Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029713 (immaturity)
 4,335 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Respiratory distress syndrome (RDS) is primarily caused by an immaturity in the synthesis and secretion of surfactant by the fetal lung type II cell. Fetal hyperinsulinemia associated with maternal diabetes places the newborn at an increased risk of developing RDS, and therefore, it has been hypothesized that insulin inhibits type II cell differentiation. We have previously shown that insulin inhibits the accumulation of surfactant-associated protein A (SP-A), the major surfactant-associated protein, in human fetal lung explants maintained in vitro. In the present study, we used Northern blot analysis to evaluate the effects of insulin on the content of SP-A messenger RNA (mRNA) as well as on the content of mRNA for the hydrophobic surfactant-associated proteins SP-B and SP-C in human fetal lung explants maintained in vitro. Lung explants were maintained in serum-free medium with or without added insulin (0.25-2500 ng/ml) for up to 6 days. We observed that insulin, at concentrations of 25-2500 ng/ml, significantly inhibited the accumulation of SP-A mRNA when compared to controls (P less than 0.01). The inhibitory effect of insulin on SP-A mRNA accumulation was dose dependent with an approximately 75% inhibition observed at 2500 ng/ml. Insulin, at the concentration of 2500 ng/ml, significantly inhibited the accumulation of SP-B mRNA by approximately 30% when compared to control levels (P less than 0.01) but had no effect at lower concentrations. Insulin had no significant effect on SP-C mRNA levels at any concentration tested. Our findings provide evidence that insulin may delay fetal lung development by inhibiting SP-A and SP-B gene expression. A deficiency of these proteins in pulmonary surfactant may account for the increased incidence of RDS in infants of diabetic mothers.
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PMID:Insulin regulation of messenger ribonucleic acid for the surfactant-associated proteins in human fetal lung in vitro. 163 13

Transforming growth factor-beta (TGF-beta), a potent inhibitor of epithelial cell proliferation, and epidermal growth factor (EGF), a mitogenic polypeptide that binds to cell surface receptors, are important regulators of cell differentiation; however, their distinct role(s) in lung development and their mechanisms of action are not well understood. We evaluated the effects of these factors on lung morphogenesis in murine fetal lungs at gestational day 14 (time:zero) and again after 7 days in culture. Baseline controls were cultured after tracheal transection in supplemented BGJb medium, and other tracheally transected lungs were cultured following addition of EGF (10 ng/ml BGJb), TGF-beta1 (2 ng/ml BFJb), or with both in combination added to the medium. The control lungs in culture had poorly developed airways and an absence of defined acinar structures. The addition of EGF resulted in hyperplasia of primary airways with stunted outgrowths, monopodial branching, and absence of distinct acinar structures. Addition of TGF-beta1 alone, led to significant elongation of primary airways, without normal airway branching; however, terminal dipodial branching was seen and the prospective pulmonary acini were well defined. Combination of these growth factors (GF) resulted in a more normal branching pattern and differentiation, suggesting their epigenetic role in lung morphogenesis and mutual interactive mechanisms that regulate lung development. These lungs had more abundant and larger lamellar bodies than those after other treatments. Control lungs remained immature with prominent glycogen aggregates with occasional dense lamellar bodies. The total protein and DNA contents were highest with EGF treatment, followed by combination treatment; these observations were supported by immunohistochemical localization of proliferating cell nuclear antigen, an indication of the proliferative state of tissues. All the surfactant proteins were relatively unaltered and their messages were up-regulated for SP-A, but down-regulated for SP-B and SP-C in the lungs treated with growth factors. In conclusion, we have demonstrated enhanced biochemical and structural development of lungs treated in vitro with GF, and propose that further research in this area may lead to therapeutic uses of GF alone or in combination with other agents for the treatment of newborn respiratory distress due to lung immaturity or hypoplastic lung development.
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PMID:Influence of epidermal growth factor and transforming growth factor beta-1 on patterns of fetal mouse lung branching morphogenesis in organ culture. 959 Apr 85

Respiratory distress syndrome (RDS) is caused by surfactant deficiency at birth. The risk of RDS decreases from the gestational age of 24 weeks to full-term. Genetic and acquired factors additionally influence the risk of RDS. Surfactant deficiency in RDS is mainly caused by immaturity and a lack of differentiation of the alveolar epithelial cells involved in surfactant synthesis and secretion. A network of hormones and growth factors regulate perinatal development. Host-related factors, including the levels of expression of surfactant proteins (SP), modulate the responsiveness of growth factors. SP-A has roles in surface activity and regulatory roles particularly in innate immunity; SP-B is essential for the processing of surfactant and for the surface activity; SP-C has roles in surfactant metabolism and function; the regulatory roles of SP-D mainly pertain to innate immunity. The genetic variation of SP-A and SP-B genes and the risk of RDS have been studied. Both SP-A and SP-B associate with susceptibility to RDS. The association between the SP-A allele and genotypes and the risk of RDS is dependent on the SP-B genotype and significantly influenced by the degree of prematurity, antenatal glucocorticoid therapy, multiple birth, and birth order. The alleles/genotypes of SP-A, SP-C, or SP-D also associate with several other inflammatory lung and airway diseases. Rare mutations in SP-B or SP-C cause serious, often fatal lung diseases. Genetic and post-genomic research is likely to eventually result in new diagnostic applications and specific therapies for the prevention of respiratory failure and inflammatory lung diseases.
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PMID:Surfactant proteins and genetic predisposition to respiratory distress syndrome. 1253 18

Respiratory distress syndrome (RDS) is a multifactorial developmental disease caused by lung immaturity and presenting as high-permeability lung edema ("hyaline membrane disease"). It is characterized by a transient deficiency of alveolar surfactant during the first week of life. During the first few days of life, the alveolar surfactant pool size increases up to that in the controls. The allelic variants of the genes encoding the surfactant proteins (SP) SP-A1, SP-A2, SP-B, and SP-C have been associated with RDS. The main SP-A haplotype, interactively with the SP-B Ile131Thr polymorphism and with constitutional and environmental factors, influence the risk. Case reports on mutations with partially functional SP-B have been published. The genetic susceptibility factors depend on the degree of prematurity at birth, consistent with sequential differentiation of the lung and gestation-dependent differences in clinical presentation. The preferentially type 2 cell expressed genes involved in critical functions (such as ATP-binding cassette transporter, ABCA3), those involved in susceptibility to acute lung damage, and those with known susceptibility to other severe lung diseases (such as G protein-coupled receptor for asthma susceptibility, GPR154 alias GPRA) will possibly serve as candidate genes in future studies. RDS associated with near-term and term births may have a different genetic predisposition and pathogenesis compared to RDS after very preterm birth. As we learn more about the molecular consequences of allelic variation, new therapies based on a new generation of surfactant diagnostics and individualized therapies may follow.
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PMID:Genetic basis of respiratory distress syndrome. 1712 71

The Iroquois genes (Irx) appear to regulate fundamental processes that lead to cell proliferation, differentiation, and maturation during development. In this report, the Iroquois homeobox 1 (Irx1) transcription factor was functionally disrupted using a LacZ insert and LacZ expression demonstrated stage-specific expression during embryogenesis. Irx1 is highly expressed in the brain, lung, digits, kidney, testis and developing teeth. Irx1 null mice are neonatal lethal and this lethality it due to pulmonary immaturity. Irx1-/- mice show delayed lung maturation characterized by defective surfactant protein secretion and Irx1 marks a population of SP-C expressing alveolar type II cells. Irx1 is specifically expressed in the outer enamel epithelium (OEE), stellate reticulum (SR) and stratum intermedium (SI) layers of the developing tooth. Irx1 mediates dental epithelial cell differentiation in the lower incisors resulting in delayed growth of the lower incisors. Irx1 is specifically and temporally expressed during developmental stages and we have focused on lung and dental development in this report. Irx1+ cells are unique to the development of the incisor outer enamel epithelium, patterning of Lef-1+ and Sox2+ cells as well as a new marker for lung alveolar type II cells. Mechanistically, Irx1 regulates Foxj1 and Sox9 to control cell differentiation during development.
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PMID:Irx1 regulates dental outer enamel epithelial and lung alveolar type II epithelial differentiation. 2874 23