OTUB1 regulates lung development, adult lung tissue homeostasis, and respiratory control

Tenascin (TN) is a hexameric extracellular matrix glycoprotein that may play an important role during lung development. TN protein is temporally and spatially restricted during lung organogenesis. The temporo-spatial and cellular expression of TN mRNA in lung remains unclear. Localization of message expression of TN in rat lung tissue was first investigated by using in situ hybridization performed with an antisense RNA probe. TN mRNA was present primarily within the mesenchyme of day 16 gestational age fetal rat lung tissue, whereas immunoreactive TN protein was found along the basement membrane. In postnatal day 3 rat lung tissue, TN mRNA was detected along alveolar septal walls and was concentrated at secondary septal tips. Expression of TN message was consistent with localization of immunoreactive TN protein. Accumulation of TN mRNA in alveolar septal tips suggests that mesenchyme may be the major source of TN mRNA. To investigate the cellular source of TN in rat lung, we studied the expression of TN in cultured rat lung fibroblasts, endothelial cells, and alveolar epithelial cells. Two TN isoforms having molecular mass of 230 and 180 kDa were in conditioned medium and in cellular extracts of lung fibroblasts and endothelial cells. TN was secreted and deposited in the extracellular matrix closely associated with the surface of lung fibroblasts and endothelial cells. Lung alveolar epithelial cells showed undetectable or barely detectable amounts of TN. These studies demonstrated that TN isoforms are expressed not only by lung fibroblasts but also by lung endothelial cells. The unique spatial localization of TN mRNA during lung development and expression of TN by different lung cell types suggested TN may be involved in matrix organization and cell-cell interactions during lung development.

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Co-methylation analysis in lung tissue identifies pathways for fetal origins of COPD

European Respiratory Journal ◽

10.1183/13993003.02347-2019 ◽

2020 ◽

Vol 56 (4) ◽

pp. 1902347

Author(s):

Priyadarshini Kachroo ◽

Jarrett D. Morrow ◽

Alvin T. Kho ◽

Carrie A. Vyhlidal ◽

Edwin K. Silverman ◽

...

Keyword(s):

Protein Kinase ◽

Lung Function ◽

Lung Tissue ◽

Gestational Age ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Fetal Lung ◽

Developmental Origins ◽

Fetal Origins ◽

Adult Lung

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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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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Global Long Noncoding RNA and mRNA Expression Changes between Prenatal and Neonatal Lung Tissue in Pigs

Genes ◽

10.3390/genes9090443 ◽

2018 ◽

Vol 9 (9) ◽

pp. 443 ◽

Cited By ~ 8

Author(s):

Long Jin ◽

Silu Hu ◽

Teng Tu ◽

Zhiqing Huang ◽

Qianzi Tang ◽

...

Keyword(s):

Immune Response ◽

Cell Proliferation ◽

Lung Tissue ◽

Long Noncoding Rna ◽

Lung Development ◽

Noncoding Rna ◽

Differentially Expressed ◽

P Value ◽

Distal Lung ◽

Neonatal Lungs

Lung tissue plays an important role in the respiratory system of mammals after birth. Early lung development includes six key stages, of which the saccular stage spans the pre- and neonatal periods and prepares the distal lung for alveolarization and gas-exchange. However, little is known about the changes in gene expression between fetal and neonatal lungs. In this study, we performed transcriptomic analysis of messenger RNA (mRNA) and long noncoding RNA (lncRNA) expressed in the lung tissue of fetal and neonatal piglets. A total of 19,310 lncRNAs and 14,579 mRNAs were identified and substantially expressed. Furthermore, 3248 mRNAs were significantly (FDR-adjusted p value ≤ 0.05, FDR: False Discovery Rate) differentially expressed and were mainly enriched in categories related to cell proliferation, immune response, hypoxia response, and mitochondrial activation. For example, CCNA2, an important gene involved in the cell cycle and DNA replication, was upregulated in neonatal lungs. We also identified 452 significantly (FDR-adjusted p value ≤ 0.05) differentially expressed lncRNAs, which might function in cell proliferation, mitochondrial activation, and immune response, similar to the differentially expressed mRNAs. These results suggest that differentially expressed mRNAs and lncRNAs might co-regulate lung development in early postnatal pigs. Notably, the TU64359 lncRNA might promote distal lung development by up-regulating the heparin-binding epidermal growth factor-like (HB-EGF) expression. Our research provides basic lung development datasets and will accelerate clinical researches of newborn lung diseases with pig models.

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Effect of tyrosine kinase inhibition on surfactant protein A gene expression during human lung development

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1998.274.4.l542 ◽

1998 ◽

Vol 274 (4) ◽

pp. L542-L551 ◽

Cited By ~ 1

Author(s):

Jonathan M. Klein ◽

Louis J. Dewild ◽

Troy A. McCarthy

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Phosphorylation ◽

Lung Tissue ◽

Receptor Tyrosine Kinase ◽

Lung Development ◽

Egf Receptor ◽

Fetal Lung ◽

Surfactant Protein ◽

Mrna Levels ◽

Human Fetal Lung

Epidermal growth factor (EGF) stimulates surfactant protein (SP) A synthesis in human fetal lung explants. Ligand binding to the EGF receptor stimulates an intrinsic receptor tyrosine kinase with subsequent activation of second messengers. We hypothesized that inhibition of EGF-receptor tyrosine kinase activity would block SP-A expression in spontaneously differentiating cultured human fetal lung tissue. Midtrimester fetal lung explants were exposed for 4 days to genistein (a broad-range inhibitor of tyrosine kinases) and tyrphostin AG-1478 (a specific inhibitor of EGF-receptor tyrosine kinase). Genistein significantly decreased SP-A and SP-A mRNA levels without affecting either tissue viability or the morphological differentiation of alveolar type II cells. Tyrphostin AG-1478 also decreased SP-A content and SP-A mRNA levels in cultured fetal lung explants. Treatment with EGF could not overcome the inhibitory effects of either genistein or tyrphostin on SP-A; however, only tyrphostin inhibited EGF-receptor tyrosine phosphorylation. We conclude that specific inhibition of EGF-receptor tyrosine kinase with tyrphostin AG-1478 blocks the expression of SP-A during spontaneous differentiation of cultured human fetal lung tissue. Furthermore, exposure to genistein also decreases SP-A expression and blocks the effects of EGF in human fetal lung tissue without inhibiting EGF-receptor tyrosine phosphorylation. These findings support the importance of tyrosine kinase-dependent signal transduction pathways in the regulation of SP-A during human fetal lung development.

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Differences in gene expression levels between early and later stages of human lung development are opposite to those between normal lung tissue and non-small lung cell carcinoma

Lung Cancer ◽

10.1016/j.lungcan.2008.02.011 ◽

2008 ◽

Vol 62 (1) ◽

pp. 23-34 ◽

Cited By ~ 50

Author(s):

Eugene P. Kopantzev ◽

Galina S. Monastyrskaya ◽

Tatyana V. Vinogradova ◽

Marina V. Zinovyeva ◽

Marya B. Kostina ◽

...

Keyword(s):

Gene Expression ◽

Cell Carcinoma ◽

Lung Tissue ◽

Lung Development ◽

Human Lung ◽

Normal Lung Tissue ◽

Normal Lung ◽

Expression Levels ◽

Gene Expression Levels

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Lung Development Genes and Adult Lung Function

American Journal of Respiratory and Critical Care Medicine ◽

10.1164/rccm.201912-2338oc ◽

2020 ◽

Vol 202 (6) ◽

pp. 853-865 ◽

Cited By ~ 1

Author(s):

Laura Portas ◽

Miguel Pereira ◽

Seif O. Shaheen ◽

Annah B. Wyss ◽

Stephanie J. London ◽

...

Keyword(s):

Lung Function ◽

Lung Development ◽

Adult Lung

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Faculty Opinions recommendation of Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13323959.14688058 ◽

2011 ◽

Author(s):

Bruce Zuraw ◽

Taylor Doherty

Keyword(s):

Influenza Virus ◽

Lung Tissue ◽

Innate Lymphoid Cells ◽

Tissue Homeostasis ◽

Lymphoid Cells

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Hierarchical Organization of Lung Progenitor Cells: Is there An Adult Lung Tissue Stem Cell?

Proceedings of the American Thoracic Society ◽

10.1513/pats.200801-011aw ◽

2008 ◽

Vol 5 (6) ◽

pp. 695-698 ◽

Cited By ~ 53

Author(s):

B. R. Stripp

Keyword(s):

Stem Cell ◽

Progenitor Cells ◽

Lung Tissue ◽

Hierarchical Organization ◽

Adult Lung ◽

Lung Progenitor

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Human SP-A1 and SP-A2 genes are differentially regulated during development and by cAMP and glucocorticoids

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1994.266.4.l367 ◽

1994 ◽

Vol 266 (4) ◽

pp. L367-L374 ◽

Cited By ~ 17

Author(s):

S. M. McCormick ◽

C. R. Mendelson

Keyword(s):

Lung Tissue ◽

Protein A ◽

Fetal Lung ◽

Companion Paper ◽

Primer Extension ◽

Northern Analysis ◽

Adult Lung ◽

Human Adult ◽

Mrna Transcripts ◽

Human Adult Lung

Expression of the surfactant protein A (SP-A) gene is lung specific, developmentally induced, and regulated by adenosine 3',5'-cyclic monophosphate (cAMP) and glucocorticoids. Humans have two highly similar genes encoding SP-A (SP-A1 and SP-A2). In the companion paper [S.M. McCormick, V. Boggaram, and C.R. Mendelson Am. J. Physiol. 266 (Lung Cell. Mol. Physiol. 10): L354-L366, 1994] we report that SP-A1 and SP-A2 RNA transcripts are alternatively spliced at their 5' ends, resulting in nine different primer-extended transcripts. In the present study, primer extension was used to assess the relative levels of expression of the SP-A1 and SP-A2 genes in human adult lung tissue and in fetal lung tissues maintained in organ culture in the absence or presence of dibutyryl (DB)cAMP (1 mM) and dexamethasone (Dex, 10(-4) M). Primer extension and Northern analysis were used to assess the effects of these agents on the levels of expression of these genes. In human adult lung tissue, 65% of the SP-A mRNA transcripts were derived from the SP-A2 gene, whereas only 35% were from SP-A1. On the other hand, in lung tissue from a 28-wk gestation neonate, only SP-A1 mRNA transcripts were detected, and, in midgestation fetal lung cultured in control medium, 65% of the SP-A mRNA was found to be SP-A1 and 35% was SP-A2.(ABSTRACT TRUNCATED AT 250 WORDS)

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