scholarly journals Mark1 regulates distal airspace expansion through type I pneumocyte flattening in lung development

2019 ◽  
Vol 132 (24) ◽  
pp. jcs235556 ◽  
Author(s):  
Katsumi Fumoto ◽  
Hisako Takigawa-Imamura ◽  
Kenta Sumiyama ◽  
Shige H. Yoshimura ◽  
Natsumi Maehara ◽  
...  
Keyword(s):  
Lung Development ◽  
Type I ◽  
Distal Airspace

scholarly journals Targeted Disruption of Mouse Dip2B Leads to Abnormal Lung Development and Prenatal Lethality

2020 ◽  
Vol 21 (21) ◽  
pp. 8223
Author(s):  
Rajiv Kumar Sah ◽  
Jun Ma ◽  
Fatoumata Binta Bah ◽  
Zhenkai Xing ◽  
Salah Adlat ◽  
...  
Keyword(s):  
Lung Development ◽  
Cell Types ◽  
Branching Morphogenesis ◽  
Brdu Incorporation ◽  
Mouse Lung ◽  
Alveolar Type ◽  
Type I ◽  
Lung Maturation ◽  
M Phase

Molecular and anatomical functions of mammalian Dip2 family members (Dip2A, Dip2B and Dip2C) during organogenesis are largely unknown. Here, we explored the indispensable role of Dip2B in mouse lung development. Using a LacZ reporter, we explored Dip2B expression during embryogenesis. This study shows that Dip2B expression is widely distributed in various neuronal, myocardial, endothelial, and epithelial cell types during embryogenesis. Target disruption of Dip2b leads to intrauterine growth restriction, defective lung formation and perinatal mortality. Dip2B is crucial for late lung maturation rather than early-branching morphogenesis. The morphological analysis shows that Dip2b loss leads to disrupted air sac formation, interstitium septation and increased cellularity. In BrdU incorporation assay, it is shown that Dip2b loss results in increased cell proliferation at the saccular stage of lung development. RNA-seq analysis reveals that 1431 genes are affected in Dip2b deficient lungs at E18.5 gestation age. Gene ontology analysis indicates cell cycle-related genes are upregulated and immune system related genes are downregulated. KEGG analysis identifies oxidative phosphorylation as the most overrepresented pathways along with the G2/M phase transition pathway. Loss of Dip2b de-represses the expression of alveolar type I and type II molecular markers. Altogether, the study demonstrates an important role of Dip2B in lung maturation and survival.

scholarly journals Neonatal oxygen adversely affects lung function in adult mice without altering surfactant composition or activity

2009 ◽  
Vol 297 (4) ◽  
pp. L641-L649 ◽  
Author(s):  
Min Yee ◽  
Patricia R. Chess ◽  
Sharon A. McGrath-Morrow ◽  
Zhengdong Wang ◽  
Robert Gelein ◽  
...  
Keyword(s):  
Lung Function ◽  
Bronchoalveolar Lavage ◽  
Protein Content ◽  
Lung Development ◽  
Lung Compliance ◽  
Lung Mechanics ◽  
Type I ◽  
Adult Mice ◽  
Epithelial Development ◽  
Surfactant Composition

Despite its potentially adverse effects on lung development and function, supplemental oxygen is often used to treat premature infants in respiratory distress. To understand how neonatal hyperoxia can permanently disrupt lung development, we previously reported increased lung compliance, greater alveolar simplification, and disrupted epithelial development in adult mice exposed to 100% inspired oxygen fraction between postnatal days 1 and 4. Here, we investigate whether oxygen-induced changes in lung function are attributable to defects in surfactant composition and activity, structural changes in alveolar development, or both. Newborn mice were exposed to room air or 40%, 60%, 80%, or 100% oxygen between postnatal days 1 and 4 and allowed to recover in room air until 8 wk of age. Lung compliance and alveolar size increased, and airway resistance, airway elastance, tissue elastance, and tissue damping decreased, in mice exposed to 60–80% oxygen; changes were even greater in mice exposed to 100% oxygen. These alterations in lung function were not associated with changes in total protein content or surfactant phospholipid composition in bronchoalveolar lavage. Moreover, surface activity and total and hydrophobic protein content were unchanged in large surfactant aggregates centrifuged from bronchoalveolar lavage compared with control. Instead, the number of type II cells progressively declined in 60–100% oxygen, whereas levels of T1α, a protein expressed by type I cells, were comparably increased in mice exposed to 40–100% oxygen. Thickened bundles of elastin fibers were also detected in alveolar walls of mice exposed to ≥60% oxygen. These findings support the hypothesis that changes in lung development, rather than surfactant activity, are the primary causes of oxygen-altered lung function in children who were exposed to oxygen as neonates. Furthermore, the disruptive effects of oxygen on epithelial development and lung mechanics are not equivalently dose dependent.

scholarly journals LPS-induced chorioamnionitis and antenatal corticosteroids modulate Shh signaling in the ovine fetal lung

2012 ◽  
Vol 303 (9) ◽  
pp. L778-L787 ◽  
Author(s):  
Jennifer J. P. Collins ◽  
Elke Kuypers ◽  
Ilias Nitsos ◽  
J. Jane Pillow ◽  
Graeme R. Polglase ◽  
...  
Keyword(s):  
Lung Development ◽  
Collagen Type ◽  
Fetal Lung ◽  
Collagen Type I ◽  
Late Gestation ◽  
Type I ◽  
Mrna Levels ◽  
Antenatal Corticosteroids ◽  
Shh Signaling ◽  
Lung Structure

Chorioamnionitis and antenatal corticosteroids mature the fetal lung functionally but disrupt late-gestation lung development. Because Sonic Hedgehog (Shh) signaling is a major pathway directing lung development, we hypothesized that chorioamnionitis and antenatal corticosteroids modulated Shh signaling, resulting in an altered fetal lung structure. Time-mated ewes with singleton ovine fetuses received an intra-amniotic injection of lipopolysaccharide (LPS) and/or maternal intramuscular betamethasone 7 and/or 14 days before delivery at 120 days gestational age (GA) (term = 150 days GA). Intra-amniotic LPS exposure decreased Shh mRNA levels and Gli1 protein expression, which was counteracted by both betamethasone pre- or posttreatment. mRNA and protein levels of fibroblast growth factor 10 and bone morphogenetic protein 4, which are important mediators of lung development, increased 2-fold and 3.5-fold, respectively, 14 days after LPS exposure. Both 7-day and 14-day exposure to LPS changed the mRNA levels of elastin ( ELN) and collagen type I alpha 1 (Col1A1) and 2 (Col1A2), which resulted in fewer elastin foci and increased collagen type I deposition in the alveolar septa. Corticosteroid posttreatment prevented the decrease in ELN mRNA and increased elastin foci and decreased collagen type I deposition in the fetal lung. In conclusion, fetal lung exposure to LPS was accompanied by changes in key modulators of lung development resulting in abnormal lung structure. Betamethasone treatment partially prevented the changes in developmental processes and lung structure. This study provides new insights into clinically relevant prenatal exposures and fetal lung development.

Ontogeny of type I procollagen expression during human fetal lung development

1995 ◽  
Vol 268 (2) ◽  
pp. L309-L320 ◽  
Author(s):  
R. M. Davila ◽  
D. deMello ◽  
E. C. Crouch
Keyword(s):  
Blood Vessels ◽  
Lung Development ◽  
Fetal Lung ◽  
Immunoperoxidase Staining ◽  
Type I ◽  
Collagen Deposition ◽  
Developmentally Regulated ◽  
Mrna Accumulation ◽  
Type I Procollagen ◽  
Fetal Lung Development

The cellular sites of type I procollagen (PCI) production were investigated during fetal and early postnatal human lung development. PCI-synthesizing cells and sites of recent collagen deposition were visualized by immunoperoxidase staining of lung tissue with monoclonal antibodies to human PCI. In selected cases, serial sections were also examined by in situ hybridization to establish the cellular sites of PCI gene expression and mRNA accumulation. PCI cytoplasmic immunostaining generally correlated with sites of mRNA accumulation and with known sites of interstitial collagen deposition, including the adventitial and muscular layers of large blood vessels, submesothelial and peribronchial connective tissue, perichondrium, and interstitial matrix. However, we also observed developmental changes in relative PCI expression for each of these compartments, heterogeneity in the level of PCI expression by cells within individual anatomic subcompartments, and variations in the level of PCI expression along the length of pulmonary blood vessels and airways. These studies emphasize the complexity of developmentally regulated alterations in procollagen production during lung development.

Type II epithelial cells are critical target for hyperoxia-mediated impairment of postnatal lung development

2006 ◽  
Vol 291 (5) ◽  
pp. L1101-L1111 ◽  
Author(s):  
Min Yee ◽  
Peter F. Vitiello ◽  
Jason M. Roper ◽  
Rhonda J. Staversky ◽  
Terry W. Wright ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Epithelial Cells ◽  
Lung Development ◽  
Type I ◽  
Type Ii Cells ◽  
Type Ii ◽  
Newborn Mice ◽  
Type I Cells ◽  
Type Ii Cell ◽  
I Cells

Type II epithelial cells are essential for lung development and remodeling, as they are precursors for type I cells and can produce vascular mitogens. Although type II cell proliferation takes place after hyperoxia, it is unclear why alveolar remodeling occurs normally in adults whereas it is permanently disrupted in newborns. Using a line of transgenic mice whose type II cells could be identified by their expression of enhanced green fluorescent protein and endogenous expression of surfactant proteins, we investigated the age-dependent effects of hyperoxia on type II cell proliferation and alveolar repair. In adult mice, type II cell proliferation was low during room air and hyperoxia exposure but increased during recovery in room air and then declined to control levels by day 7. Eight weeks later, type II cell number and alveolar compliance were indistinguishable from those in room air controls. In newborn mice, type II cell proliferation markedly increased between birth and postnatal day 7 before declining by postnatal day 14. Exposure to hyperoxia between postnatal days 1 and 4 inhibited type II cell proliferation, which resumed during recovery and was aberrantly elevated on postnatal day 14. Eight weeks later, recovered mice had 70% fewer type II cells and 30% increased lung compliance compared with control animals. Recovered mice also had higher levels of T1α, a protein expressed by type I cells, with minimal changes detected in genes expressed by vascular cells. These data suggest that perinatal hyperoxia adversely affects alveolar development by disrupting the proper timing of type II cell proliferation and differentiation into type I cells.

Late appearance of a type I alveolr epithelialar cell marker during fetal rat lung development

1994 ◽  
Vol 102 (4) ◽  
pp. 297-304 ◽  
Author(s):  
S. I. Danto ◽  
S. M. Zabski ◽  
E. D. Crandall
Keyword(s):  
Lung Development ◽  
Type I ◽  
Rat Lung ◽  
Cell Marker ◽  
Fetal Rat ◽  
Fetal Rat Lung

scholarly journals WNT5a-ROR Signaling Is Essential for Alveologenesis

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 384 ◽  
Author(s):  
Changgong Li ◽  
Susan M Smith ◽  
Neil Peinado ◽  
Feng Gao ◽  
Wei Li ◽  
...  
Keyword(s):  
Lung Development ◽  
Lung Fibroblasts ◽  
Chronic Obstructive ◽  
Type I ◽  
Loss Of Function ◽  
Obstructive Pulmonary Disease ◽  
Alveolar Epithelial ◽  
Isolated Lung ◽  
And Migration

WNT5a is a mainly “non-canonical” WNT ligand whose dysregulation is observed in lung diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma. Germline deletion of Wnt5a disrupts embryonic lung development. However, the temporal-specific function of WNT5a remains unknown. In this study, we generated a conditional loss-of-function mouse model (Wnt5aCAG) and examined the specific role of Wnt5a during the saccular and alveolar phases of lung development. The lack of Wnt5a in the saccular phase blocked distal airway expansion and attenuated differentiation of endothelial and alveolar epithelial type I (AT1) cells and myofibroblasts. Postnatal Wnt5a inactivation disrupted alveologenesis, producing a phenotype resembling human bronchopulmonary dysplasia (BPD). Mutant lungs showed hypoalveolization, but endothelial and epithelial differentiation was unaffected. The major impact of Wnt5a inactivation on alveologenesis was on myofibroblast differentiation and migration, with reduced expression of key regulatory genes. These findings were validated in vitro using isolated lung fibroblasts. Conditional inactivation of the WNT5a receptors Ror1 and Ror2 in alveolar myofibroblasts recapitulated the Wnt5aCAG phenotype, demonstrating that myofibroblast defects are the major cause of arrested alveologenesis in Wnt5aCAG lungs. Finally, we show that WNT5a is reduced in human BPD lung samples, indicating the clinical relevance and potential role for WNT5a in pathogenesis of BPD.

Glucuronyl C5-epimerase is crucial for epithelial cell maturation during embryonic lung development

Glycobiology ◽  
2020 ◽  
Author(s):  
Hao Cui ◽  
Xiaowen Cheng ◽  
Tahira Batool ◽  
Xiao Zhang ◽  
Jin-Ping Li
Keyword(s):  
Lung Development ◽  
Surfactant Protein ◽  
Branching Morphogenesis ◽  
Sulfated Polysaccharide ◽  
Alveolar Epithelial Cells ◽  
Type I ◽  
Alveolar Epithelial ◽  
Neonatal Lethality ◽  
Key Enzyme ◽  
Distal Lung

Abstract Glucuronyl C5-epimerase (Hsepi) is a key enzyme in the biosynthesis of heparan sulfate that is a sulfated polysaccharide expressed on the cell surface and in the extracellular matrix of alveolar walls and blood vessels. Targeted interruption of the Hsepi gene, Glce, in mice resulted in neonatal lethality, which is most likely due to lung atelectasis. In this study, we examined the potential mechanisms behind the defect in lung development. Histological analysis of the lungs from embryos revealed no difference in the morphology between wild-type and mutant animals up to E16.5. This suggests that the initial events leading to formation of the lung primordium and branching morphogenesis are not disturbed. However, the distal lung of E17.5–18.5 mutants is still populated by epithelial tubules, lacking the typical saccular structural characteristic of a normal E17.5 lung. Immunostaining revealed strong signals of surfactant protein-C, but a weaker signal of T1α in the mutant lungs in comparison to WT littermates, suggesting differentiation of type I alveolar epithelial cells (AT1) is impaired. One of the parameters contributed to the failure of AT1 maturation is reduced vascularization in the developing lungs.

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