Cellular distribution of insulin-like growth factor binding protein mRNAs and peptides during rat lung development

1997 ◽  
Vol 155 (2) ◽  
pp. 313-327 ◽  
Author(s):  
LD Wallen ◽  
W Myint ◽  
K Nygard ◽  
S Shimasaki ◽  
DR Clemmons ◽  
...  
Keyword(s):  
Airway Epithelium ◽  
Lung Development ◽  
Fetal Lung ◽  
Northern Analysis ◽  
Postnatal Life ◽  
Mrna Levels ◽  
Igf Binding Proteins ◽  
Paracrine Factors ◽  
Igfbp 3

A role for IGF binding proteins (IGFBPs) in lung development is suggested by the identification of IGFBPs in lung tissue and production of IGFBPs by fetal lung cells in culture. To characterize the expression of IGFBPs during lung development in the rat in vivo (16 days gestation through adulthood), the expression of IGFBP mRNAs (IGFBP-1 to IGFBP-6) was examined by Northern analysis and in situ hybridization, and IGFBP peptides (IGFBP-2, IGFBP-3, and IGFBP-5) were localized by immunohistochemistry. IGFBP-1 mRNA was not detectable. IGFBP-2 mRNA (1.8 kb) was expressed in both fetal and postnatal life with peak expression during the fetal pseudoglandular stage. IGFBP-2 mRNA was localized mainly to airway epithelium. IGFBP-3 mRNA (2.4 kb) was maximally expressed postnatally in the saccular stage of lung development; it was identified in airway epithelium and interstitium in the fetal lung, but predominantly in airway epithelium after birth. IGFBP-4 (2.6 kb) and IGFBP-5 (6.0 kb) mRNA levels were maximal after birth, from 3 to 21 days postnatal (saccular and alveolar stage). IGFBP-4 mRNA was localized primarily to the interstitium and blood vessels early in development, but was abundant in airway epithelium in the adult. IGFBP-5 mRNA was most abundant in the airway epithelium. IGFBP-3, IGFBP-4, IGFBP-5, and to a lesser extent IGFBP-6 were localized to the large cartilaginous airways in the adult. IGFBP-2, IGFBP-3, and IGFBP-5 peptides were distributed more widely than their respective mRNAs, with a temporal pattern of immunoreactivity following that of their mRNAs. Maximal staining was noted in airway epithelium for IGFBP-2 in the newborn, for IGFBP-3 in the saccular stage (newborn to 3 days postnatal), and for IGFBP-5 in the alveolar stage (5 to 21 days postnatal). Our studies demonstrate that IGFBP-2, IGFBP-3, IGFBP-4, and IGFBP-5 are synthesized and distributed in spatially and temporally different patterns in the developing lung. The widespread distribution of IGFBP immunoreactivity compared with their respective mRNAs suggests that IGFBPs are important paracrine factors in the regulation of IGF action in the developing lung.

Glucocorticoids upregulate tropoelastin expression during late stages of fetal lung development

1995 ◽  
Vol 268 (3) ◽  
pp. L491-L500 ◽  
Author(s):  
R. A. Pierce ◽  
W. I. Mariencheck ◽  
S. Sandefur ◽  
E. C. Crouch ◽  
W. C. Parks
Keyword(s):  
Lung Development ◽  
Matrix Protein ◽  
Fetal Lung ◽  
Extracellular Matrix Protein ◽  
Transferase Activity ◽  
Mrna Levels ◽  
Pregnant Rats ◽  
Fetal Lung Development ◽  
Chloramphenicol Acetyl Transferase Activity

The production of elastin, an essential extracellular matrix protein of terminal airway interstitium, occurs mostly during early development. Because glucocorticoids influence airway maturation, we studied the effect of dexamethasone (Dex) on tropoelastin expression during fetal lung development. Timed-pregnant rats were treated with Dex (1 mg/kg daily), and fetal lungs were collected 3 days later at 17, 19, and 21 days of gestation. Dex treatment resulted in about a threefold increase in tropoelastin mRNA levels at 19 days concomitant with accelerated airway development. By in situ hybridization, Dex treatment increased the number of tropoelastin-expressing cells and the level of tropoelastin mRNA per cell. In organ culture, Dex increased lung tropoelastin expression and augmented cortisol stimulation of tropoelastin expression. In fetal pulmonary artery smooth muscle cells, 10(-8) M Dex upregulated tropoelastin mRNA expression and increased tropoelastin promoter-chloramphenicol acetyl transferase activity in transient transfections. These data indicate that pharmacologically administered glucocorticoids transcriptionally upregulate fetal lung tropoelastin expression and suggest that steroid hormones may be important regulators of elastin production in vivo.

Circulating insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs) and tissue mRNA levels of IGFBP-2 and IGFBP-4 in the ovine fetus

1995 ◽  
Vol 145 (3) ◽  
pp. 545-557 ◽  
Author(s):  
J M Carr ◽  
J A Owens ◽  
P A Grant ◽  
P E Walton ◽  
P C Owens ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Mrna Level ◽  
Common Factor ◽  
Late Gestation ◽  
Mrna Levels ◽  
Igf Binding Proteins ◽  
Fetal Sheep ◽  
Igf I ◽  
Igf Binding ◽  
Igfbp 3

Abstract The IGF-binding proteins (IGFBPs) are a family of at least six structurally related proteins, which bind the IGFs and modulate their actions, including the regulation of preand postnatal growth. In this study we have examined the relationship between circulating and tissue mRNA levels of IGFBPs and related this to circulating IGFs in the fetal sheep over the gestational period when rapid growth and development occurs. Circulating IGFBP-2, as measured by Western ligand blot (WLB), increases between early and mid gestation, remains high, then declines throughout late gestation (P=0·0002). Circulating IGFBP-3 increases throughout gestation, as measured by WLB or RIA (P=0·04 and P=0·0001 respectively), as does circulating IGFBP-4 (P=0·004). These ontogenic changes in circulating IGFBPs-2 and -4 are paralleled by changes in liver mRNA for these proteins and, for IGFBP-2, by those in kidney IGFBP-2 mRNA also. This suggests that liver and kidney may be the primary contributors to circulating IGFBP-2 and the liver to circulating IGFBP-4. IGFBP-2 mRNA is present in the heart and lung in early gestation but barely detectable in these tissues after approximately 60 days gestation. IGFBP-4 mRNA is also present in the heart in early but not late gestation, but is abundant in the lung throughout gestation. These results demonstrate tissue specific and developmental regulation of IGFBPs-2 and -4 at the mRNA level. To assess any role the circulating IGFs may play in mediating these changes in IGFBPs, or vice versa, both plasma IGF-I and IGF-II were measured by RIA. Circulating IGF-I increases as gestation progresses (P=0·0001), while circulating IGF-II increases between early and mid gestation, remains high (P=0·01), then declines. Circulating IGF-I is positively correlated with fetal weight (r=0·66, P=0·03), circulating IGFBP-3 (r=0·54, P=0·01) and IGFBP-4 (r=0·52, P=0·01). Circulating IGF-II positively correlates with circulating IGFBP-2 (r=0·48, P=0·02) throughout gestation and at 1 day postnatally. These relationships are consistent with circulating IGF-I influencing IGFBPs-3 and -4, and similarly, IGF-II determining IGFBP-2, or vice versa. Alternatively, these correlations may reflect coordinate regulation of IGF and IGFBP by a common factor. Journal of Endocrinology (1995) 145, 545–557

scholarly journals Insulin-like Growth Factor II Signaling in Neoplastic Proliferation Is Blocked by Transgenic Expression of the Metalloproteinase Inhibitor Timp-1

1999 ◽  
Vol 146 (4) ◽  
pp. 881-892 ◽  
Author(s):  
David C. Martin ◽  
John L. Fowlkes ◽  
Bojana Babic ◽  
Rama Khokha
Keyword(s):  
Growth Factor ◽  
T Antigen ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Early Event ◽  
Mrna Levels ◽  
Insulin Like Growth Factor ◽  
Igf Binding Proteins ◽  
Protein Levels ◽  
Igf I ◽  
Igfbp 3

Insulin-like growth factor (IGF) II is overexpressed in many human cancers and is reactivated by, and crucial for viral oncogene (SV40 T antigen, [TAg])–induced tumorigenesis in several tumor models. Using a double transgenic murine hepatic tumor model, we demonstrate that tissue inhibitor of metalloproteinase 1 (TIMP-1) blocks liver hyperplasia during tumor development, despite TAg-mediated reactivation of IGF-II. Because the activity of IGFs is controlled by IGF-binding proteins (IGFBPs), we investigated whether TIMP-1 overexpression altered the IGFBP status in the transgenic liver. Ligand blotting showed that IGFBP-3 protein levels were increased in TIMP-1–overexpressing double transgenic littermates, whereas IGFBP-3 mRNA levels were not different, suggesting that TIMP-1 affects IGFBP-3 at a posttranscriptional level. IGFBP-3 proteolysis assays demonstrated that IGFBP-3 degradation was lower in TIMP-1–overexpressing livers, and zymography showed that matrix metalloproteinases (MMPs) were present in the liver homogenates and were capable of degrading IGFBP-3. As a consequence of reduced IGFBP-3 proteolysis and elevated IGFBP-3 protein levels, dissociable IGF-II levels were significantly lower in TIMP-1–overexpressing animals. This decrease in bioavailable IGF-II ultimately resulted in diminished IGF-I receptor signaling in vivo as evidenced by diminished receptor kinase activity and decreased tyrosine phosphorylation of the IGF-I receptor downstream effectors, insulin receptor substrate 1 (IRS-1), extracellular signal regulatory kinase (Erk)-1, and Erk-2. Together, these results provide evidence that TIMP-1 inhibits liver hyperplasia, an early event in TAg-mediated tumorigenesis, by reducing the activity of the tumor-inducing mitogen, IGF-II. These data implicate the control of MMP-mediated degradation of IGFBPs as a novel therapy for controlling IGF bioavailability in cancer.

Retinoid receptors in the developing human lung

2002 ◽  
Vol 103 (6) ◽  
pp. 613-621 ◽  
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.

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

1998 ◽  
Vol 274 (4) ◽  
pp. L542-L551 ◽  
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.

Developmental changes of fetal rat lung Na-K-ATPase after maternal treatment with dexamethasone

1997 ◽  
Vol 272 (4) ◽  
pp. L665-L672 ◽  
Author(s):  
D. H. Ingbar ◽  
S. Duvick ◽  
S. K. Savick ◽  
D. E. Schellhase ◽  
R. Detterding ◽  
...  
Keyword(s):  
Sodium Pump ◽  
Alveolar Epithelium ◽  
Fetal Lung ◽  
Dry Weight ◽  
Fluid Secretion ◽  
Northern Analysis ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Duration Of Treatment ◽  
Beta Subunit Gene

Late in gestation, the prenatal fetal alveolar epithelium switches from fluid secretion to resorption of salt and water via apical sodium channels and basal Na-K-ATPase. The amounts of lung sodium pump activity protein and mRNA increase in the lung just before birth. Because maternal glucocorticoids (GC) may promote maturation of the alveolar epithelium and augment fetal surfactant apoprotein levels, we hypothesized that GC increase the fetal lung Na-K-ATPase alpha- and beta-subunit gene expression in development. Timed-pregnant Sprague-Dawley rats were injected daily with intraperitoneal dexamethasone (1 mg/kg) or saline for 1, 3, or 5 days before death at fetal day (FD) 17 or 19. Maternal GC treatment altered the fetal lung wet to dry weight, decreasing it at FD17 and increasing it at FD19. Northern analysis of total lung RNA for the alpha1- and beta1-pump subunits demonstrated differential regulation of the mRNA in response to GC. At FD17, beta1-mRNA increased after 1 (FD16) or 3 days (FD14-FD16) of GC treatment, whereas alpha1-mRNA was not altered. There were accompanying increases in beta1-, but not alpha1-, protein. At FD19, GC treatment for 5 days (FD14-FD18) increased beta1- and decreased alpha1-mRNA levels, but treatment for 1 (FD18) or 3 days (FD16-FD18) had no effect. In all groups, the alpha1-Na-K-ATPase protein was predominantly on the basolateral surface of airspace epithelium by immunofluorescence. In summary, maternal dexamethasone differentially affected the fetal lung mRNA levels of the two sodium pump subunits in a complex manner, with increased beta1-mRNA levels dependent on duration of treatment and fetal age.

scholarly journals Perinatal expression of IGFBPs in rat lung and its hormonal regulation in fetal lung explants

1997 ◽  
Vol 273 (6) ◽  
pp. L1174-L1181 ◽  
Author(s):  
J. Koenraad Van De Wetering ◽  
Robert H. Elfring ◽  
Marja A. Oosterlaken-Dijksterhuis ◽  
Jan A. Mol ◽  
Henk P. Haagsman ◽  
...  
Keyword(s):  
Hormonal Regulation ◽  
Developmental Regulation ◽  
Mrna Level ◽  
Rat Lung ◽  
Igf Binding Proteins ◽  
Igf System ◽  
Explant Cultures ◽  
Igfbp 3

To gain more insight into the regulation of the expression of insulin-like growth factor (IGF) binding proteins (IGFBPs) in the lung, the developmental patterns of the abundance of the mRNAs encoding IGFBPs were measured in the perinatal rat lung and in explant cultures of fetal rat lung. In hormone-free explant cultures, the levels of the mRNAs encoding IGFBP-2 through -5 changed with a pattern similar to that occurring in vivo (although in the case of IGFBP-3 to -5 at a faster rate), indicating that the developmental regulation of the expression of these IGFBPs in perinatal lung is mimicked in the explants. For the IGFBP-6 mRNA level, the pattern in vitro differed from that in vivo. In the explant cultures, dexamethasone decreased the production of IGFBP-3 and -4 and decreased the abundance of the mRNAs encoding IGFBP-2 to -5 but increased the abundance of IGFBP-6 mRNA. These observations indicate that glucocorticoids may be involved in the developmental regulation of the expression of these components of the IGF system and that the IGF system may be involved in the physiological effects of glucocorticoids on lung development. No appreciable effects of 3,3′,5-triiodothyronine on the expression of the IGFBPs were observed.

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.

ROCK2 is involved in accelerated fetal lung development induced by in vivo lung distension

2010 ◽  
Vol 45 (10) ◽  
pp. 966-976 ◽  
Author(s):  
Marc Cloutier ◽  
Monique Tremblay ◽  
Bruno Piedboeuf
Keyword(s):  
Lung Development ◽  
Fetal Lung ◽  
Fetal Lung Development

Effects of the JNK inhibitor anthra[1,9-cd]pyrazol-6(2H)-one (SP-600125) on soluble guanylyl cyclase α1gene regulation and cGMP synthesis

2005 ◽  
Vol 289 (4) ◽  
pp. C778-C784 ◽  
Author(s):  
Joshua S. Krumenacker ◽  
Alexander Kots ◽  
Ferid Murad
Keyword(s):  
Pc12 Cells ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Fetal Lung ◽  
Cell Types ◽  
Mrna Levels ◽  
Disease States ◽  
Jun Kinase ◽  
Constitutively Active

The decreased expression of the nitric oxide (NO) receptor, soluble guanylyl cyclase (sGC), occurs in response to multiple stimuli in vivo and in cell culture and correlates with various disease states such as hypertension, inflammation, and neurodegenerative disorders. The ability to understand and modulate sGC expression and cGMP levels in any of these conditions could be a valuable therapeutic tool. We demonstrate herein that the c-Jun NH2-terminal kinase JNK II inhibitor anthra[1,9- cd]pyrazol-6(2 H)-one (SP-600125) completely blocked the decreased expression of sGCα1-subunit mRNA by nerve growth factor (NGF) in PC12 cells. Inhibitors of the ERK and p38 MAPK pathways, PD-98059 and SB-203580, had no effect. SP-600125 also inhibited the NGF-mediated decrease in the expression of sGCα1protein as well as sGC activity in PC12 cells. Other experiments revealed that decreased sGCα1mRNA expression through a cAMP-mediated pathway, using forskolin, was not blocked by SP-600125. We also demonstrate that TNF-α/IL-1β stimulation of rat fetal lung (RFL-6) fibroblast cells resulted in sGCα1mRNA inhibition, which was blocked by SP-600125. Expression of a constitutively active JNKK2-JNK1 fusion protein in RFL-6 cells caused endogenous sGCα1mRNA levels to decrease, while a constitutively active ERK2 protein had no effect. Collectively, these data demonstrate that SP-600125 may influence the intracellular levels of the sGCα1-subunit in certain cell types and may implicate a role for c-Jun kinase in the regulation of sGCα1expression.

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