Lung Development Genes and Adult Lung Function

COPD likely has developmental origins; however, the underlying molecular mechanisms are not fully identified. Investigation of lung tissue-specific epigenetic modifications such as DNA methylation using network approaches might facilitate insights linking in utero smoke (IUS) exposure and risk for COPD in adulthood.We performed genome-wide methylation profiling for adult lung DNA from 160 surgical samples and 78 fetal lung DNA samples isolated from discarded tissue at 8–18 weeks of gestation. Co-methylation networks were constructed to identify preserved modules that shared methylation patterns in fetal and adult lung tissues and associations with fetal IUS exposure, gestational age and COPD.Weighted correlation networks highlighted preserved and co-methylated modules for both fetal and adult lung data associated with fetal IUS exposure, COPD and lower adult lung function. These modules were significantly enriched for genes involved in embryonic organ development and specific inflammation-related pathways, including Hippo, phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), Wnt, mitogen-activated protein kinase and transforming growth factor-β signalling. Gestational age-associated modules were remarkably preserved for COPD and lung function, and were also annotated to genes enriched for the Wnt and PI3K/AKT pathways.Epigenetic network perturbations in fetal lung tissue exposed to IUS and of early lung development recapitulated in adult lung tissue from ex-smokers with COPD. Overlapping fetal and adult lung tissue network modules highlighted putative disease pathways supportive of exposure-related and age-associated developmental origins of COPD.

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On Genetics, Lung Developmental Biology, and Adult Lung Function

American Journal of Respiratory and Critical Care Medicine ◽

10.1164/rccm.202006-2123ed ◽

2020 ◽

Vol 202 (6) ◽

pp. 791-793 ◽

Cited By ~ 1

Author(s):

Erik Melén ◽

Gerard H. Koppelman ◽

Stefano Guerra

Keyword(s):

Developmental Biology ◽

Lung Function ◽

Adult Lung

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00023.2009 ◽

2009 ◽

Vol 297 (4) ◽

pp. L641-L649 ◽

Cited By ~ 89

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.

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Retinoid receptors in the developing human lung

Clinical Science ◽

10.1042/cs1030613 ◽

2002 ◽

Vol 103 (6) ◽

pp. 613-621 ◽

Cited By ~ 38

Author(s):

Yuichiro KIMURA ◽

Takashi SUZUKI ◽

Chika KANEKO ◽

Andrew D. DARNEL ◽

Takuya MORIYA ◽

...

Keyword(s):

Real Time ◽

Quantitative Pcr ◽

Lung Development ◽

Thyroid Hormone Receptor ◽

Fetal Lung ◽

Mesenchymal Cells ◽

Mrna Levels ◽

Adult Lung ◽

Real Time Quantitative Pcr ◽

Retinoid Receptors

Nuclear receptors and their ligands are known to play very important roles in lung development. Among these receptors, retinoid receptors, members of the steroid/thyroid hormone receptor superfamily, are classified into retinoic acid receptor (RAR) isoforms α, β, and γ and retinoid X receptor (RXR) isoforms α, β, and γ. In addition, isoforms I and II of the orphan receptor chicken ovalbumin upstream promoter-transcription factor (COUP-TF) have been shown to negatively regulate the activation of retinoid receptors. Both of these receptors have been shown to regulate lung development in the mouse. In the present study we utilized immunohistochemistry and real-time quantitative PCR to examine the expression of RAR-α, -β and -γ, RXR-α, -β and -γ and COUP-TFII in the human fetal lung at 13–16 gestational weeks, a very critical stage of human pulmonary development, in order to study possible roles in pulmonary morphogenesis by comparing these findings with those of the adult lung. RXR-γ immunoreactivity was detected at both proximal (epithelia and mesenchyme of the trachea and bronchi associated with cartilage) and distal (epithelia and mesenchyme of smaller distal bronchi) sites in the fetal lung, but was markedly weaker in the adult lung. RAR-β immunoreactivity was detected in distal mesenchymal cells of the fetal lung, but was not discernible in distal mesenchymal cells in the adult lung (bronchioles, alveolar ducts and alveolus). Relatively intense RAR-γ immunoreactivity was detected in the chondrocytes of bronchial cells. COUP-TFII immunoreactivity was detected with a similar pattern to that of RAR-β. Real-time quantitative PCR analyses revealed that mRNA levels of RXR-γ at proximal and distal sites (ratio of fetal lung/adult lung: 3.4±0.05-fold and 3.1±0.03-fold respectively; P<0.01), RAR-β at distal sites (2.4±0.01-fold; P<0.05) and RAR-γ at proximal sites (2.2±0.11-fold; P<0.05) were significantly higher in the fetus than in the adult.

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