pattern, differentiation, interactions between epithelium and mesenchyme and / or endothelium, as well as genes regulating these processes have been addressed by the pulmonary biologists through careful molecular biology and genetic experimental approaches. The mammalian lung develops by outpouching from the foregut endoderm as two lung buds into the surrounding splanchnic mesenchyme. Several different regions of the foregut are specified to develop into different thoracic and visceral organs. The lung-buds further elongate and branch, and the foregut longitudinally gets separated into esophagus and trachea. In rodents (mice and rats), this occurs around embryonic day 11, where the right lung bud develops into four different lobes and left lung develops as a single lobe. In humans, these processes occur by 3-4 weeks of embryonic development, where the right lung is a trilobar lung and the left lung is a bilobar lung. Several generations of dichotomous branching occur during embryonic development, followed by secularization and alveolarization pre- and post-natally, which transform a fluid-filled lung into an air-breathing lung able to sustain the newborn. During these different developmental stages from embryonic to newborn stage, the lung architecture undergoes profound changes, which are marked by a series of programmed events regulated by master genes (e.g., homeobox genes), nuclear transcription factors, hormones, growth factors and other factors. These programmed events can be altered by undesirable exposure to overdoses of hormones/vitamins/growth factors, synthetic drugs, environmental toxins, radiation and other agents. In the recent years molecular techniques have opened avenues to study specific functions of genes or their products (proteins) in vivo or in vitro at a cellular or an organelle level, some of these include targeted disruption, knock-in / knock-out genes, in vitro mutagenesis, use of sense and anti-sense oligonucleotides. Some of these aspects with reference to regulation of normal lung development and growth and a specific example of pulmonary hypoplasia as an abnormal lung formation are discussed in this review.

PMID: 12456356


Growth factors in lung development and disease: friends or foe?

Respir Res. 2002;3:2. Epub 2001 Oct 9.

Desai TJ, Cardoso WV. Source Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA. Abstract Growth factors mediate tissue interactions and regulate a variety of cellular functions that are critical for normal lung development and homeostasis. Besides their involvement in lung pattern formation, growth and cell differentiation during organogenesis, these factors have been also implicated in modulating injury-repair responses of the adult lung. Altered expression of growth factors, such as transforming growth factor beta1, vascular endothelial growth factor and epidermal growth factor, and/or their receptors, has been found in a number of pathological lung conditions. In this paper, we discuss the dual role of these molecules in mediating beneficial feedback responses or responses that can further damage lung integrity; we shall also discuss the basis for their prospective use as therapeutic agents.

PMID 11806837

Airway and blood vessel interaction during lung development

J Anat. 2002 Oct;201(4):325-34.

Hislop AA. Source Unit of Vascular Biology and Pharmacology, Institute of Child Health, London, UK.


In the adult lung the pulmonary arteries run alongside the airways and the pulmonary veins show a similar branching pattern to the arteries, though separated from them. During early fetal development the airways act as a template for pulmonary blood vessel development in that the vessels form by vasculogenesis around the branching airways. In later lung development the capillary bed is essential for alveolar formation. This paper reviews evidence for the interaction of the airways and blood vessels in both normal and abnormal lung development.

PMID 12430957

Origin, differentiation, and maturation of human pulmonary veins

Am J Respir Cell Mol Biol. 2002 Mar;26(3):333-40.

Hall SM, Hislop AA, Haworth SG.

Unit of Vascular Biology and Pharmacology, Institute of Child Health, University College, London, United Kingdom. Abstract Recent studies on human embryonic and fetal lungs show that the pulmonary arteries form by vasculogenesis. Little is known of the early development of the pulmonary veins. Using immunohistochemical techniques and serial reconstruction, we studied 18 fetal and neonatal lungs. Sections were stained with antibodies specific for endothelium (CD31, von Willebrand factor) and smooth muscle (alpha and gamma smooth muscle actin, smooth muscle myosin, calponin, caldesmon, and desmin) and antibodies specific for the matrix glycoprotein tenascin, the receptor protein tyrosine kinase EphB4, and its ligand ephrinB2. Kiel University-raised antibody number 67 (Ki67) expression allowed qualitative assessment of cell replication. By 34 d gestation, there was continuity between the aortic sac, pulmonary arteries, capillaries, pulmonary veins, and atrium. The pulmonary veins formed by vasculogenesis in the mesenchyme surrounding the terminal buds during the pseudoglandular period and probably by angiogenesis in the canalicular and alveolar stages. EphB4 and ephrinB2 did not distinguish between presumptive venous and arterial endothelium as they do in mouse. All venous smooth muscle cells derived directly from the mesenchyme, gradually acquiring smooth muscle specific proteins from 56 d gestation. Thus, both pulmonary arteries and veins arise by vasculogenesis, but the origins of their smooth muscle cells and their cytoskeletal protein content are different.

PMID 11867341

Airway and blood vessel interaction during lung development

J Anat. 2002 Oct;201(4):325-34.

Hislop AA. Author information

Abstract In the adult lung the pulmonary arteries run alongside the airways and the pulmonary veins show a similar branching pattern to the arteries, though separated from them. During early fetal development the airways act as a template for pulmonary blood vessel development in that the vessels form by vasculogenesis around the branching airways. In later lung development the capillary bed is essential for alveolar formation. This paper reviews evidence for the interaction of the airways and blood vessels in both normal and abnormal lung development.

Histology images of lung stages

PMID 12430957

Invited review: Clearance of lung liquid during the perinatal period

J Appl Physiol. 2002 Oct;93(4):1542-8.

Barker PM, Olver RE.

Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina 27599-7220, USA.


At birth, the distal lung epithelium undergoes a profound phenotypic switch from secretion to absorption in the course of adaptation to air breathing. In this review, we describe the developmental regulation of key membrane transport proteins and the way in which epinephrine, oxygen, glucocorticoids, and thyroid hormones interact to bring about this crucial change in function. Evidence from molecular, transgenic, cell culture, and whole lung studies is presented, and the clinical consequences of the failure of the physiological mechanisms that underlie perinatal lung liquid absorption are discussed.

PMID 12235057


Prenatal origins of human intrapulmonary arteries: formation and smooth muscle maturation

Am J Respir Cell Mol Biol. 2000 Aug;23(2):194-203.

Hall SM, Hislop AA, Pierce CM, Haworth SG.

Unit of Vascular Biology and Pharmacology, Cardiovascular and Respiratory Sciences, Institute of Child Health, University College of London, London, United Kingdom.

Abstract Recent studies on the morphogenesis of the pulmonary arteries have focused on nonhuman species such as the chick and the mouse. Using immunohistochemical techniques, we have studied 16 lungs from human embryos and fetuses from 28 d of gestation to newborn, using serial sections stained with a panel of antibodies specific for endothelium, smooth muscle, and extracellular matrix proteins. Cell replication was also assessed. Serial reconstruction showed a continuity of circulation between the heart and the capillary plexus from at least 38 d of gestation. The intrapulmonary arteries appeared to be derived from a continuous expansion of the primary capillary plexus that is from within the mesenchyme, by vasculogenesis. The arteries formed by continuous coalescence of endothelial tubes alongside the newly formed airway. Findings were consistent with the pulmonary arterial smooth muscle cells being derived from three sites in a temporally distinct sequence: the earliest from the bronchial smooth muscle, later from the mesenchyme surrounding the arteries, and last from the endothelial cells. Despite their different origins, all smooth muscle cells followed the same sequence of expression of smooth muscle-specific cytoskeletal proteins with increasing age. The order of appearance of these maturing proteins was from the subendothelial cells outward across the vessel wall and from hilum to periphery. The airways would seem to act as a template for pulmonary artery development. This study provides a framework for studying the signaling mechanisms controlling the various aspects of lung development.

intrapulmonary arteries

  • appeared to be derived from a continuous expansion of the primary capillary plexus from within the mesenchyme, by vasculogenesis.
  • arteries formed by continuous coalescence of endothelial tubes alongside the newly formed airway.

pulmonary arterial smooth muscle cells derived from three sites in a temporally distinct sequence

  1. earliest from the bronchial smooth muscle
  2. from the mesenchyme surrounding the arteries
  3. last from the endothelial cells.
  • all smooth muscle cells followed the same sequence of expression of smooth muscle-specific cytoskeletal proteins with increasing age.
  • order of appearance of these maturing proteins was from the subendothelial cells outward across the vessel wall and from hilum to periphery.

The airways would seem to act as a template for pulmonary artery development.

PMID 10919986

Prenatal origins of human intrapulmonary arteries: formation and smooth muscle maturation

Am J Respir Cell Mol Biol. 2000 Aug;23(2):194-203.

Hall SM, Hislop AA, Pierce CM, Haworth SG. Source Unit of Vascular Biology and Pharmacology, Cardiovascular and Respiratory Sciences, Institute of Child Health, University College of London, London, United Kingdom.


Recent studies on the morphogenesis of the pulmonary arteries have focused on nonhuman species such as the chick and the mouse. Using immunohistochemical techniques, we have studied 16 lungs from human embryos and fetuses from 28 d of gestation to newborn, using serial sections stained with a panel of antibodies specific for endothelium, smooth muscle, and extracellular matrix proteins. Cell replication was also assessed. Serial reconstruction showed a continuity of circulation between the heart and the capillary plexus from at least 38 d of gestation. The intrapulmonary arteries appeared to be derived from a continuous expansion of the primary capillary plexus that is from within the mesenchyme, by vasculogenesis. The arteries formed by continuous coalescence of endothelial tubes alongside the newly formed airway. Findings were consistent with the pulmonary arterial smooth muscle cells being derived from three sites in a temporally distinct sequence: the earliest from the bronchial smooth muscle, later from the mesenchyme surrounding the arteries, and last from the endothelial cells. Despite their different origins, all smooth muscle cells followed the same sequence of expression of smooth muscle-specific cytoskeletal proteins with increasing age. The order of appearance of these maturing proteins was from the subendothelial cells outward across the vessel wall and from hilum to periphery. The airways would seem to act as a template for pulmonary artery development. This study provides a framework for studying the signaling mechanisms controlling the various aspects of lung development.

PMID 10919986


Development of the innervation and airway smooth muscle in human fetal lung

Am J Respir Cell Mol Biol. 1999 Apr;20(4):550-60.

Sparrow MP, Weichselbaum M, McCray PB.

Department of Physiology, University of Western Australia, Nedlands, Australia. Abstract Human and porcine fetal airways have been shown to contract spontaneously from the first trimester, the latter also contracting in response to neural stimulation. Our object was to map immunohistochemically the innervation and its relationship to the airway smooth muscle (ASM) in the human fetal lung from early gestation to the postnatal period. Whole mounts of the bronchial tree were stained with antibodies to the pan-neuronal marker protein gene product 9.5, the Schwann cell marker S-100, and the ASM contractile protein alpha-actin, and imaged using confocal microscopy. By the end of the embryonic period (53 d gestation), the branching epithelial tubules in the primordial lung were covered with ASM to the base of the terminal sacs. An extensive plexus of nerve trunks containing nerve bundles, forming ganglia, and Schwann cells ensheathed the ASM. By 16 wk (canalicular stage), maturation of the innervation was advanced with two major nerve trunks running the length of the bronchial tree, giving rise to varicosed fibers lying on the ASM. An extensive nerve plexus in the mucosa was also present. The distal airways of infants who had died of Sudden Infant Death Syndrome were also covered with smooth muscle and were well innervated. Thus, an essentially complete coat of ASM and an abundant neural plexus ensheathing the airways are an integral part of the branching epithelial tubules from early in lung development.

PMID: 10100986


Development of the right outflow tract and pulmonary arterial supply

Ann R Coll Surg Engl. 1975 Oct;57(4):186-97.

Skidmore FD.


The branchial arch vessels of the human embryo have been studied by histological and radiographic methods and the modelling that occurs during the period Day 25-Day 52 postfertilization is described. It has been shown that the myoendocardial reticulum is reamed out by blood flow and it is suggested that hydrodynamic force is the fundamental factor which determines chamber structure of the heart and flow pattern in the outflow tracts and great vessels. The sixth aortic arch vessels contribute tissue to the pulmonary trunk and proximal pulmonary arteries. The 'postbranchial pulmonary arteries' are morphologically distinct and form the pulmonary arteries at the lung hila. The primitive pulmonary plexus around the tips of the developing tracheobronchial primordia is formed from segmental vessels arising from the dorsal aorta. Bronchial arteries can be demonstrated only late in intrauterine life. The numerous bronchopulmonary precapillary anastomoses which are found in the fetus at this time have been demonstrated radiographically.

PMID 1103698


Respiratory System Development

  • ‘’’asthma - Flow limitation during tidal expiration in early life significantly associated with the development of physician-diagnosed asthma by the age of 2 years. Infants with abnormal lung function soon after birth may have a genetic predisposition to asthma or other airway abnormalities that predict the risk of subsequent lower respiratory tract illness. PMID 8176553
  • ‘’’azygos lobe - Common condition (0.5% of population). The right lung upper lobe expands either side of the posterior cardinal. There is also some course variability of the phrenic nerve in the presence of an azygos lobe.

  • ‘’’bronchopulmonary dysplasia - (BPD) A chronic lung disease which can occur following premature birth and related lung injury. Most infants who develop BPD are born more than 10 weeks before their due dates, weigh less than 1,000 grams (about 2 pounds) at birth, and have breathing problems.
  • ‘’’congenital diaphragmatic hernia - (1 in 3,000 live births) Failure of the pleuroperitoneal foramen (foramen of Bochdalek) to close (left side), allows viscera into thorax -iIntestine, stomach or spleen can enter the pleural cavity, compressing the lung. rare (Morgagni hernia) -an opening in the front of the diaphragm. Congenital Diaphragmatic Hernia | GeneReviews
  • ‘’’congenital laryngeal webs - Laryngeal abnormality due to embryonic (week 10) incomplete recanalization of the laryngotracheal tube during the fetal period. Rare abnormality occuring mainly at the level of the vocal folds (glottis).
  • ‘’’cystic fibrosis - Inherited disease of the mucus and sweat glands, causes mucus to be thick and sticky. Clogging the lungs, causing breathing problems and encouraging bacterial grow. (Covered elsewhere in the course)
  • ‘’’environmental factors term referring to developmental environment impact on respiratory system. <pubmed>20444669</pubmed>
  • hyaline membrane disease - (Newborn Respiratory Distress Syndrome) a membrane-like substance from damaged pulmonary cells.
  • ‘’’lobar emphysema (Overinflated Lung) - There is an overinflated left upper lobe There is a collapsed lower lobe The left lung is herniating across the mediastinum
  • ‘’’meconium aspiration syndrome - (MAS) Meconium is the gastrointestinal contents that accumulate in the intestines during the fetal period. Fetal stress in the third trimester, prior to/at/ or during parturition can lead to premature meconium discharge into the amniotic fluid and sunsequent ingestion by the fetus and damage to respiratory function. Damage to placental vessels meconium myonecrosis may also occur.
  • ‘’’newborn respiratory distress syndrome - (Hyaline Membrane Disease) membrane-like substance from damaged pulmonary cells, absence of surfactant, if prolonged can be irreversible, intrauterine asphyxia, prematurity and maternal diabetes medline plus | eMedicine
  • ‘’’tracheoesophageal fistula - Tracheo-Oesophageal Fistula, Oesophageal Atresia - Oesophageal Atresia with or without tracheo-oesophageal fistula Fistula - an abnormal communication between 2 structures (organs, vessels, cavities) that do not normally connect.