Dissertation > Excellent graduate degree dissertation topics show

Fstll Is Required for Lung Maturation at Birth

Author: GengYan
Tutor: NingWen
School: Nanjing University
Course: Biology
Keywords: Fstll respiratory failure differentiation of alveolar epithelial cell surfactant protein BMP4
CLC: Q954.48
Type: PhD thesis
Year: 2011
Downloads: 18
Quote: 0
Read: Download Dissertation


Normal formation and function of the lung is essential for the transition of the fetus to an air-breathing environment at birth. In the later part of gestation, the fetal lung undergoes an important maturation process, including the terminal differentiation of functional typeⅠand typeⅡalveolar epithelial cells (AEC1 and AEC2) and the production of surfactant necessary to decrease alveolar surface tension. Failure of this process always leads to respiratory distress syndrome of newborn infants.Here we showed that Follistatin-like 1 (Fstll), a secreted, follistatin-module containing glycoprotein, is essential for lung maturation and pulmonary surfactant protein homeostasis. Fstll expressed throughout the developing lungs with the highest expression at E17.5.Fstl1-/- mice died of respiratory failure shortly after birth due to impaired lung development. Although the gross phenotype was largely normal in E18.5 Fstl1-/ lungs, with similar size, lobe numbers, and lung/body dry weight ratio in comparable with their wild type littermates, Fstl1-/- lungs was strikingly condense. Histology analysis of mutant lungs showed thickened hypercellular intersaccular septa and apparently collapsed alveoli. We further confirmed that the deletion of Fstll did not affect lung branching morphogenesis at pseudoglandular stage, but delayed saccular development was visible in all Fstl1-/- embryos from E16.5 onwards. The abnormal thickness of the saccular walls in mutant lungs may be caused by the increased number of alveolar epithelial cells due to their higher proliferation rate at pseudoglandular stage. Transmission electron microscopy revealed a marked increase in the number of immature saccular epithelial cells in E18.5 Fstl1-/- lungs. In the septa of WT lungs, squamous AEC1 cells and capillary endothelial cells constituting the blood-air barrier that facilitates efficient gas exchange were clearly visible. By contrast, the septa of Fstl1-/- lungs contained an increased number of cuboidal undifferentiated alveolar epithelial cells and fewer squamous AEC1 cells and capillary endothelial cells. Consequently, the blood-air barrier was much thicker in Fstl1-/-lungs than that in WT lungs. We also examined the expressions of T1αand Aqp5 (markers of AEC-Ⅰcells) and Sftpc (marker of AEC-Ⅱcells) using QRT-PCR and immunohistochemistry. In contrast to the increased expression level of Sftpc mRNA, the expression levels of T1αand Aqp5 mRNAs were severely attenuated in E18.5 Fstl1-/- lungs. Western blot analysis showed that deletion of Fstl1 did not significantly affect the expression of pro-SP-B and pro-SP-C from E18.5 lung tissues. However, production of mature SP-B and SP-C were strikingly decreased in Fstl1-/- lungs. Therefore, saccular dysfunction caused by reduced surfactant production of immature AEC-Ⅱcells fails to prevent Fstl1-/- lung atelectasis. Collectively, these defects likely underlie the mortality of Fstl1 homozygous mutant pups.Through microarray analysis, we identified a group of genes regulating lipid homeostasis, Cell adhesion_ECM remodeling, and Immune response affected in E18.5 Fstl1-/- lungs. Moreover, deletion of the Fstl1 gene caused decreased expression of CTGF, a growth factor that regulates lung epithelial cell proliferation and differentiation.Mechanistically, Fstl1 interacted directly with BMP4, negatively regulated BMP4/Smad1/5/8 signaling, and inhibited BMP4-induced surfactant gene expression. Reducing BMP signaling activity by Noggin or Dorsomorphin rescued pulmonary atelectasis of Fstl1 deficient mice. Therefore, we provide in vivo and in vitro evidence to demonstrate that Fstl1 modulates lung development and alveolar maturation, in part, through BMP4 signaling. promoter to control the Fstl1 gene (SPC-Fstl1 transgenic mice). Western blot and q-RT-PCR analyses showed extremely high expression level of Fstl1 in the transgenic lungs. Immunohistochemical analysis demonstrated extensive activation of Fstl1 in the lung epithelium as early as embryonic day (E) 12.5. However, lung morphogenesis and lung function were not altered. Furthermore, we cross the transgenic mice with the Fstl1+/- to get the compound mice (SPC-Fstl1;Fstl1+/-). Over-expression of Fstl1 in the respiratory epithelial cells does not alter lung structure and postnatal survival and could not rescue the atelectasis phenotype of Fstl1-/- mice.

Related Dissertations

  1. Cloning, Expression and Polymorphism Analysis of BMP4 Gene in Hu Sheep,S826
  2. Activition of Surfactant Protein A and D in Aspergillus Fumigatus-Induced Innate Immune Responses in Human Cornea Epithelial Cells,R772.21
  3. Experimental Studies of JieZe Prescription Gel on Natural Defensive Factors in Mice Vagina,R285.5
  4. Clinical Observation of Shenqifuzheng Injection in the Treatment of Chronic Respiratory Failure and Acute Exacerbation,R259
  5. Therapeutic Effects of High Frequency Jet Ventilation Combined with Tracheal Gas Insufflation on Acute Lung Injury,R563.8
  6. Clinical Study of Noninvasive Positive Pressure in Patients with Type Ⅱ Respiratory Failure Due to COPD and Varying Levels of APACHEⅡ,R563.9
  7. The Influence of Air Mixed Pollutants on the Expression of SP-B in Serum and Lung Tissue of Rats,R114
  8. Molecular Biological Study of Rongchang Pig’s Pulmonary Surfactant Protein A,S828
  9. A Clinical Epidemiologic Study of Neonatal Respiratory Failure in a Children’s Hospital of Hunan Province,R722.1
  10. A Clinical Study on Preterm Infants with Respiratory Failure,R722.6
  11. Analysis on Relevant Factors of Noninvasive Positive Pressure Ventilation in the Patients with Acute Respiratory Failure,R563.8
  12. The Effects of Ischemic Postconditioning on SP-A, NO Expression on Ischemia Reperfusion Injury in Rat Lung,R563
  13. A Study on the Case Fatality Rate and Determinants of Respiratory Failure in Neonates at a Gestational Age of 34 Weeks or More,R722.1
  14. Protective Effects of Keratinocyte Growth Factor-2 on Lipopolysacchride-induced Acute Lung Injury and Its Potential Mechanisms,R563
  15. Recombinant Human Keratinocyte Growth Factor-2 Protects Ventilator-induced Lung Injury in Rats and Its Mechanism,R563
  16. Hyperoxia-induced chronic lung disease in preterm rat lung tissue Foxa_2 Expression and significance,R722.6
  17. The Expression of Surfactant Protein Genes Hyperoxia-induced Neonatal Rat Lung Injury,R722.1
  18. A Preliminary Study of the Mechanism of Fetal Lung Lesions in Intrahepatic Cholestasis of Pregnancy,R714.2
  19. Investigation of Relationship between Surfactant Protein D and Acute Exacerbation of Chronic Obstructive Pulmonary Disease,R563.9
  20. Goat BMP4 gene polymorphism and production traits Correlations,S827
  21. Expression of FGF10 and BMP4 in Intestinal Atresia Proximal Segment,R726.5

CLC: > Biological Sciences > Zoology > Animal morphology > Animal Embryology ( of animals,animal viviparous learn ) > Tissues and organs and systems ( physical changes )
© 2012 www.DissertationTopic.Net  Mobile