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

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)

Download Full-text

Characterization of mRNA transcripts and organization of human SP-A1 and SP-A2 genes

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1994.266.4.l354 ◽

1994 ◽

Vol 266 (4) ◽

pp. L354-L366 ◽

Cited By ~ 14

Author(s):

S. M. McCormick ◽

V. Boggaram ◽

C. R. Mendelson

Keyword(s):

Sequence Analysis ◽

Transcription Initiation ◽

Fetal Lung ◽

Surfactant Protein ◽

Companion Paper ◽

Initiation Site ◽

Oligonucleotide Primer ◽

Untranslated Sequence ◽

Mrna Transcripts ◽

Human Fetal Lung

In the present study, we have characterized the mRNA transcripts and intron-exon organization of the human surfactant protein (SP)A1 and SP-A2 genes. By primer extension analysis of mRNA isolated from human fetal lung explants using an oligonucleotide primer to exon II (as delineated in the SP-A1 gene), a minimum of nine primer extended transcripts was observed. Rapid amplification of cDNA ends was used to amplify the primer extended transcripts for sequence analysis. Sequence analysis of 47 full-length primer extended cDNAs and comparison with the sequences of the genes encoding SP-A1 and SP-A2 revealed four different classes of transcripts of the SP-A2 gene and five different classes of transcripts of the gene encoding SP-A1. A major difference between SP-A2 and SP-A1 mRNA transcripts is that SP-A2 transcripts are always comprised of sequences contained within six exons; the extra exon in SP-A2 (exon II of VI) encodes additional 5'-untranslated sequence and is located between exons I and II of SP-A1. By contrast, the majority of transcripts of the SP-A1 gene are comprised of sequences contained within five exons. In the cases of both SP-A1 and SP-A2 genes, a small proportion of the mRNA transcripts contain sequences present in alternate exons. In addition, the majority of the SP-A1 mRNA transcripts are initiated 5 bp downstream of the transcription initiation site of SP-A2. In our companion paper [McCormick and Mendelson. Am. J. Physiol. 266 (Lung Cell. Mol. Physiol. 10): L367-L374, 1994], we report that the SP-A1 and SP-A2 genes are differentially regulated during development and by adenosine 3',5'-cyclic monophosphate and glucocorticoids in human fetal lung in culture.

Download Full-text

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.

Download Full-text

Differential immunolocalization of VEGF in rat and human adult lung, and in experimental rat lung fibrosis: Light, fluorescence, and electron microscopy

The Anatomical Record ◽

10.1002/(sici)1097-0185(19990101)254:1<61::aid-ar8>3.0.co;2-d ◽

1999 ◽

Vol 254 (1) ◽

pp. 61-73 ◽

Cited By ~ 59

Author(s):

Heinz Fehrenbach ◽

Michael Kasper ◽

Michael Haase ◽

Dieter Schuh ◽

Martin M�ller

Keyword(s):

Electron Microscopy ◽

Lung Fibrosis ◽

Rat Lung ◽

Adult Lung ◽

Human Adult ◽

Fluorescence And Electron Microscopy ◽

Human Adult Lung ◽

Light Fluorescence

Download Full-text

Faculty Opinions recommendation of Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts.

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

10.3410/f.718000913.793475053 ◽

2013 ◽

Author(s):

Keith Meyer

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Adult Lung ◽

Human Adult ◽

Human Adult Lung

Download Full-text

Endocrine-like cells of the pulmonary epithelium of the human adult lung

Cell and Tissue Research ◽

10.1007/bf00232822 ◽

1977 ◽

Vol 178 (1) ◽

Cited By ~ 38

Author(s):

Esther Hage ◽

J. Hage ◽

G. Juel

Keyword(s):

Pulmonary Epithelium ◽

Adult Lung ◽

Human Adult ◽

Human Adult Lung

Download Full-text

11β-Hydroxysteroid dehydrogenase type 2 and the regulation of surfactant protein A by dexamethasone metabolites

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00396.2005 ◽

2006 ◽

Vol 290 (4) ◽

pp. E653-E660 ◽

Cited By ~ 11

Author(s):

Mark R. Garbrecht ◽

Thomas J. Schmidt ◽

Zygmunt S. Krozowski ◽

Jeanne M. Snyder

Keyword(s):

Human Lung ◽

Protein A ◽

Fetal Lung ◽

Hydroxysteroid Dehydrogenase ◽

Surfactant Protein ◽

Biologically Active ◽

Surfactant Protein A ◽

Human Adult ◽

Sensitive Organ ◽

Lung Epithelial

Glucocorticoid (GC) metabolism by the 11β-hydroxysteroid dehydrogenase (HSD) system is an important prereceptor regulator of GC action. The HSD enzymes catalyze the interconversion of the endogenous, biologically active GC cortisol and its inactive 11-dehydro metabolite cortisone. The role of the HSD enzymes in the metabolism of synthetic GCs, such as dexamethasone (Dex), is more complex. The human lung is a classic GC-sensitive organ; however, the roles of the HSD enzymes (HSD1 and HSD2) in the human lung are poorly understood. In the present study, we examined the expression of the HSD enzymes in human adult and fetal lung tissues and the human lung epithelial cell line NCI-H441. We observed that human adult and fetal lung tissues, as well as H441 cells, express HSD2 protein and that it is upregulated by Dex (10−7 M). By contrast, HSD1 protein was undetectable. We also show that the Dex-mediated regulation of surfactant protein A is attenuated by inhibition of HSD2 activity. Furthermore, we demonstrate that unlike the inactive, 11-dehydro metabolite of cortisol (i.e., cortisone), the 11-dehydro metabolite of Dex, 11-dehydro-Dex, competes for binding to the GC receptor (GR) in human lung epithelial cells and retains GR agonist activity. Together, these data suggest that differences exist in the biological activities of the metabolites of cortisol and Dex.

Download Full-text

Heterogeneous Proliferative Characteristics of Human Adult Lung Fibroblast Lines and Clonally Derived Fibroblasts from Control and Fibrotic Tissue

American Review of Respiratory Disease ◽

10.1164/ajrccm/137.3.579 ◽

1988 ◽

Vol 137 (3) ◽

pp. 579-584 ◽

Cited By ~ 165

Author(s):

Manel Jordana ◽

Jerry Schulman ◽

Charlie McSharry ◽

Louis B. Irving ◽

Michael T. Newhouse ◽

...

Keyword(s):

Lung Fibroblast ◽

Adult Lung ◽

Human Adult ◽

Fibrotic Tissue ◽

Human Adult Lung

Download Full-text

Differential regulation of SP-A1 and SP-A2 genes by cAMP, glucocorticoids, and insulin

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1998.274.2.l177 ◽

1998 ◽

Vol 274 (2) ◽

pp. L177-L185 ◽

Cited By ~ 18

Author(s):

A. R. Kumar ◽

J. M. Snyder

Keyword(s):

Cell Line ◽

Lung Surfactant ◽

Protein A ◽

Fetal Lung ◽

Surfactant Protein ◽

Model Systems ◽

Mrna Levels ◽

Mrna Transcripts ◽

Lung Surfactant Protein ◽

Human Fetal Lung

In the human fetal lung, surfactant protein A (SP-A) is encoded by two highly similar genes, SP-A1 and SP-A2, which are developmentally and hormonally regulated. Using primer extension analysis, we evaluated the levels of SP-A1 and SP-A2 mRNA transcripts in human fetal lung explants and in a human adult lung adenocarcinoma cell line (H441 cells) cultured in the absence or presence of either dibutyryladenosine 3′,5′-cyclic monophosphate (DBcAMP, 1 mM), dexamethasone (10−7 M), or insulin (2.5 μg/ml). In the human fetal lung explants, the content of SP-A1 mRNA was approximately four times that of SP-A2 mRNA. DBcAMP increased SP-A1 mRNA levels by 100% and SP-A2 mRNA levels by 500%, thus reducing the ratio of SP-A1 mRNA to SP-A2 mRNA to ∼1:1. Dexamethasone inhibited all of the SP-A1 and SP-A2 mRNA transcripts to the same extent, by ∼70%, whereas insulin inhibited all SP-A mRNA transcripts by ∼60%. The ratio of SP-A1 to SP-A2 mRNA in dexamethasone- or insulin-treated explants was the same as the ratio observed in controls. In the H441 cells, SP-A1 mRNA levels were ∼1.5 times that of SP-A2 mRNA levels. DBcAMP increased both SP-A1 and SP-A2 mRNA levels by 100%. Dexamethasone inhibited SP-A1 mRNA levels in the cell line by 60%, whereas SP-A2 mRNA levels were not significantly affected. Insulin inhibited SP-A1 mRNA levels in the cell line by 40% without affecting SP-A2 mRNA levels. These findings suggest that the two human SP-A genes are regulated differently in the two model systems.

Download Full-text

Numerical Modelling and Analysis of Peripheral Airway Asymmetry and Ventilation in the Human Adult Lung

Journal of Biomechanical Engineering ◽

10.1115/1.4006809 ◽

2012 ◽

Vol 134 (6) ◽

Cited By ~ 8

Author(s):

F. S. Henry ◽

C. J. Llapur ◽

A. Tsuda ◽

R. S. Tepper

Keyword(s):

Phase Iii ◽

Adult Lung ◽

Human Adult ◽

Airway Trees ◽

Structural Abnormalities ◽

Peripheral Airway ◽

Experimental Trend ◽

Human Adult Lung ◽

Conducting Airways ◽

Phase Iii Slope

We present a new one-dimensional model of gas transport in the human adult lung. The model comprises asymmetrically branching airways, and heterogeneous interregional ventilation. Our model differs from previous models in that we consider the asymmetry in both the conducting and the acinar airways in detail. Another novelty of our model is that we use simple analytical relationships to produce physiologically realistic models of the conducting and acinar airway trees. With this new model, we investigate the effects of airway asymmetry and heterogeneous interregional ventilation on the phase III slope in multibreath washouts. The model predicts the experimental trend of the increase in the phase III slope with breath number in multibreath washout studies for nitrogen, SF6 and helium. We confirm that asymmetrical branching in the acinus controls the magnitude of the first-breath phase III slope and find that heterogeneous interregional ventilation controls the way in which the slope changes with subsequent breaths. Asymmetry in the conducting airways appears to have little effect on the phase III slope. That the increase in slope appears to be largely controlled by interregional ventilation inhomogeneities should be of interest to those wishing to use multibreath washouts to detect the location of the structural abnormalities within the lung.

Download Full-text