Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Friedmacher, F; Hofmann, AD; Takahashi, T; Takahashi, H; Kutasy, B; Puri, P.
Prenatal administration of all-trans retinoic acid upregulates leptin signaling in hypoplastic rat lungs with experimental congenital diaphragmatic hernia.
Pediatr Surg Int. 2014; 30(12):1183-1190
Doi: 10.1007/s00383-014-3605-8
Web of Science
PubMed
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FullText_MUG
- Leading authors Med Uni Graz
- Friedmacher Florian
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- Abstract:
- Pulmonary hypoplasia (PH), characterized by alveolar immaturity, is one of the leading causes of respiratory insufficiency in newborns with congenital diaphragmatic hernia (CDH). Leptin (Lep) and its receptor (Lep-R) play an important role in fetal lung growth by stimulating alveolar differentiation and maturation. Lep and Lep-R are strongly expressed by alveolar cells during the saccular stage of fetal lung development. Lep-deficient mice exhibit decreased alveolarization with reduced pulmonary surfactant phospholipid synthesis, similar to human and nitrofen-induced PH. Prenatal administration of all-trans retinoic acid (ATRA) has been shown to stimulate alveolarization in nitrofen-induced PH. Recent studies have demonstrated that Lep and Lep-R expression in developing lungs is regulated by ATRA. We hypothesized that prenatal treatment with ATRA increases pulmonary Lep and Lep-R expression in the nitrofen model of CDH-associated PH. Time-mated rats received either 100 mg nitrofen or vehicle via oral-gastric lavage on embryonic day 9.5 (E9.5). Control and nitrofen-exposed dams were randomly assigned to either intraperitoneal ATRA (5 mg/kg/d) or placebo administration on E18.5, E19.5 and E20.5. Fetal lungs were harvested on E21.5, and divided into Control+Placebo, Control+ATRA, Nitrofen+Placebo and Nitrofen+ATRA. Alveolarization was assessed using stereo- and morphometric analysis techniques. Surfactant phospholipid synthesis was analyzed by labeling for surfactant protein B (SP-B). Pulmonary gene expression levels of Lep and Lep-R were determined using quantitative real-time polymerase chain reaction. Immunohistochemical staining for Lep and Lep-R was performed to evaluate alveolar protein expression and localization. In vivo administration of ATRA resulted in significantly increased lung-to-body weight ratio with enhanced radial alveolar count and decreased mean linear intercept compared to placebo treatment. Immunofluorescence analysis demonstrated markedly increased pulmonary SP-B expression in Nitrofen+ATRA compared to Nitrofen+Placebo. Relative mRNA expression of Lep and Lep-R was significantly increased in Nitrofen+ATRA compared to Nitrofen+Placebo. Lep and Lep-R immunoreactivity was markedly increased in interstitial and alveolar epithelial cells of Nitrofen+ATRA compared to Nitrofen+Placebo. Increased Lep and Lep-R expression after prenatal administration of ATRA in nitrofen-induced PH suggests that ATRA may have therapeutic potential in attenuating CDH-associated PH by stimulating alveolarization and de novo surfactant production.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Disease Models, Animal -
- Female -
- Hernias, Diaphragmatic, Congenital - drug therapy
- Hernias, Diaphragmatic, Congenital - genetics
- Hernias, Diaphragmatic, Congenital - metabolism
- Immunohistochemistry -
- Leptin - biosynthesis
- Leptin - genetics
- Lung - embryology
- Lung - metabolism
- Organogenesis - drug effects
- Pregnancy -
- Pregnancy, Animal -
- RNA, Messenger - genetics
- Rats -
- Rats, Sprague-Dawley -
- Real-Time Polymerase Chain Reaction -
- Signal Transduction -
- Tretinoin - pharmacology
- Up-Regulation - drug effects
- Find related publications in this database (Keywords)
- Retinoic acid
- Leptin
- Leptin receptor
- Pulmonary hypoplasia
- Congenital diaphragmatic hernia