Talk:Respiratory System - Postnatal

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Cite this page: Hill, M.A. (2021, September 21) Embryology Respiratory System - Postnatal. Retrieved from


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.

Institute of Anatomy, University of Bern, Baltzerstrasse 2, 3012, Bern, Switzerland. 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


Sonic Hedgehog Signaling Regulates Myofibroblast Function during Alveolar Septum Formation in Murine Postnatal Lung

Am J Respir Cell Mol Biol. 2017 Sep;57(3):280-293. doi: 10.1165/rcmb.2016-0268OC.

Kugler MC1, Loomis CA2,3,4, Zhao Z3, Cushman JC5, Liu L1, Munger JS1,2. Author information 1 1 Division of Pulmonary, Critical Care and Sleep Medicine. 2 2 Department of Cell Biology. 3 3 Department of Pathology. 4 4 Department of Dermatology, New York University School of Medicine, New York, New York; and. 5 5 University of Michigan, Ann Arbor, Michigan. Abstract Sonic Hedgehog (Shh) signaling regulates mesenchymal proliferation and differentiation during embryonic lung development. In the adult lung, Shh signaling maintains mesenchymal quiescence and is dysregulated in diseases such as idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease. Our previous data implicated a role for Shh in postnatal lung development. Here, we report a detailed analysis of Shh signaling during murine postnatal lung development. We show that Shh pathway expression and activity during alveolarization (postnatal day [P] 0-P14) are distinct from those during maturation (P14-P24). This biphasic pattern is paralleled by the transient presence of Gli1+;α-smooth muscle actin (α-SMA)+ myofibroblasts in the growing alveolar septal tips. Carefully timed inhibition of Hedgehog (Hh) signaling during alveolarization defined mechanisms by which Shh influences the mesenchymal compartment. First, interruption of Hh signaling at earlier time points results in increased lung compliance and wall structure defects of increasing severity, ranging from moderately enlarged alveolar airspaces to markedly enlarged airspaces and fewer secondary septa. Second, Shh signaling is required for myofibroblast differentiation: Hh inhibition during early alveolarization almost completely eliminates Gli1+;α-SMA+ cells at the septal tips, and Gli1-lineage tracing revealed that Gli1+ cells do not undergo apoptosis after Hh inhibition but remain in the alveolar septa and are unable to express α-SMA. Third, Shh signaling is vital to mesenchymal proliferation during alveolarization, as Hh inhibition decreased proliferation of Gli1+ cells and their progeny. Our study establishes Shh as a new alveolarization-promoting factor that might be affected in perinatal lung diseases that are associated with impaired alveolarization. KEYWORDS: Sonic hedgehog signaling; fibroblast; myofibroblast; postnatal lung development; α-smooth muscle actin PMID: 28379718 PMCID: PMC5625221 DOI: 10.1165/rcmb.2016-0268OC


Transplantation of alveolar type II cells stimulates lung regeneration during compensatory lung growth in adult rats

J Thorac Cardiovasc Surg. 2012 Mar;143(3):711-719.e2. Epub 2011 Oct 27.

Wada H, Yoshida S, Suzuki H, Sakairi Y, Mizobuchi T, Komura D, Sato Y, Yokoi S, Yoshino I. Source Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.


OBJECTIVE: It is controversial whether lung regeneration contributes to compensatory lung growth after pulmonary resection in mature individuals. The objectives of this study were to clarify the molecular mechanisms that regulate the process of compensatory lung growth and investigate the influence of transplantation of lung cells enriched in alveolar type II cells on compensatory lung growth. METHODS: Serial changes of morphology and gene expression were examined in the remnant right lung after pneumonectomy in adult male Wistar rats. One day after surgery, animals received endotracheal transplants of rat lung cells enriched in alveolar type II cells at a dose of 2.5 × 10(6) cells. Serial morphologic changes were examined in comparison with pneumonectomy alone. Engraftment of lung cells was validated with a sex-mismatch model. RESULTS: The alveolar density with mean linear intercept was always lower in pneumonectomized rats than in sham surgical controls for 6 months after surgery. Microarray analysis revealed that multiple genes related to proliferation (but not specific alveolar development) were initially up-regulated and then returned to normal after 1 month. In the pneumonectomized rats with transplantation, the alveolar density was equivalent to that in the sham controls. Engraftment of the transplanted cells from male donors in the alveoli of female recipients was proven by detection of Y-chromosome positive cells and quantified by real-time polymerase chain reaction for the Sry gene. This occurred in pneumonectomized rats but not in sham controls. CONCLUSIONS: We postulate that lung cell transplantation stimulates lung regeneration in the remnant lung after pneumonectomy in mature rats. Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

PMID 22035964


Developmental alveologenesis: new roles for ApoE and LDL receptor

Pediatr Res. 2011 Nov;70(5):458-61. Massaro D, Massaro GD.

Source Department of Medicine, Georgetown University School of Medicine, Washington, District of Columbia 20057, USA.


Pulmonary developmental alveologenesis occurs, in substantial part, by subdivision (septation) of the gas-exchange saccules of the morphologically immature lung. It determines the starting point of age- and disease-related alveolar loss. Because alveologenesis requires additional cell membranes, we previously asked whether apoE-/-, which delivers lipids to cells, affects pulmonary alveologenesis; male apoE-/- mice had impaired alveologenesis. We now report that, in contrast to male apoE-/- mice, female apoE mice had full developmental alveologenesis. Among mice null for LDL receptor (Ldlr-/-), the receptor for apoE-/-, females had full alveologenesis; by contrast, Ldlr-/- males, as previously shown for apoE males, had impaired alveologenesis. Thus, the absence of apoE and its receptor, Ldlr, results in impaired developmental alveologenesis in males, but their absence does not impair architectural developmental alveologenesis in females. We conclude 1) regulation of alveologenesis is a new function for apoE and Ldlr, 2) one expressed in a sexually dimorphic manner, and 3) females have different molecular requirements for alveologenesis than males, which protects them from its impairment by the absence of apoE and its receptor.

PMID 21796016


Lung growth in infants and toddlers assessed by multi-slice computed tomography

Acad Radiol. 2010 Sep;17(9):1128-35. Epub 2010 Jun 14.

Rao L, Tiller C, Coates C, Kimmel R, Applegate KE, Granroth-Cook J, Denski C, Nguyen J, Yu Z, Hoffman E, Tepper RS. Source Department of Pediatrics, James Whitcomb Riley Hospital for Children, Herman B. Wells Center for Pediatric Research, Indiana University, Indianapolis, IN 46202-5225, USA.


RATIONALE AND OBJECTIVES: Postnatal lung growth and development have primarily been evaluated from a very limited number of autopsied lungs, but it remains unclear whether alveolarization of the lung is complete during infancy and whether the conducting airways grow proportionately. The purpose of this study was to evaluate lung growth and development in vivo in infants and toddlers using multislice computed tomography. MATERIALS AND METHODS: Thirty-eight subjects (14 male, 24 female) aged 17 to 142 weeks underwent low-dose volumetric high-resolution computed tomographic imaging at an inflation pressure of 20 cm H(2)O during an induced respiratory pause. Lung volume and weight were determined, as well as airway dimensions (inner and outer area and wall area) for the trachea and the next three to four generations. RESULTS: Lung volume, air volume, and tissue volume increased linearly with body length. The air and tissue components of the lung parenchyma increased at a constant rate with each other. In addition, airway caliber decreased with increasing generation from the trachea into each lobe. Airway caliber was also correlated with body length; however, there was no interaction effect between airway generation and body length on transformed airway size. CONCLUSIONS: In vivo assessment suggests that the growth of the lung parenchyma in infants and toddlers occurred with a constant relationship between air volume and lung tissue, which is consistent with lung growth occurring primarily by the addition of alveoli rather than the expansion of alveoli. In addition, the central conducting airways grow proportionately in infants and toddlers. This information may be important for evaluating subjects with arrested lung development. Copyright 2010 AUR. Published by Elsevier Inc. All rights reserved.

PMID 20542449

Normal development of the lung and premature birth

Paediatr Respir Rev. 2010 Sep;11(3):135-42. Epub 2010 Jan 25.

Smith LJ, McKay KO, van Asperen PP, Selvadurai H, Fitzgerald DA. Source Department of Respiratory Medicine, The Children's Hospital at Westmead, Locked Bag 4001 Westmead NSW Australia 2145.


The following review focuses on the normal development of the lung from conception to birth. The defined periods of lung development-Embryonic, Pseudoglandular, Canalicular, Saccular and Alveolar-will be explored in detail in relation to gestational age. Cellular differentiation, formation of the conducting airways and respiratory zone and development of the alveoli will be reviewed. Pulmonary vascular development will also be examined within these periods to relate the formation of the blood-air barrier to the lungs for their essential function of gas exchange after birth. The development of the surfactant and cortisol systems will also be discussed as these need to be mature before the lungs are able to take on their role of respiration following birth. It is clear that premature birth interrupts normal lung development so the effect of preterm birth on lung development will be examined and the respiratory consequences of very preterm birth will be briefly explored. Crown Copyright 2009. Published by Elsevier Ltd. All rights reserved.

PMID 20692626


Flow limitation during tidal expiration in symptom-free infants and the subsequent development of asthma

J Pediatr. 1994 May;124(5 Pt 1):681-8.

Young S, Arnott J, Le Souef PN, Landau LI. Source Department of Respiratory Medicine, Princess Margaret Hospital for Children, Perth, Western Australia.


During a longitudinal study of lung function and airway responsiveness in a cohort of healthy infants, we identified a subgroup of symptom-free infants at the age of 1 month with flow limitation during tidal expiration. We report a 2-year follow-up of 252 infants who were first studied at 1 month of age. Maximal flow at functional residual capacity (VmaxFRC) was measured from a forced expiratory flow-volume curve by the rapid thoracic compression technique. The pattern of tidal breathing was assessed with the ratio of the time to reach maximal expiratory flow during expiration to the total expiratory time (Tme/Te ratio). Histamine inhalation challenge was used to determine the level of airway responsiveness. Compliance and resistance of the total respiratory system were measured from a passive expiration after occlusion at end inspiration. Data regarding the family history of asthma, atopy, and parental smoking were obtained by questionnaire. Flow limitation was considered present when the forced expiratory flow did not exceed tidal flow at functional residual capacity. Nineteen infants were identified with flow limitation at 5 weeks of age; all had a family history of asthma, atopy, and/or parental smoking. These 19 infants were compared with 35 infants with no family history of asthma or parental smoking and 38 gender-, history-, and age-matched control infants without flow limitation during tidal expiration. At the age of 1 month, the flow-limited group had reduced VmaxFRC, Tme/Te, and respiratory compliance and increased respiratory resistance. At 6 and 12 months of age, although no longer flow limited, these infants still had significantly reduced lung function and increased airway responsiveness. Flow limitation in early life was also significantly associated with the development of physician-diagnosed asthma by the age of 2 years (odds ratio, 7.4; 95% confidence interval, 1.4 to 35.2). 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


Postnatal human lung growth

Thorax. 1982 Aug;37(8):564-71.

Thurlbeck WM.


Standard morphometric methods were applied to the lungs of 36 boys and 20 girls aged from 6 weeks to 14 years, dying as a result of trauma or after short illnesses. Individual lung units, alveolar dimensions, and number of alveoli per unit area and volume did not differ between boys and girls, but boys had bigger lungs than girls for the same stature. This resulted in a larger total number of alveoli and a larger aveolar surface area in boys than in girls for a given age and stature. There may be more respiratory bronchioles in boys than girls. There was rapid alveolar multiplication during the first two years of life and alveolar dimensions and number of alveoli per unit area and volume did not change much during this period. There was little or no increase in the total number of alveoli after the age of 2 years but the data are hard to interpret. There is a wide scatter of the total number of alveoli in the growing lung, in keeping with the observation that the total number of alveoli is very variable in adults. Prediction data are given for the various morphometric variables studied.

PMID 7179184


  • antenatal before birth.
  • alveoli number at birth - from 20 - 50 million and eventually in the adult 300 million.
  • Bronchopulmonary dysplasia - (BPD) the most common serious sequela of premature birth.
  • Bronchiolitis - is a viral infection of the lower respiratory tract and most common lower respiratory tract infection in infants. Respiratory syncytial virus (RSV) is responsible for 70 percent of all cases overall and Parainfluenza, adenovirus and influenza account for most of the remaining cases. (HSTAT Management of Bronchiolitis in Infants and Children)
  • Chronic obstructive pulmonary disease (COPD) causes include smoking (85–90 percent of all cases), genetic factors (alpha-1 antitrypsin deficiency), passive smoking (children), occupational exposures, air pollution, and hyperresponsive airways. (HSTAT Management of Acute Exacerbations of Chronic Obstructive Pulmonary Disease)
  • Clara cells non-ciliated cell found in the small airways (bronchioles) consisting of ciliated simple epithelium, these cells secrete glycosaminoglycans (Clara cell secretory protein, CCSP) to protect the bronchiole lining.
  • Congenital Diaphragmatic Hernia (CDH) disorder with an incidence of 1 in 2500 live births.
  • fetal breathing-like movements (FBMs) or Fetal respiratory movements are thought to be regular muscular contrations occurring in the third trimester, preparing the respiratory muscular system for neonatal function and to have a role in late lung development.
  • FEV - Forced Expiratory Volume
  • forced expiratory volume - (FEV) Spirometry term for the fraction of the forced vital capacity that is exhaled in a specific number of seconds. Abbreviated FEV with a subscript indicating how many seconds the measurement lasted.
  • glucocorticoid treatment - antenatal therapy to promote the maturation of the human fetal lung. Given as a synthetic glucocorticoid between 24 and 32 weeks of pregnancy to promote lung maturation in fetuses at risk of preterm delivery.
  • lamellar bodies the storage form of surfactant in type II alveolar cells, seen as centrically layered "packages" of phospholipid. A count of lamellar bodies can be used as an assay for measuring fetal lung maturity.
  • maternal diabetes if not controlled in pregnancy may delay fetal pulmonary maturation.
  • Persistent Pulmonary Hypertension of the Newborn (PPHN) serious newborn condition due to due to the failure of closure one of the prenatal circulatory shunts, the ductus arteriosus. Occurs in about 1-2 newborns per 1000 live births and results in hypoxemia. (More? Respiratory Development - Birth)
  • Pharyngitis inflammation of the pharynx involving lymphoid tissues of the posterior pharynx and lateral pharyngeal bands.
  • pneumocyte or alveolar type I and type II cells.
  • pulmonary hypoplasia can be due to anencephaly, renal hypoplasia or abnormalities of the thoracic cage
  • pulmonary neuroendocrine cells (PNEC) single or innervated clusters of cells (neuroepithelial bodies) that line the airway epithelium, thought to have a role in regulating fetal lung growth and differentiation. At birth may also act as airway oxygen sensors involved in newborn adaptation. These cells synthesis and release amine (serotonin, 5-HT) and a several neuropeptides (bombesin).
  • Respiratory distress syndrome (RDS) due to a surfactant deficiency at birth, particulary in preterm birth.
  • secondary alveolar septa formed during the alveolar stage and are formed by projections of connective tissue and a double capillary loop.
  • Spirometry - clinical measure of respiratory airflow.
  • surfactant produced by alveolar type II cells is a mixture of lipids and proteins that both maintains alveolar integrity and plays a role in the control of host defense and inflammation in the lung.
  • Surfactant therapy (American Academy of Pediatrics Policy | Canadian Paediatric Society Recommendations)
  • thyroid hormone involved in the regulation of fetal lung development.
  • vascular endothelial growth factor (VEGF) a secreted growth factor acting through receptors on endothelial cells to regulate vasculogenesis through their development, growth and function.

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Blue Histology

Lung Development Stages

Text from: <pubmed>10852845</pubmed>| PMC1637815 | Environ Health Perspect.


The lungs in humans first appear at the end of the first month of gestation as an evagination of epithelium from the foregut. The bud rapidly divides as a series of branching tubes in a dichotomous pattern. These tubular branches invade and interdigitate with mesenchymal tissues. Branching morphogenesis during this period forms the most proximal portions of the future tracheobronchial tree. As these tissues grow, they push into the future pleuroperitoneal cavity of the embryo. During embryogenesis, transcription factors play an important role in gene expression and regulation. Transcription factors are essential in both the stimulation and inhibition of gene expression to regulate the proper temporal and spatial patterning of lung development. Hepatocyte nuclear factor- 3 (12) and the homeobox gene TTF-1 (13) are examples of transcription factors serving as important regulators of early differentiation of the pulmonary epithelium during this period. Lung development is also highly dependent on interactions between the epithelium and mesenchyme. This dual origin of lung tissues is critical in development. Removal of mesenchyme from the tip of a lung bud during early phases of development with transplantation to the side of a higher ordered segment abolishes further branching at the site of removal while stimulating growth of a

Pseudoglandular stage.

Tubular branching of the human lung airways continues from the fifth to the seventeenth week of gestation. As early as 2 months of gestational age, all segmental bronchi are present. During this period, the lungs take on the appearance of a glandlike structure. This stage is the most critical for the formation of all conducting airways. During this period, the airway tubular structures are lined with tall columnar epithelium, whereas the more distal structures are lined with cuboidal epithelium. A number of signals arising from epithelial mesenchymal interactions during this time continue to modulate cellular proliferation temporally as well as spatially (4). These regulatory signals lead to further branching morphogenesis by affecting the rate of cellular proliferation (15). The presence of extracellular matrix molecules, including collagen, fibronectin, laminin, glycosaminoglycans, and proteoglycans, as well as cell membrane-bound integrins, also plays an important role in directing lung development by influencing the rates of cellular proliferation and differentiation (3,16,1/). Mechanical distention exerted on the lung as well as on specific cell types can also significantly affect gene expression and, ultimately, lung growth and development (4). A variety of growth factors and growth factor receptors are also important in controlling cellular functions (3). Epidermal growth factor, transforming growth factor-a, and retinoic acid all act to affect branching morphogenesis and cellular differentiation (18,19). Epithelial differentiation of ciliated, goblet, and basal cells first appears in the most central airways during this stage of development. Cartilage and smooth muscle cells are also first noted in the trachea and extend more peripherally with progressive growth of the lungs. During this stage of

Canalicular stage.

This stage lasts from week 16 to week 24 in the human fetus. Lung morphology changes dramatically during this time because of differentiation of the pulmonary epithelium, resulting in the formation of the future air-blood tissue barrier. Surfactant synthesis and the canalization of the lung parenchyma by capillaries begin. During this stage, the future gas exchange regions can be easily distinguished from the future conducting airways of the lungs.

Saccular stage.

The saccular stage of lung development in humans lasts from week 24 to near term. The most peripheral airways form widened airspaces, termed saccules. These saccules widen and lengthen the airspace, in large measure by the addition of new generations. During this stage, the future gas exchange region expands significantly. Populations of fibroblastic cells also undergo differentiation during this stage. These fibroblast-like cells are responsible for the production of the extracellular matrix, collagen, and elastin. It is also presumed that they play an important role in epithelial differentiation and control of surfactant secretion in connection with the growth of the gas exchange region during this stage. The vascular tree also grows in length and diameter during this time.

Columnar cells that are undifferentiated characterize the first epithelial cells lining fetal lung tubules. The first epithelial cells to differentiate in the trachea are neuroendocrine cells, followed closely by ciliated cells, and finally basal and secretory cells in rapid sequence. This process of differentiation covers a developmental period ranging from days to months. In rodents including the mouse, rat, and hamster, complete epithelial differentiation of the trachea occurs in as little as 2 days. In primate trachea, cellular differentiation takes up to 6 months to be complete. In most species, epithelial cell differentiation of the trachea usually is not complete until just before birth. For more peripheral airway generations, cellular differentiation is likely to continue into the early postnatal period. Fetal epithelial cells are typically filled with glycogen that is gradually replaced with a granular cytoplasm filled with numerous organelles during cellular differentiation. These glycogen-filled cells are found throughout the tracheobronchial tree as well as into the most peripheral saccules. Differentiation of the epithelium is highly site specific, giving rise to more than 10 different cell types. For example, within the saccules of the lungs, cells lining these surfaces differentiate to form both squamous type 1 cells as well as cuboidal type 2 cells. The presence of glycogen within these cells may persist into early postnatal life.