{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T04:24:09Z","timestamp":1791433449730,"version":"4.3.3"},"reference-count":105,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,10,2]],"date-time":"2021-10-02T00:00:00Z","timestamp":1633132800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Oxygen toxicity continues to be one of the inevitable injuries to the immature lung. Reactive oxygen species (ROS) production is the initial step leading to lung injury and, subsequently, the development of bronchopulmonary dysplasia (BPD). Today, BPD remains the most important disease burden following preterm delivery and results in life-long restrictions in lung function and further important health sequelae. Despite the tremendous progress in the pathomechanistic understanding derived from preclinical models, the clinical needs for preventive or curative therapies remain unmet. This review summarizes the clinical progress on guiding oxygen delivery to the preterm infant and elaborates future directions of research that need to take into account both hyperoxia and hypoxia as ROS sources and BPD drivers. Many strategies have been tested within clinical trials based on the mechanistic understanding of ROS actions, but most have failed to prove efficacy. The majority of these studies were tested in an era before the latest modes of non-invasive respiratory support and surfactant application were introduced or were not appropriately powered. A comprehensive re-evaluation of enzymatic, antioxidant, and anti-inflammatory therapies to prevent ROS injury is therefore indispensable. Strategies will only succeed if they are applied in a timely and vigorous manner and with the appropriate outcome measures.<\/jats:p>","DOI":"10.3390\/ijms221910694","type":"journal-article","created":{"date-parts":[[2021,10,4]],"date-time":"2021-10-04T09:24:15Z","timestamp":1633339455000},"page":"10694","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Oxygen Toxicity to the Immature Lung\u2014Part II: The Unmet Clinical Need for Causal Therapy"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4307-8759","authenticated-orcid":false,"given":"Judith","family":"Behnke","sequence":"first","affiliation":[{"name":"Department of General Pediatrics and Neonatology, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Lung Research Center (DZL), Feulgenstrasse 12, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constanze M.","family":"Dippel","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics and Neonatology, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Lung Research Center (DZL), Feulgenstrasse 12, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4288-6631","authenticated-orcid":false,"given":"Yesi","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics and Neonatology, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Lung Research Center (DZL), Feulgenstrasse 12, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Rekers","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics and Neonatology, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Lung Research Center (DZL), Feulgenstrasse 12, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annesuse","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics and Neonatology, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Lung Research Center (DZL), Feulgenstrasse 12, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Lauer","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics and Neonatology, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Lung Research Center (DZL), Feulgenstrasse 12, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics and Neonatology, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Lung Research Center (DZL), Feulgenstrasse 12, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Behnke","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine V, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Lung Research Center (DZL), Klinikstrasse 33, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus-Peter","family":"Zimmer","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics and Neonatology, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Lung Research Center (DZL), Feulgenstrasse 12, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saverio","family":"Bellusci","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Universities of Giessen and Marburg Lung Center (UGMLC), Cardiopulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University, Aulweg 130, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4587-1734","authenticated-orcid":false,"given":"Harald","family":"Ehrhardt","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics and Neonatology, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Lung Research Center (DZL), Feulgenstrasse 12, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/s41572-019-0127-7","article-title":"Bronchopulmonary dysplasia","volume":"5","author":"Goss","year":"2019","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Thiess, T., Lauer, T., Woesler, A., Stehle, S., Neusius, J., Zimmer, K.-P., Eckert, G.P., and Ehrhardt, H. (2021). Correlation of early nutritional supply and development of Bronchopulmonary Dysplasia in preterm infants <1000 g. Front. Pediatr., 1028.","DOI":"10.3389\/fped.2021.741365"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1136\/gutjnl-2020-321173","article-title":"Bacteria-derived long chain fatty acid exhibits anti-inflammatory properties in colitis","volume":"70","author":"Pujo","year":"2021","journal-title":"Gut"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1801225","DOI":"10.1183\/13993003.01225-2018","article-title":"Airway microbiome in adult survivors of extremely preterm birth: The EPICure study","volume":"53","author":"Rofael","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.jpeds.2018.08.042","article-title":"Airway microbiome and development of Bronchopulmonary Dysplasia in preterm infants: A systematic review","volume":"204","author":"Pammi","year":"2019","journal-title":"J. Pediatr."},{"key":"ref_6","first-page":"CD007836","article-title":"Animal derived surfactant extract for treatment of respiratory distress syndrome","volume":"2","author":"Seger","year":"2009","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_7","first-page":"CD004454","article-title":"Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth","volume":"12","author":"McGoldrick","year":"2020","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"510","DOI":"10.3389\/fped.2019.00510","article-title":"Health care burden of Bronchopulmonary Dysplasia among extremely preterm infants","volume":"7","author":"Mowitz","year":"2019","journal-title":"Front. Pediatr."},{"key":"ref_9","unstructured":"Choi, Y., Rekers, L., Dong, Y., Holzfurtner, L., Goetz, M., Shahzad, T., Zimmer, K.-P., Behnke, Ju., Behnke, Jo., and Bellusci, S. Oxygen toxicity to the immature lung\u2014Part I: Pathomechanistic understanding and preclinical perspectives. Int. J. Mol. Sci., under revision."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s40659-020-00318-y","article-title":"Short-term perinatal oxygen exposure may impair lung development in adult mice","volume":"53","author":"Kumar","year":"2020","journal-title":"Biol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1183\/09031936.00032809","article-title":"Oxidative stress in resuscitation and in ventilation of newborns","volume":"34","author":"Gitto","year":"2009","journal-title":"Eur. Respir. J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1002\/ppul.21199","article-title":"Effect of cumulative oxygen exposure on respiratory symptoms during infancy among VLBW infants without bronchopulmonary dysplasia","volume":"45","author":"Stevens","year":"2010","journal-title":"Pediatr. Pulmonol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e20161452","DOI":"10.1542\/peds.2016-1452","article-title":"Targeted oxygen in the resuscitation of preterm infants, a randomized clinical trial","volume":"139","author":"Oei","year":"2017","journal-title":"Pediatrics"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.jpeds.2018.05.053","article-title":"Preterm infant outcomes after randomization to initial resuscitation with FiO2 0.21 or 1.0","volume":"201","author":"Thamrin","year":"2018","journal-title":"J. Pediatr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"274","DOI":"10.3389\/fped.2019.00274","article-title":"Oxygen saturation targeting during delivery room stabilization: What does this mean for regional cerebral oxygenation?","volume":"7","author":"Pichler","year":"2019","journal-title":"Front. Pediatr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e439","DOI":"10.1542\/peds.2009-0434","article-title":"2.; Arduini, A.; Escobar, J.J.; Sastre, J.; et al. Preterm resuscitation with low oxygen causes less oxidative stress, inflammation, and chronic lung disease","volume":"124","author":"Vento","year":"2009","journal-title":"Pediatrics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e1488","DOI":"10.1542\/peds.2013-0978","article-title":"Resuscitation of preterm neonates with limited versus high oxygen strategy","volume":"132","author":"Kapadia","year":"2013","journal-title":"Pediatrics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1016\/j.jpeds.2014.02.019","article-title":"Resuscitation of preterm infants with different inspired oxygen fractions","volume":"164","author":"Rook","year":"2014","journal-title":"J. Pediatr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"F446","DOI":"10.1136\/archdischild-2016-312366","article-title":"Outcomes of oxygen saturation targeting during delivery room stabilisation of preterm infants","volume":"103","author":"Oei","year":"2018","journal-title":"Arch. Dis. Child. Fetal Neonat. Ed."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/s41390-019-0643-x","article-title":"Inhaled nitric oxide as an adjunct to neonatal resuscitation in premature infants: A pilot, double blind, randomized controlled trial","volume":"87","author":"Sekar","year":"2020","journal-title":"Pediatr. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1159\/000356561","article-title":"Optimal oxygenation of extremely low birth weight infants: A meta-analysis and systematic review of the oxygen saturation target studies","volume":"105","author":"Saugstad","year":"2014","journal-title":"Neonatology"},{"key":"ref_22","first-page":"CD011190","article-title":"Effects of targeting lower versus higher arterial oxygen saturations on death or disability in preterm infants","volume":"4","author":"Askie","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Multicenter Study Group (2000). Supplemental therapeutic oxygen for prethreshold retinopathy of prematurity (STOP-ROP), a randomized, controlled trial. I: Primary outcomes. Pediatrics, 105, 295\u2013310.","DOI":"10.1542\/peds.105.2.295"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1159\/000499361","article-title":"European consensus guidelines on the management of respiratory distress syndrome\u20142019 Update","volume":"115","author":"Sweet","year":"2019","journal-title":"Neonatology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e20161576","DOI":"10.1542\/peds.2016-1576","article-title":"Oxygen targeting in extremely low birth weight infants","volume":"138","author":"Cummings","year":"2016","journal-title":"Pediatrics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1542\/peds.2011-2121","article-title":"Enrollment of extremely low birth weight infants in a clinical research study may not be representative","volume":"129","author":"Rich","year":"2012","journal-title":"Pediatrics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1001\/jama.2019.1660","article-title":"Effect of sustained inflations vs intermittent positive pressure ventilation on bronchopulmonary dysplasia or death among extremely preterm infants: The SAIL randomized clinical trial","volume":"321","author":"Kirpalani","year":"2019","journal-title":"JAMA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1186\/s13063-020-04660-0","article-title":"Application of two different nasal CPAP levels for the treatment of respiratory distress syndrome in preterm infants\u2014\u201cThe OPTTIMMAL-Trial\u201d\u2014Optimizing PEEP to the IMMAture lungs: Study protocol of a randomized controlled trial","volume":"21","author":"Waitz","year":"2020","journal-title":"Trials"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"L976","DOI":"10.1152\/ajplung.00465.2019","article-title":"Intermittent CPAP limits hyperoxia-induced lung damage in a rabbit model of bronchopulmonary dysplasia","volume":"318","author":"Gie","year":"2020","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1159\/000438818","article-title":"The effect of continuous positive airway pressure in a mouse model of hyperoxic neonatal lung injury","volume":"109","author":"Reyburn","year":"2016","journal-title":"Neonatology"},{"key":"ref_31","first-page":"177","article-title":"Non-invasive ventilation in neonatology","volume":"116","author":"Behnke","year":"2019","journal-title":"Dtsch. Arztebl. Int."},{"key":"ref_32","first-page":"185","article-title":"Standardisation of oxygen exposure in the development of mouse models for bronchopulmonary dysplasia","volume":"10","author":"Nardiello","year":"2017","journal-title":"Dis. Model. Mech."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1016\/j.ajpath.2013.12.021","article-title":"Lung development alterations in newborn mice after recovery from exposure to sublethal hyperoxia","volume":"184","author":"Park","year":"2014","journal-title":"Am. J. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.resp.2019.05.006","article-title":"Intermittent hypoxemia and oxidative stress in preterm infants","volume":"266","author":"Vento","year":"2019","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1001\/jama.2015.8841","article-title":"Association between intermittent hypoxemia or bradycardia and late death or disability in extremely preterm infants","volume":"314","author":"Poets","year":"2015","journal-title":"JAMA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1038\/pr.2012.132","article-title":"The relationship between patterns of intermittent hypoxia and retinopathy of prematurity in preterm infants","volume":"72","author":"Kaffashi","year":"2012","journal-title":"Pediatr. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"L208","DOI":"10.1152\/ajplung.00463.2016","article-title":"Intermittent hypoxia during recovery from neonatal hyperoxic lung injury causes long-term impairment of alveolar development: A new rat model of BPD","volume":"312","author":"Mankouski","year":"2017","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/pr.2016.240","article-title":"Long-term effects of recurrent intermittent hypoxia and hyperoxia on respiratory system mechanics in neonatal mice","volume":"81","author":"Dylag","year":"2017","journal-title":"Pediatr. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"17545","DOI":"10.1002\/jcb.29019","article-title":"Effect of intermittent hypoxia or hyperoxia on lung development in preterm rat neonates during constant oxygen therapy","volume":"120","author":"Wang","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/s41390-018-0253-z","article-title":"Neonatal intermittent hypoxemia events are associated with diagnosis of bronchopulmonary dysplasia at 36 weeks postmenstrual age","volume":"85","author":"Raffay","year":"2019","journal-title":"Pediatr. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1038\/s41390-018-0223-5","article-title":"Oxygen desaturations in the early neonatal period predict development of bronchopulmonary dysplasia","volume":"85","author":"Fairchild","year":"2019","journal-title":"Pediatr. Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Jensen, E.A., Whyte, R.K., Schmidt, B., Bassler, D., Vain, N.E., and Roberts, R.S. (2021). Association between intermittent hypoxemia and severe bronchopulmonary dysplasia in preterm infants. Am. J. Respir. Crit. Care Med.","DOI":"10.1164\/rccm.202105-1150OC"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.freeradbiomed.2019.03.035","article-title":"Oxygen radical disease in the newborn, revisited: Oxidative stress and disease in the newborn period","volume":"142","author":"Perez","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"9652897","DOI":"10.1155\/2018\/9652897","article-title":"The potentials and caveats of mesenchymal stromal cell-based therapies in the preterm infant","volume":"2018","author":"Gronbach","year":"2018","journal-title":"Stem Cells Int."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.15252\/emmm.201607308","article-title":"Attenuated PDGF signaling drives alveolar and microvascular defects in neonatal chronic lung disease","volume":"9","author":"Oak","year":"2017","journal-title":"EMBO Mol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1161\/CIRCULATIONAHA.105.541524","article-title":"Vascular endothelial growth factor gene therapy increases survival, promotes lung angiogenesis, and prevents alveolar damage in hyperoxia-induced lung injury: Evidence that angiogenesis participates in alveolarization","volume":"112","author":"Ladha","year":"2005","journal-title":"Circulation"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"101078","DOI":"10.1016\/j.siny.2020.101078","article-title":"Oxygen metabolism and oxygenation of the newborn","volume":"25","author":"Andresen","year":"2020","journal-title":"Semin. Fetal Neonatal Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1111\/apa.13233","article-title":"The development of lung biochemical monitoring can play a key role in the early prediction of bronchopulmonary dysplasia","volume":"105","author":"Fabiano","year":"2016","journal-title":"Acta Paediatr."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.freeradbiomed.2013.03.003","article-title":"Developmental differences in hyperoxia-induced oxidative stress and cellular responses in the murine lung","volume":"61","author":"Berkelhamer","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1164\/rccm.201702-0353OC","article-title":"Vascular endothelial mitochondrial function predicts death or pulmonary outcomes in preterm infants","volume":"196","author":"Kandasamy","year":"2017","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1164\/rccm.201002-0181OC","article-title":"Epithelial cell death is an important contributor to oxidant-mediated acute lung injury","volume":"183","author":"Budinger","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s40348-016-0051-9","article-title":"Pathogenesis of bronchopulmonary dysplasia: When inflammation meets organ development","volume":"3","author":"Shahzad","year":"2016","journal-title":"Mol. Cell. Pediatr."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1165\/rcmb.2014-0160OC","article-title":"Alterations in gene expression and DNA methylation during murine and human lung alveolar septation","volume":"53","author":"Cuna","year":"2015","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.jpeds.2018.07.009","article-title":"The oxygen load supplied during delivery room stabilization of preterm infants modifies the DNA methylation profile","volume":"202","author":"Cernada","year":"2018","journal-title":"J. Pediatr."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/s41390-018-0176-8","article-title":"Oxygen therapy of the newborn from molecular understanding to clinical practice","volume":"85","author":"Saugstad","year":"2019","journal-title":"Pediatr. Res."},{"key":"ref_56","first-page":"CD000501","article-title":"Vitamin A supplementation to prevent mortality and short- and long-term morbidity in very low birth weight infants","volume":"2016","author":"Darlow","year":"2016","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1542\/peds.104.6.1369","article-title":"Vitamin A supplementation in very low birth weight neonates: Rationale and evidence","volume":"104","author":"Shenai","year":"1999","journal-title":"Pediatrics"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1007\/s00431-019-03412-w","article-title":"Oral vitamin A supplementation in very low birth weight neonates: A randomized controlled trial","volume":"178","author":"Basu","year":"2019","journal-title":"Eur. J. Pediatr."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1159\/000357212","article-title":"Early postnatal additional high-dose oral vitamin A supplementation versus placebo for 28 days for preventing bronchopulmonary dysplasia or death in extremely low birth weight infants","volume":"105","author":"Meyer","year":"2014","journal-title":"Neonatology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e2020009985","DOI":"10.1542\/peds.2020-009985","article-title":"Enteral vitamin A for reducing severity of bronchopulmonary dysplasia: A randomized trial","volume":"147","author":"Rakshasbhuvankar","year":"2021","journal-title":"Pediatrics"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1055\/s-2003-38315","article-title":"Role of antioxidant nutrients and lipid peroxidation in premature infants with respiratory distress syndrome and bronchopulmonary dysplasia","volume":"20","author":"Falciglia","year":"2003","journal-title":"Am. J. Perinatol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1183\/09031936.93.04020188","article-title":"Failure of supplementation with vitamin E to prevent bronchopulmonary dysplasia in infants less than 1500 g birth weight","volume":"4","author":"Watts","year":"1991","journal-title":"Eur. Respir. J."},{"key":"ref_63","first-page":"CD003665","article-title":"Vitamin E supplementation for prevention of morbidity and mortality in preterm infants","volume":"4","author":"Brion","year":"2003","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1002\/ppul.1950200306","article-title":"Glutathione metabolism in newborns: Evidence for glutathione deficiency in plasma, bronchoalveolar lavage fluid, and lymphocytes in prematures","volume":"20","author":"Jain","year":"1995","journal-title":"Pediatr. Pulmonol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1067\/S0022-3476(03)00419-0","article-title":"N-acetylcysteine does not prevent bronchopulmonary dysplasia in immature infants: A randomized controlled trial","volume":"143","author":"Ahola","year":"2003","journal-title":"J. Pediatr."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1159\/000080089","article-title":"N-acetylcysteine administration during the first week of life does not improve lung function in extremely low birth weight infants","volume":"86","author":"Sandberg","year":"2004","journal-title":"Biol. Neonat."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1056\/NEJMoa1611942","article-title":"Docosahexaenoic acid and bronchopulmonary dysplasia in preterm infants","volume":"376","author":"Collins","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1183\/09031936.00012412","article-title":"Prevention of hyperoxia-mediated pulmonary inflammation in neonatal rats by caffeine","volume":"41","author":"Weichelt","year":"2013","journal-title":"Eur. Respir. J."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1111\/apa.14586","article-title":"High-versus low-dose caffeine in preterm infants: A systematic review and meta-analysis","volume":"108","author":"Russo","year":"2019","journal-title":"Acta Paediatr."},{"key":"ref_70","first-page":"CD000509","article-title":"Inhaled nitric oxide for respiratory failure in preterm infants","volume":"1","author":"Barrington","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1542\/peds.111.3.469","article-title":"Pulmonary outcome at 1 year corrected age in premature infants treated at birth with recombinant human CuZn superoxide dismutase","volume":"111","author":"Davis","year":"2003","journal-title":"Pediatrics"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.jpeds.2014.02.054","article-title":"Respiratory outcomes of the surfactant positive pressure and oximetry randomized trial (SUPPORT)","volume":"165","author":"Stevens","year":"2014","journal-title":"J. Pediatr."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1056\/NEJMoa1309220","article-title":"Late outcomes of a randomized trial of high-frequency oscillation in neonates","volume":"370","author":"Zivanovic","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1159\/000336639","article-title":"Reduction of retinopathy of prematurity in extremely low gestational age newborns treated with recombinant human Cu\/Zn superoxide dismutase","volume":"102","author":"Parad","year":"2012","journal-title":"Neonatology"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/0304-4165(90)90105-6","article-title":"Characterization of antioxidant activities of pulmonary surfactant mixtures","volume":"1035","author":"Matalon","year":"1990","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1002\/ppul.21116","article-title":"Superoxide dismutase and catalase activity in naturally derived commercial surfactants","volume":"44","author":"Dani","year":"2009","journal-title":"Pediatr. Pulmonol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1159\/000014035","article-title":"Surface tension, glutathione content and redox ratio of the tracheal aspirate fluid of premature infants with IRDS","volume":"74","author":"Boda","year":"1998","journal-title":"Biol. Neonat."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/jp.2010.210","article-title":"Pilot trial of late booster doses of surfactant for ventilated premature infants","volume":"31","author":"Merrill","year":"2011","journal-title":"J. Perinatol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.jpeds.2015.09.031","article-title":"Randomized trial of late surfactant treatment in ventilated preterm infants receiving inhaled nitric oxide","volume":"168","author":"Ballard","year":"2016","journal-title":"J. Pediatr."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/S0022-3476(00)90010-6","article-title":"The effect of selenium supplementation on outcome in very low birth weight infants: A randomized controlled trial. The New Zealand Neonatal Study Group","volume":"136","author":"Darlow","year":"2000","journal-title":"J. Pediatr."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2945","DOI":"10.1089\/ars.2009.2671","article-title":"Antenatal steroids and antioxidant enzyme activity in preterm infants: Influence of gender and timing","volume":"11","author":"Vento","year":"2009","journal-title":"Antioxid. Redox Signal."},{"key":"ref_82","first-page":"CD001146","article-title":"Early (<8 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants","volume":"10","author":"Doyle","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_83","first-page":"CD001145","article-title":"Late (7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants","volume":"10","author":"Doyle","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1159\/000244241","article-title":"Influence of postnatally administered glucocorticoids on rat lung growth","volume":"68","author":"Tschanz","year":"1995","journal-title":"Biol. Neonat."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1056\/NEJMoa1501917","article-title":"Early inhaled budesonide for the prevention of bronchopulmonary dysplasia","volume":"373","author":"Bassler","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1056\/NEJMoa1708831","article-title":"Long-term effects of inhaled budesonide for bronchopulmonary dysplasia","volume":"378","author":"Bassler","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1164\/rccm.201505-0861OC","article-title":"Intratracheal administration of budesonide\/surfactant to prevent bronchopulmonary dysplasia","volume":"193","author":"Yeh","year":"2016","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Park, H.W., Lim, G., Park, Y.-M., Chang, M., Son, J.S., and Lee, R. (2020). Association between vitamin D level and bronchopulmonary dysplasia: A systematic review and meta-analysis. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0235332"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"335","DOI":"10.3389\/fped.2020.00335","article-title":"Low-dose vitamin D protects hyperoxia-induced bronchopulmonary dysplasia by inhibiting neutrophil extracellular traps","volume":"8","author":"Chen","year":"2020","journal-title":"Front. Pediatr."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1002\/ppul.23500","article-title":"Protective effect of vitamin D against hyperoxia-induced lung injury in newborn rats","volume":"52","author":"Kose","year":"2017","journal-title":"Pediatr. Pulmonol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.jpeds.2016.03.028","article-title":"A comparison of 3 vitamin D dosing regimens in extremely preterm infants: A randomized controlled trial","volume":"174","author":"Fort","year":"2016","journal-title":"J. Pediatr."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1111\/apa.15338","article-title":"Preeclampsia was a risk factor for pulmonary interstitial emphysema in preterm infants born \u226432 weeks of gestational age","volume":"110","author":"Behnke","year":"2021","journal-title":"Acta Paediatr."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1111\/apa.15388","article-title":"Reply to risk factors for pulmonary interstitial emphysema in the preterm infant: Still more challenges than answers","volume":"110","author":"Behnke","year":"2021","journal-title":"Acta Paediatr."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"176","DOI":"10.3389\/fped.2019.00176","article-title":"Bronchopulmonary Dysplasia: Crosstalk between PPAR\u03b3, WNT\/\u03b2-catenin and TGF-\u03b2 pathways: The potential therapeutic role of PPAR\u03b3 agonists","volume":"7","author":"Lecarpentier","year":"2019","journal-title":"Front. Pediatr."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Goetz, M.J., Kremer, S., Behnke, J., Staude, B., Shahzad, T., Holzfurtner, L., Chao, C.-M., Morty, R.E., Bellusci, S., and Ehrhardt, H. (2021). MSC based therapies to prevent or treat BPD-A narrative review on advances and ongoing challenges. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031138"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"L909","DOI":"10.1152\/ajplung.00367.2015","article-title":"Absence of TNF-\u03b1 enhances inflammatory response in the newborn lung undergoing mechanical ventilation","volume":"310","author":"Ehrhardt","year":"2016","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1165\/rcmb.2014-0037OC","article-title":"Hypoxia-inducible factor-1 stimulates postnatal lung development but does not prevent O2-induced alveolar injury","volume":"52","author":"Tibboel","year":"2015","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1164\/rccm.201706-1218LE","article-title":"Early identification of bronchopulmonary dysplasia using novel biomarkers by proteomic screening","volume":"197","author":"Sass","year":"2018","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"L644","DOI":"10.1152\/ajplung.00131.2019","article-title":"Early angiogenic proteins associated with high risk for bronchopulmonary dysplasia and pulmonary hypertension in preterm infants","volume":"318","author":"Arjaans","year":"2020","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1159\/000487388","article-title":"Update on vitamin E and its potential role in preventing or treating bronchopulmonary dysplasia","volume":"113","author":"Stone","year":"2018","journal-title":"Neonatology"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/apa.12883","article-title":"Less invasive surfactant administration is associated with improved pulmonary outcomes in spontaneously breathing preterm infants","volume":"104","author":"Kribs","year":"2015","journal-title":"Acta Paediatr."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1016\/S0140-6736(11)60986-0","article-title":"Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): An open-label, randomised, controlled trial","volume":"378","author":"Kribs","year":"2011","journal-title":"Lancet"},{"key":"ref_103","first-page":"CD003212","article-title":"Nasal Intermittent Positive Pressure Ventilation (NIPPV) versus Nasal Continuous Positive Airway Pressure (NCPAP) for preterm neonates after extubation","volume":"2","author":"Lemyre","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"204","DOI":"10.12680\/balneo.2019.258","article-title":"Complementary therapeutic approaches in asthma","volume":"10","author":"Maierean","year":"2019","journal-title":"Balneo"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Behnke, J., Kremer, S., Shahzad, T., Chao, C.-M., B\u00f6ttcher-Friebertsh\u00e4user, E., Morty, R.E., Bellusci, S., and Ehrhardt, H. (2020). MSC based therapies-new perspectives for the injured lung. J. Clin. Med., 9.","DOI":"10.3390\/jcm9030682"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10694\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:08:45Z","timestamp":1760166525000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10694"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,2]]},"references-count":105,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ijms221910694"],"URL":"https:\/\/doi.org\/10.3390\/ijms221910694","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,2]]}}}