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      Leptin Promotes Fetal Lung Maturity and Upregulates SP-A Expression in Pulmonary Alveoli Type-II Epithelial Cells Involving TTF-1 Activation

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          Abstract

          The placental hormone leptin has important functions in fetal and neonatal growth, and prevents depressed respiration in leptin-deficient mice. The effect of leptin on respiratory distress suffered by low birth weight and premature infants has been studied. However, it is unclear how leptin enhances lung maturity in the fetus and ameliorates neonatal respiratory distress. In the present study, we found that antenatal treatment with leptin for 2 d significantly enhanced the relative alveolus area and improved the maturity of fetal lungs in a rat model of fetal growth restriction (FGR). Mean birth weight and lung wet weight were higher in the leptin-treated group than in the PBS-treated group, indicating promotion of fetal growth. Leptin upregulated the intracellular expression and extracellular secretion of surfactant protein (SP) A in type-II alveolar epithelial cells (AECs) in vivo and in vitro. Dual positive effects of leptin were found on protein expression and transcriptional activity of thyroid transcription factor-1 (TTF-1), a nuclear transcription essential for branching morphogenesis of the lung and expression of SP-A in type-II AECs. Knockdown of TTF-1 by RNA interference indicated that TTF-1 may play a vital role in leptin-induced SP-A expression. These results suggest that leptin may have great therapeutic potential for the treatment of FGR, and leptin-mediated SP-A induction and lung maturity of the fetus are TTF-1 dependent.

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          Most cited references43

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          Identification and expression cloning of a leptin receptor, OB-R.

          The ob gene product, leptin, is an important circulating signal for the regulation of body weight. To identify high affinity leptin-binding sites, we generated a series of leptin-alkaline phosphatase (AP) fusion proteins as well as [125I]leptin. After a binding survey of cell lines and tissues, we identified leptin-binding sites in the mouse choroid plexus. A cDNA expression library was prepared from mouse choroid plexus and screened with a leptin-AP fusion protein to identify a leptin receptor (OB-R). OB-R is a single membrane-spanning receptor most related to the gp130 signal-transducing component of the IL-6 receptor, the G-CSF receptor, and the LIF receptor. OB-R mRNA is expressed not only in choroid plexus, but also in several other tissues, including hypothalamus. Genetic mapping of the gene encoding OB-R shows that it is within the 5.1 cM interval of mouse chromosome 4 that contains the db locus.
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            The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain.

            TTF-1, a homeodomain-containing transcription factor, which is required for the specific expression of the thyroglobulin and thyroperoxidase gene promoters in differentiated thyroid cell lines, is expressed at the very beginning of rat thyroid differentiation. TTF-1 mRNA is detected in the endodermal cells of the thyroid rudiment in the rat embryo and precedes the expression of the two known target genes by 5 days. No delay is observed between the appearance of TTF-1 mRNA and protein, which shows a clear nuclear localization. In the adult thyroid, TTF-1 is present only in the endoderm-derived follicular cells. Two additional domains of expression of TTF-1 have been observed, the lung and restricted areas of the brain. In the lung, TTF-1 mRNA and protein are also present at the earliest stages of differentiation and are later confined to the bronchial epithelium. In the brain, TTF-1 appears to be restricted to structures of diencephalic origin, including the developing neurohypophysis. The early detection of TTF-1 in the endodermal cells of the thyroid and lung anlage and in restricted neuroblast populations indicates that TTF-1 may have a role in cell determination in these three systems and that additional mechanisms may be involved in the activation of thyroid-specific gene expression.
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              Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994.

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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                22 July 2013
                : 8
                : 7
                : e69297
                Affiliations
                [1 ]Department of Obstetrics and Gynecology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
                [2 ]Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen University, Guangzhou, China
                [3 ]Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
                [4 ]Department of Biochemistry, Zhongshan Medical School, Sun Yat-sen University, Guangzhou, China
                [5 ]Center for Disease Model Animals, Sun Yat-sen University, Guangzhou, China
                Virgen Macarena University Hospital, School of Medicine, Spain
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: WBC HC JPZ. Performed the experiments: HC HH JPZ ZHW. Analyzed the data: WBC HC JPZ RC. Contributed reagents/materials/analysis tools: HC HH JPZ ZHW. Wrote the paper: WBC HC.

                Article
                PONE-D-12-40163
                10.1371/journal.pone.0069297
                3718688
                23894445
                c12125ea-cd69-437b-a137-083b0622f636
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 30 November 2012
                : 12 June 2013
                Page count
                Pages: 12
                Funding
                This study was supported partially by National Nature Science Foundation of China (Nos. 81000259, 30973207 and 81070746), Guangdong Natural Science Foundation (Nos. 10151008901000007 and 10451008901004246), Fundamental Research Funds for the Central Universities (Youth Program 09YKPY73, 12ykpy29) and Research Fund for the Doctoral Program of Higher Education of China (No. 20090171120075). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Model Organisms
                Animal Models
                Rat
                Molecular Cell Biology
                Signal Transduction
                Signaling Pathways
                Leptin Signal Transduction
                Medicine
                Obstetrics and Gynecology
                Pregnancy
                Preterm Labor
                Pediatrics
                Child Development
                Growth Retardation
                Neonatology
                Pediatric Pulmonology

                Uncategorized
                Uncategorized

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