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)

The mammalian lung develops through branching morphogenesis which is controlled by growth factors, hormones, and extracellular matrix proteins. We have evaluated the role of EGF-receptor signaling in lung morphogenesis by analyzing the developmental phenotype of lungs in mice with an inactivated the EGF-receptor gene both in vivo and in organ culture. Neonatal EGF-receptor-deficient mice often show evidence of lung immaturity which can result in visible respiratory distress. The lungs of these mutant mice had impaired branching and deficient alveolization and septation, resulting in a 50% reduction in alveolar volume and, thus, a markedly reduced surface for gas exchange. The EGF-receptor inactivation also resulted in type II pneumocyte immaturity, which was apparent from their increased glycogen content and a reduced number of lamellar bodies. The defective branching was already evident at Day 12 of embryonic development. When explants of embryonic lungs from Day 12 embryos were cultured under defined conditions, the branching defect in EGF-receptor-deficient lungs was even more pronounced, with only half as many terminal buds as normal lungs. EGF treatment stimulated the expression of surfactant protein C and thyroid transcription factor-1 in cultured normal lungs, but not in EGF-receptor-deficient lungs, suggesting that EGF-receptor signaling regulates the expression of these marker genes during type II pneumocyte maturation. Taken together, our data indicate that signal transduction through the EGF receptor plays a major role in lung development and that its inactivation leads to a respiratory distress-like syndrome.
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PMID:Impaired lung branching morphogenesis in the absence of functional EGF receptor. 920 41

Although retinoic acid (RA) has been shown to be critical for lung development, little is known about when RA is required and the role of individual RA receptors (RAR) in this process. Previously reported data from an RA responsive element RARE-lacZ reporter mouse show that when epithelial tubules are branching and differentiating RA signaling becomes markedly down-regulated in the epithelium. It is unclear why this down-regulation occurs and what role it might play in the developing lung. Here we analyze the effects of preventing potential progenitors of the distal lung from turning off RA signaling by locally expressing constitutively activated RARalpha or RARbeta chimeric receptors (RARVP16) in branching airways of transgenic mice. Continued RA activation resulted in lung immaturity in both cases, but the phenotypes were remarkably different. RARalphaVP16 lungs did not expand to form saccules or morphologically identifiable type I cells. High levels of surfactant protein C (Sp-C), thyroid transcription factor-1 (Ttf1), and Gata6, but not Sp-A or Sp-B in the epithelium at birth suggested that in these lungs differentiation was arrested at an early stage. These alterations were not observed in RARbetaVP16 lungs, which showed relatively less severe changes. Our data suggest a model in which activation of RAR signaling at the onset of lung development establishes an initial program that assigns distal cell fate to the prospective lung epithelium. Down-regulation of RA signaling, however, is required to allow completion of later steps of this differentiation program that ultimately form mature type I and II cells.
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PMID:Down-regulation of retinoic acid receptor alpha signaling is required for sacculation and type I cell formation in the developing lung. 1294 94

Defects in the surfactant biosynthesis are associated with respiratory distress syndrome, commonly occurring in premature infants due to lung immaturity. However, interstitial lung diseases have also been observed in full-term infants with mutations in the SFTPC, SFTPB, NKX2-1, or ABCA3 genes, involved in the surfactant metabolism. Herein, we report a newborn baby with neonatal respiratory distress and diffuse lung disease caused by ABCA3 mutation. The baby died at 5 weeks of age after developing pulmonary hypertension. Genomic DNA was analyzed for four genes involved in surfactant metabolism out of which the c. 4545C>G (p.Tyr1515*) homozygous mutation in exon 29 of ABCA3 was identified which is one of the most frequent mutation causing lethal neonatal respiratory failure in a term neonate. This case study emphasizes the importance of raising awareness about this diagnosis in the clinical settings for fruitful outcomes in health-care delivery.
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PMID:The most frequent ABCA3 nonsense mutation -p.Tyr1515* (Y1515X) causing lethal neonatal respiratory failure in a term neonate. 2880 95

Respiratory distress is one of the most common clinical presentations in newborns requiring admission to a Neonatal Intensive Care Unit (NICU). Many of these infants develop respiratory distress secondary to surfactant deficiency, which causes an interstitial lung disease that can occur in both preterm and term infants. Pulmonary surfactant is a protein and lipid mixture made by type II alveolar cells, which reduces alveolar surface tension and prevents atelectasis. The etiology of surfactant deficiency in preterm infants is pulmonary immaturity and inadequate production. Term infants may develop respiratory insufficiency secondary to inadequate surfactant, either from exposure to factors that delay surfactant synthesis (such as maternal diabetes) or from dysfunctional surfactant arising from a genetic mutation. The genetics of surfactant deficiencies are very complex. Some mutations are lethal in the neonatal period, while others cause a wide range of illness severity from infancy to adulthood. Genes that have been implicated in surfactant deficiency include SFTPA1, SFTPA2, SFTPB, SFTPC, and SFTPD (which encode for surfactant proteins A, B, C, and D, respectively); ABCA3 (crucial for surfactant packaging and secretion); and NKX2 (a transcription factor that regulates the expression of the surfactant proteins in lung tissue). This article discusses the interplay between the genotypes and phenotypes of newborns with surfactant deficiency to assist clinicians in determining which patients warrant a genetic evaluation.
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PMID:Persistent Respiratory Distress in the Term Neonate: Genetic Surfactant Deficiency Diseases. 3154 95