Talk:Respiratory System Development

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Cite this page: Hill, M.A. (2024, March 28) Embryology Respiratory System Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Respiratory_System_Development


http://embryology.med.unsw.edu.au/Notes/respire.htm original page

10 Most Recent Papers

Note - This sub-heading shows an automated computer PubMed search using the listed sub-heading term. References appear in this list based upon the date of the actual page viewing. Therefore the list of references do not reflect any editorial selection of material based on content or relevance. In comparison, references listed on the content page and discussion page (under the publication year sub-headings) do include editorial selection based upon relevance and availability. (More? Pubmed Most Recent)


Respiratory System Development

<pubmed limit=5>Respiratory System Development</pubmed>


2015

2014

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.

Abstract

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.

Abstract

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

2013

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

Abstract

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.

Abstract

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

http://www.nature.com/srep/2013/130218/srep01304/full/srep01304.html

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

Abstract

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 - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1464504

2012

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

Abstract

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

http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1002866

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.

Abstract

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


2011

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.

Abstract

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. e.rawlins@gurdon.cam.ac.uk.

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

2010

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. mmiller@oehha.ca.gov 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. emorrise@mail.med.upenn.edu

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


2009

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.

Abstract

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.

Abstract

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

2008

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. johannes.schittny@ana.unibe.ch

Abstract

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

2006

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. burri@ana.unibe.ch

Abstract

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

2003

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. mchinoy@psu.edu 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

http://www.ncbi.nlm.nih.gov/pubmed/12456356

2002

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. A.Hislop@ich.ucl.ac.uk

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.

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. S.Hall@ich.ucl.ac.uk 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

http://ajrcmb.atsjournals.org/cgi/content/full/26/3/333


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. pbarker@med.unc.edu

Abstract

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

http://jap.physiology.org/cgi/content/full/93/4/1542

2000

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

http://ajrcmb.atsjournals.org/cgi/content/full/23/2/194


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.

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.

PMID 10919986

http://ajrccm.atsjournals.org/content/175/10/978.long

1999

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. msparrow@cyllene.uwa.edu.au 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

1975

Development of the right outflow tract and pulmonary arterial supply

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

Skidmore FD.

Abstract

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