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      Animal Models, Learning Lessons to Prevent and Treat Neonatal Chronic Lung Disease

      review-article
      1 , *
      Frontiers in Medicine
      Frontiers Media S.A.
      prematurity, lung injury, inflammation, oxidant injury

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          Abstract

          Bronchopulmonary dysplasia (BPD) is a unique injury syndrome caused by prolonged injury and repair imposed on an immature and developing lung. The decreased septation and decreased microvascular development phenotype of BPD can be reproduced in newborn rodents with increased chronic oxygen exposure and in premature primates and sheep with oxygen and/or mechanical ventilation. The inflammation caused by oxidants, inflammatory agonists, and/or stretch injury from mechanical ventilation seems to promote the anatomic abnormalities. Multiple interventions targeted to specific inflammatory cells or pathways or targeted to decreasing ventilation-mediated injury can substantially prevent the anatomic changes associated with BPD in term rodents and in preterm sheep or primate models. Most of the anti-inflammatory therapies with benefit in animal models have not been tested clinically. None of the interventions that have been tested clinically are as effective as anticipated from the animal models. These inconsistencies in responses likely are explained by the antenatal differences in lung exposures of the developing animals relative to very preterm humans. The animals generally have normal lungs while the lungs of preterm infants are exposed variably to intrauterine inflammation, growth abnormalities, antenatal corticosteroids, and poorly understood effects from the causes of preterm delivery. The animal models have been essential for the definition of the mediators that can cause a BPD phenotype. These models will be necessary to develop and test future-targeted interventions to prevent and treat BPD.

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          Most cited references140

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          Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.

          Respiratory distress syndrome (RDS) is a serious complication of preterm birth and the primary cause of early neonatal mortality and disability. To assess the effects on fetal and neonatal morbidity and mortality, on maternal mortality and morbidity, and on the child in later life of administering corticosteroids to the mother before anticipated preterm birth. We searched the Cochrane Pregnancy and Childbirth Group Trials Register (30 October 2005). Randomised controlled comparisons of antenatal corticosteroid administration (betamethasone, dexamethasone, or hydrocortisone) with placebo or with no treatment given to women with a singleton or multiple pregnancy, expected to deliver preterm as a result of either spontaneous preterm labour, preterm prelabour rupture of the membranes or elective preterm delivery. Two review authors assessed trial quality and extracted data independently. Twenty-one studies (3885 women and 4269 infants) are included. Treatment with antenatal corticosteroids does not increase risk to the mother of death, chorioamnionitis or puerperal sepsis. Treatment with antenatal corticosteroids is associated with an overall reduction in neonatal death (relative risk (RR) 0.69, 95% confidence interval (CI) 0.58 to 0.81, 18 studies, 3956 infants), RDS (RR 0.66, 95% CI 0.59 to 0.73, 21 studies, 4038 infants), cerebroventricular haemorrhage (RR 0.54, 95% CI 0.43 to 0.69, 13 studies, 2872 infants), necrotising enterocolitis (RR 0.46, 95% CI 0.29 to 0.74, eight studies, 1675 infants), respiratory support, intensive care admissions (RR 0.80, 95% CI 0.65 to 0.99, two studies, 277 infants) and systemic infections in the first 48 hours of life (RR 0.56, 95% CI 0.38 to 0.85, five studies, 1319 infants). Antenatal corticosteroid use is effective in women with premature rupture of membranes and pregnancy related hypertension syndromes. The evidence from this new review supports the continued use of a single course of antenatal corticosteroids to accelerate fetal lung maturation in women at risk of preterm birth. A single course of antenatal corticosteroids should be considered routine for preterm delivery with few exceptions. Further information is required concerning optimal dose to delivery interval, optimal corticosteroid to use, effects in multiple pregnancies, and to confirm the long-term effects into adulthood.
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            The new BPD: an arrest of lung development.

            Alan Jobe (1999)
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              Physiology of transition from intrauterine to extrauterine life.

              The transition from fetus to newborn is the most complex adaptation that occurs in human experience. Lung adaptation requires coordinated clearance of fetal lung fluid, surfactant secretion, and onset of consistent breathing. The cardiovascular response requires striking changes in blood flow, pressures, and pulmonary vasodilation. Energy metabolism and thermoregulation must be quickly controlled. The primary mediators that prepare the fetus for birth and support the multiorgan transition are cortisol and catecholamine. Abnormalities in adaptation are frequently found following preterm birth or cesarean delivery at term, and many of these infants need delivery room resuscitation to assist in this transition.
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                Author and article information

                Contributors
                Journal
                Front Med (Lausanne)
                Front Med (Lausanne)
                Front. Med.
                Frontiers in Medicine
                Frontiers Media S.A.
                2296-858X
                07 August 2015
                2015
                : 2
                : 49
                Affiliations
                [1] 1Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati , Cincinnati, OH, USA
                Author notes

                Edited by: Anne Hilgendorff, Helmholtz Zentrum München, Germany; Andrew Bush, Royal Brompton Hospital and Imperial College London, UK

                Reviewed by: Gunnar N. Hillerdal, Karolinska University Hospital, Sweden; Michael Adam O’Reilly, The University of Rochester, USA

                *Correspondence: Alan H. Jobe, Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, ML#7029, Cincinnati, OH 45229-3039, USA, alan.jobe@ 123456cchmc.org

                Specialty section: This article was submitted to Pulmonary Medicine, a section of the journal Frontiers in Medicine

                Article
                10.3389/fmed.2015.00049
                4528292
                26301222
                d221f6ce-987a-4367-ba34-905efbb65d69
                Copyright © 2015 Jobe.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 17 March 2015
                : 14 July 2015
                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 149, Pages: 13, Words: 12164
                Funding
                Funded by: NIH-NHLBI-U10-10180
                Categories
                Medicine
                Review

                prematurity,lung injury,inflammation,oxidant injury
                prematurity, lung injury, inflammation, oxidant injury

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