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At least 541 records · Page 30Linked to original sources
PubMed2000

Stretch-induced upregulation of VEGF gene expression in murine pulmonary culture: a role for angiogenesis in lung development.

BACKGROUND/PURPOSE: The authors' have shown pulmonary alveolarization (capillary and alveolar growth) both after fetal tracheal occlusion and postnatal pulmonary distension. The trophic and developmental mechanisms responsible for this growth remain largely unknown; however, experimental systems have defined an enhanced expression of angiogenic proteins in response to tissue stretch. The authors hypothesize that the stimulation of pulmonary alveolarization after stretch is secondary to upregulation of the potent endothelial cell mitogen vascular endothelial growth factor (VEGF) and that the endothelial cell represents the central stimulus of parenchymal growth. METHODS: A mixed primary pulmonary cell culture obtained by enzymatic digestion of fetal, neonatal, and adult mouse lung was plated on Bioflex elastomer bottom plates, grown to confluence, rendered quiescent, and subjected to continuous cycles of stretch-relaxation with nonstretched cells as controls. Cells were harvested at time-points 0, 30 minutes, 2 hours, 4 hours, 8 hours, and 24 hours. RNA was extracted and VEGF gene expression analyzed by semiquantitative reverse transcription polymerase chain reaction (RT-PCR). Similar cell groups were harvested, processed, and analyzed utilizing Western Blot techniques. VEGF PCR of mRNA isolated from fetal sheep subjected to surgical creation of diaphragmatic hernia both with (DH-TL) and without (DH) tracheal ligation also was analyzed. RESULTS: VEGF mRNA isoforms 120, 164, and 188 showed increased expression in all stretched groups, which was noted by 30 minutes with maximal expression seen at 2 to 4 hours and a return to baseline expression by 24 hours. VEGF protein was similarly elevated in all stretched cell groups. In preliminary studies, DH/TL sheep showed upregulation of VEGF compared with DH sheep alone. CONCLUSIONS: These data show in an in vitro system that "pulmonary stretch" upregulates VEGF mRNA and protein expression supporting the role of angiogenesis in the stretch-induced pulmonary alveolarization. The authors speculate that such angiogenic activity is a rate-limiting factor in stimulating alveolar epithelial development, and as a treatment modality, therapeutic angiogenesis may provide a noninvasive method with which to treat pulmonary hypoplasia.

Aging↗
PubMed2002

Retinoid receptors in the developing human lung.

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 alpha, beta, and gamma and retinoid X receptor (RXR) isoforms alpha, beta, and gamma. 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-alpha, -beta and -gamma, RXR-alpha, -beta and -gamma 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-gamma 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-beta 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-gamma immunoreactivity was detected in the chondrocytes of bronchial cells. COUP-TFII immunoreactivity was detected with a similar pattern to that of RAR-beta. Real-time quantitative PCR analyses revealed that mRNA levels of RXR-gamma 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-beta at distal sites (2.4+/-0.01-fold; P <0.05) and RAR-gamma at proximal sites (2.2+/-0.11-fold; P <0.05) were significantly higher in the fetus than in the adult.

Adult↗
PubMed1994

Alveolar-capillary gas transfer in lungs: development of concepts and current state.

Progress in research on pulmonary gas exchange, with special reference to the contribution of Gerhard Thews and associates, is reviewed. In particular, the following aspects are considered. (1) Oxygen transfer kinetics of red blood cells. Recent measurements, particularly on red blood cells in thin blood films, yield more rapid equilibration kinetics than previously recorded. A reevaluation of the roles of diffusion and chemical reaction in alveolar O2 uptake may become necessary. (2) Gas exchange in functionally inhomogeneous lungs. Besides the classical ventilation/perfusion (VA/Q) inequality, a variation of the diffusing capacity-to-perfusion ratio (DL/Q) appears to be of importance. The combination of VA/Q and DL 1Q inequalities may lead to a better understanding of alveolar gas exchange, particularly in diseased lungs. (3) Pulmonary diffusing capacity (DL) for oxygen. The rebreathing technique, which strongly reduces the effects of inequal VA/Q distribution effects, appears to be particularly suited for measurement of overall alveolar-capillary diffusion. But neither the factors determining DL, obtained by rebreathing or other methods, nor the relationships between DL for various gases are yet fully understood.

Animals↗
PubMed1983

Effect of semicarbazide on the surfactant phospholipid percentages during fetal and postnatal lung development in rat.

1. The effect of 100 mg/kg of semicarbazide on phosphatidylcholine, phosphatidylethanolamine, sphingomyeline, phosphatidylserine and lysophosphatidylcholine of the pulmonary surfactant was studied in offspring of treated rats on the 10th day of gestation. 2. The relative percentages of phosphatidylcholine were smaller in the offspring of treated rats than in controls, but the opposite was observed with the other phospholipids. 3. Significant statistical differences at almost all ages studied were observed in phosphatidylcholine and phosphatidylethanolamine. 4. The ratio of phosphatidylcholine to sphingomyeline, an index of lung maturity, was smaller in the offspring of treated rats, with statistically significant differences just before birth and on the first day of life.

Aging↗
PubMed1996

New insights into lung growth and development.

Lung development requires a complex series of developmentally controlled interactions that involve mechanical forces, genetic and endocrine influences, and cell-cell communication. At each step, cell-matrix or cell-cell signaling mediated by peptide growth factors and extracellular matrix components is crucial in directing cell proliferation, differentiation, and migration. Although a comprehensive understanding of how these components interact to guide lung organogenesis has been elusive, the action and control of peptide growth factors in autocrine and paracrine signaling, mesenchymal-epithelial interactions in controlling branching morphogenesis, cell-cell communication in the regulation of cellular differentiation, and factors regulating pattern formation are being clarified.

Animals↗
PubMed1983

Ultrastructural immunocytochemical localization of fibronectin in the developing rat lung.

In a previous study changes in the macrodistribution of fibronectin during rat-lung development were examined. Using the peroxidase-antiperoxidase immunocytochemical technique, we have demonstrated the presence of fibronectin in embryonic, neonatal, and adult rat lung at the ultrastructural level. In the embryo, fibronectin is found both in an intra- and extracellular association with isolated pneumoblasts, and in a periodic distribution along the basal lamina. The neonate displays fibronectin in an intracellular association with early type-I cells and on their basal and luminal surfaces, but not in association with type-II cells. Neonatal basal lamina is diffusely labeled by anti-fibronectin antiserum. Fibronectin in adult tissue is found both intracellularly and on the basal and luminal surfaces of type-I cells but not in type-II cells. The basal lamina and interstitial connective tissue are slightly or non-reactive. These observations confirm and extend our initial suggestion that fibronectin is involved in rat-lung development.

Animals↗
PubMed1987

[Inhibiting factors of fetal lung development].

The authors studied autopsy with fetal pulmonary hypoplasia among port mortem examined stillbirths and newborns. Besides pulmonary hypoplasia they found malformations of the urinary tract, diaphragmatic defects and thoracal deformities. A common consequence of these malformations is in their interpretation the inhibition of thoracal and/or diaphragmatic movements, resulting finally in pulmonary hyperplasia.

Female↗
PubMed2004

Slit and robo expression in the developing mouse lung.

Mammalian lung development is mediated through complex interactions between foregut endoderm and surrounding mesenchyme. As airway branching progresses, the mesenchyme undergoes dramatic remodeling and differentiation. Little is understood about the mechanisms that direct mesenchymal organization during lung development. A screen for candidate genes mediating this process identified Slit, a ligand for the Roundabout (Robo) receptor previously associated with guidance of axonal projections during central nervous system development. Here, we demonstrate by in situ hybridization that two Slit genes (Slit-2 and Slit-3) and two Robo genes (Robo-1 and Robo-2) are expressed in fetal lung mesenchyme. Slit-2 and Robo-1 expression is present throughout mesenchyme at midgestation and is not detectable by newborn day 1. Slit-3 and Robo-2 expression is restricted to specific, complementary subsets of mesenchyme. Robo-2 is expressed in mesenchymal cells immediately adjacent to large airways, whereas Slit-3 expression predominates in mesenchyme remote from airway epithelium. The temporal and spatial distribution of Slit and Robo mRNAs indicate that these genes may direct the functional organization and differentiation of fetal lung mesenchyme.

Animals↗
PubMed2004

Expression of epithelial sodium channel alpha-subunit mRNAs with alternative 5'-untranslated regions in the developing human lung.

In preparation for birth, lung epithelia must switch from net fluid secretion, required for lung development, to net absorption, which prepares the lungs for postnatal gas exchange. The apical membrane amiloride-sensitive epithelial Na channel (ENaC) is the rate-limiting step for Na+ and fluid absorption. Expression of alpha-ENaC mRNA has been detected in human lung as early as the embryonic stage of development. However, humans express multiple transcripts for alpha-ENaC, containing differing 5'-untranslated regions (UTR) with unknown effects on protein translation, and different ontogenies for individual transcripts could provide a novel mechanism for developmental regulation of ENaC function. To assess the relative expression of the two most abundant alpha-ENaC transcripts (alpha-ENaC1 and alpha-ENaC2) during lung development, we performed nonradioactive in situ hybridization using probes specific to the alternative 5'-UTRs. Both transcripts were expressed throughout intrauterine lung development (8 to 40 wk gestation), and expression was localized to the surface epithelial cells of the conductive and respiratory airways in both ciliated cells and nonciliated Clara cells. alpha-ENaC mRNA expression was also identified in the serous cells of the submucosal glands surrounding the proximal airways. In the mature prenatal lung, subsets of alveolar type II (ATII) cells expressed one or both of the alpha-ENaC transcripts. Our observations demonstrate that a developmentally regulated switch between alpha-ENaC 5'-UTR variants is not the trigger by which the developing human lung becomes a fluid-absorbing organ at birth, that individual ATII cells express neither, one, or both of the alpha-ENaC transcripts, and that the overall expression is linked to epithelial cell differentiation and lung maturation.

5' Untranslated Regions↗
PubMed2003

Effects of short-term dexamethasone treatment on collagen synthesis and degradation markers in preterm infants with developing lung disease.

AIM: To assess the effects of dexamethasone treatment on collagen turnover in preterm infants. METHODS: The serum concentrations of the amino-terminal propeptide of type I and III procollagens (PINP and PIIINP), which reflect rates of type I and III collagen synthesis, respectively, and the carboxy-terminal telopeptide of type I procollagen (ICTP), which reflects the rate of type I collagen degradation, were monitored in 13 preterm infants receiving dexamethasone and 13 matched control infants without glucocorticoid treatment for a total period of 12 mo. Dexamethasone was started at a median age of 12 d and continued at tapering doses for a median total duration of 10 d. Blood samples were taken immediately after birth, at 7, 14 and 28 d of age and at 2, 3, 6, 9 and 12 mo. The same markers were also measured just before the initiation of dexamethasone and on days 1, 3, and 7 of treatment. RESULTS: A striking decrease in all of the markers was already observed in every case on day 1 of dexamethasone, the suppression being greatest on day 3 and still considerable on day 7. The percentages from the pretreatment levels recorded on days 1, 3 and 7 were: for PINP 51, 26 and 45%; for PIIINP 63, 44% and 52%; and for ICTP 64, 41 and 51%. A rebound rise in PINP levels was seen in dexamethasone-treated infants, the levels exceeding those of the controls at 3 and 6 mo of age. A similar phenomenon was noted concerning PIIINP at 3 mo. The levels settled down at 9 and 12 mo. CONCLUSION: Dexamethasone causes an immediate, inevitable, deep suppression of type I and III collagen synthesis and also type I collagen degradation. This should be taken into consideration, e.g. when assessing for the indications for steroid treatment in sick preterm infants and its dosing and duration.

Anti-Inflammatory Agents↗
PubMed2001

Molecular regulation of lung development.

There is increasing evidence suggesting that formation of the tracheobronchial tree and alveoli results from heterogeneity of the epithelial-mesenchymal interactions along the developing respiratory tract. Recent genetic data support this idea and show that this heterogeneity is likely the result of activation of distinct networks of signaling molecules along the proximal-distal axis. Among these signals, fibroblast growth factors, retinoids, Sonic hedgehog, and transforming growth factors appear to play prominent roles. We discuss how these and other pattern regulators may be involved in initiation, branching, and differentiation of the respiratory system.

Animals↗
PubMed2002

Disruption of the gene encoding the latent transforming growth factor-beta binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer.

Transforming growth factor-betas (TGF-betas) are multifunctional growth factors that are secreted as inactive (latent) precursors in large protein complexes. These complexes include the latency-associated propeptide (LAP) and a latent transforming growth factor-beta binding protein (LTBP). Four isoforms of LTBPs (LTBP-1-LTBP-4) have been cloned and are believed to be structural components of connective tissue microfibrils and local regulators of TGF-beta tissue deposition and signaling. By using a gene trap strategy that selects for integrations into genes induced transiently during early mouse development, we have disrupted the mouse homolog of the human LTBP-4 gene. Mice homozygous for the disrupted allele develop severe pulmonary emphysema, cardiomyopathy, and colorectal cancer. These highly tissue-specific abnormalities are associated with profound defects in the elastic fiber structure and with a reduced deposition of TGF-beta in the extracellular space. As a consequence, epithelial cells have reduced levels of phosphorylated Smad2 proteins, overexpress c-myc, and undergo uncontrolled proliferation. This phenotype supports the predicted dual role of LTBP-4 as a structural component of the extracellular matrix and as a local regulator of TGF-beta tissue deposition and signaling.

Adaptor Proteins, Signal Transducing↗
PubMed1985

Mg2-dependent phosphatidate phosphohydrolase of rat lung: development of an assay employing a defined chemical substrate which reflects the phosphohydrolase activity measured using membrane-bound substrate.

An assay of pulmonary phosphatidate phosphohydrolase activity has been developed that employs a chemically defined liposome substrate of equimolar phosphatidate and phosphatidylcholine. Enzyme assays employing this substrate resolved two distinct activities based upon their requirements for Mg2+. Assays were performed in the presence and absence of 2 mM MgCl2 and the Mg2+-dependent phosphatidate phosphohydrolase activity calculated by difference. The Mg2+-independent phosphatase activity resembled that found using aqueous dispersions of phosphatidate (PAaq). Approximately 90% of the Mg2+-dependent phosphatidate phosphohydrolase activity was recovered in the cytosol and the remainder was associated with the microsomal fraction. The Mg2+-dependent phosphatidate phosphohydrolase activity has kinetic parameters of Km = 55 microM, Vmax = 1.6 nmol/min/mg protein for the microsomal fraction, and Km = 215 microM, Vmax = 6.8 nmol/min/mg protein for the cytosolic fraction. These parameters resembled those found using the microsomal membrane-bound (PAmb) substrate. In addition, the pH optima and sensitivity to detergents and thermal inactivation are equal to those for the PAmb-dependent phosphatidate phosphohydrolase activity. In the course of these studies the microsomal and cytosolic activities were qualitatively equal, indicative of a single enzyme in two subcellular locations. In conclusion, the assay of Mg2+-dependent phosphatidate phosphohydrolase activity measured using equimolar phosphatidate and phosphatidylcholine liposomes is equivalent to that activity previously described using microsomal membrane-bound substrate. However, the chemically-defined system provides a more simplified starting point for further studies on this important enzyme.

Animals↗
PubMed1998

epicardin: A novel basic helix-loop-helix transcription factor gene expressed in epicardium, branchial arch myoblasts, and mesenchyme of developing lung, gut, kidney, and gonads.

We report the cloning, chromosomal localization, and analysis of the expression pattern of epicardin, a member of the basic helix-loop-helix (bHLH) family of transcription factors. Within its bHLH domain, the human and murine epicardin genes were most similar to paraxis, a bHLH gene important for segmentation of embryonic paraxial mesoderm. In situ hybridization studies revealed strong epicardin expression in murine embryos at 9.5 days postcoitum (dpc) in a region of the septum transversum at the base of the heart known as the proepicardial organ. This mesenchymal structure extends villous projections from which epicardial precursor cells emerge and migrate out over the surface of the myocardium. Strong expression was seen in individual migratory cells and clusters at 9.5 dpc and in a continuous epicardial cell layer in more mature hearts. Also from 9.5 dpc, epicardin transcripts were seen in endocardial cushions of the atrioventricular canal and outflow tract, in skeletal myoblasts within branchial arches and in condensing mesenchyme of gut, kidney, urinary tract, gonads, spleen, and lung. Northern analysis showed that expression persisted in mature visceral organs and heart, but was transient in skeletal muscle. The central role played by bHLH factors in pathways for tissue determination in the embryo suggests a function for epicardin in specification of select mesodermal cell populations associated with heart, cranial skeletal muscle, gut, and urogenital system.

Amino Acid Sequence↗
PubMed2000

Glycoconjugate sugar residues in the chick embryo developing lung: a lectin histochemical study.

A lectin histochemical study was performed to investigate the distribution and changes of the oligosaccharidic component of the glycoconjugates in the lung of chick embryos, of 1-day-old chick, and of the adult animal. For this purpose, a battery of seven horseradish peroxidase-conjugated lectins (PNA, SBA, DBA, WGA, Con A, LTA, and UEA I) were employed. During the first phase of parabronchi and atria formation, D-galactose-(beta1-->3)-N-acetyl-D-galactosamine, beta-N-acetyl-D-galactosamine, D-glucosamine, alpha-D-mannose, and sialic acid, present at the level of the surface and of cytoplasmic granules of the lining epithelial cells, seem to play a role in regulating morphogenetic phenomena. In the subsequent phases, the parabronchial lumen and the atrial cavities were characterized by the presence of lectin-reactive material rich in terminal D-galactose-(beta1-->3)-N-acetyl-D-galactosamine, beta-N-acetyl-D-galactosamine, D-glucosamine and alpha-D-mannose. From day 18 onwards and immediately after hatching, the free border of the cells lining the air capillaries was characterized by the presence of beta-N-acetyl-D-galactosamine and alpha-D-mannose. The appearance of these sugar residues was concomitant with the beginning of respiratory activity.

Aging↗
PubMed1978

Collagen and non-collagen protein synthesis in developing lung exposed to tobacco smoke.

The present investigation was conducted to determine the rate of collagen and non-collagen protein synthesis by rat lung under in vitro conditions. The rate of synthesis of non-collagen protein was greater than the rate of collagen synthesis in animals between 1 and 95 days of age. Synthesis of both types of proteins was highest in 1-day-old animals. Rate of synthesis of non-collagen protein was markedly diminished after 7 days of age and that of collagen decreased after 14 days. Per gram lung, the total amount of collagen increased 3.5-fold between Day 7 and 95 whereas total protein was relatively constant. When lung was exposed to smoke under in vitro conditions synthesis of collagen and non-collagen protein was almost completely depressed.

Age Factors↗