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      Proton-pump inhibitor omeprazole attenuates hyperoxia induced lung injury

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          Abstract

          Background

          The administration of supplemental oxygen to treat ventilatory insufficiency may lead to the formation of reactive oxygen species and subsequent tissue damage. Cytochrome P4501A1 (CYP1A1) can modulate hyperoxic lung injury by a currently unknown mechanism. Our objective was to evaluate the effect of administration of omeprazole on the induction of CYP1A1 and its influence on hyperoxic lung injury in an established preterm rabbit model.

          Methods

          Omeprazole was administered either (1) directly to the fetus, (2) to the mother or (3) after birth to the pups in different doses (2–10 or 20 mg/kg). Controls were injected with the same amount of saline. Pups were housed in normoxia (21 %) or hyperoxia (>95 %) for 5 days. Outcome parameters were induction of CYP1A1 measured by real-time polymerase chain reaction (RT-PCR) immediately after delivery, at day 3 and day 5 as well as lung function, morphometry and immunohistochemistry assessed at day 5 of life. Transcriptome analysis was used to define the targeted pathways.

          Results

          Daily neonatal injections demonstrated a dose-dependent increase in CYP1A1. Lung function tests showed a significant improvement in tissue damping, tissue elasticity, total lung capacity, static compliance and elastance. Morphometry revealed a more developed lung architecture with thinned septae in animals treated with the highest dose (20 mg/kg) of omeprazole. Surfactant protein B, vascular endothelial growth factor and its receptor were significantly increased on immunohistochemical stainings after omeprazole treatment.

          Conclusions

          Neonatal administration of omeprazole induces CYP1A1 in a dose-dependent matter and combined pre- and postnatal administration attenuates hyperoxic lung injury in preterm rabbits, even with the lowest dose of omeprazole without clear CYP1A1 induction.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12967-016-1009-3) contains supplementary material, which is available to authorized users.

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          Most cited references 41

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          Cognitive and academic consequences of bronchopulmonary dysplasia and very low birth weight: 8-year-old outcomes.

          To examine the effects of bronchopulmonary dysplasia (BPD) and very low birth weight (VLBW) on the cognitive and academic achievement of a large sample of 8-year-old children. Infants who were VLBW and had BPD (n = 98) or did not have BPD (n = 75) and term infants (n = 99) were followed prospectively to age 8. Groups were compared on measures assessing 4 broad areas of functioning: intelligence, achievement, gross motor, and attentional skills. Measures included the Wechsler Intelligence Scale for Children III, the Woodcock Johnson Test of Achievement-Revised, the Bruininks-Oseretsky Test of Motor Proficiency, the Tactual Performance Test (spatial memory), and the Continuous Performance Test (attention). School outcomes were assessed by parent and teacher report, as well as from school records. Groups were comparable on socioeconomic status, sex, and race. The total sample of BPD, VLBW, and term children was compared on all outcome measures. In addition, neurologic risk was assessed in the present sample and included the following: intraventricular hemorrhage, echodense lesions, porencephaly, hydrocephalus, ventriculoperitoneal shunt, meningitis, and periventricular leukomalacia. Individual difference analyses were conducted for neurologically intact children in all 3 groups. Finally, treatment effects were examined by comparing BPD children who had received steroids as part of their treatment with BPD children who had not. The BPD group demonstrated deficits compared with VLBW and term children in intelligence; reading, mathematics, and gross motor skills; and special education services. VLBW children differed from term children in all of the above areas, except reading recognition, comprehension, and occupational therapy. Attentional differences were obtained between BPD and term children only. The BPD group (54%) was more likely to be enrolled in special education classes than VLBW (37%) or term children (25%). In addition, more BPD children (20%) achieved full-scale IQ scores <70, in the mental retardation range, compared with either VLBW (11%) or term (3%) children, with all VLBW children significantly more likely than term children to achieve IQs in the subaverage category. After controlling for birth weight and neurologic problems, BPD and/or duration on oxygen predicted lower performance IQ, perceptual organization, full-scale IQ, motor and attentional skills, and special education placement. The qualitative classification of BPD (present or absent) was a significant predictor for lower scores on measures of applied problems; motor skills; and incidence of speech-language, occupational, and physical therapies. Individual difference analyses were performed to ascertain whether differences between the risk groups were primarily attributable to neurologic complications. Even with the neurologically intact sample of BPD and VLBW children, differences between the term comparison group and both the BPD and VLBW groups were found for many outcome measures. When birth weight and neurologic complications were controlled, BPD and severity of BPD were associated with lower performance and full-scale IQ, poorer perceptual organization, attention, and motor skills, as well as lower school achievement and greater participation in special education, including occupational, physical, and speech-language therapies. Treatment protocol may in part be responsible for differences observed in our BPD sample. Steroid and nonsteroid groups of BPD children differed significantly in performance IQ (72.8 vs 84.8) and full-scale IQ (77.0 vs 85.2); perceptual organization (74.0 vs 85.2); Bruininks-Oseretsky Test of Motor Proficiency score (36.6 vs 44.7); and participation in special education (78% vs 48%), occupational therapy (71% vs 44%), and physical therapy (71% vs 41%). In every instance, BPD children who received steroids fared more poorly than BPD children who did not receive steroids. BPD and duration on oxygen have long-term adverse effects on cognitive and academic achievement above and be beyond the effects of VLBW. The problems that have been identified at 8 years of age highlight the need for continued monitoring of the learning, behavior, and development of BPD children to intervene with children who are at risk for school problems.
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            Outcomes of extremely low birth weight infants with bronchopulmonary dysplasia: impact of the physiologic definition.

            We compared neurodevelopmental outcomes of extremely low birth weight (ELBW) infants with and without bronchopulmonary dysplasia (BPD), using the physiologic definition. ELBW (birth weights 30% and 66 who failed the room air challenge. Infants on room air (n=505) and those who passed the room air challenge (n=51) were classified as "no BPD" (n=556). At follow up, infants with BPD had significantly lower mean weight and head circumference. Moderate to severe cerebral palsy (7 vs. 2.1%) and spastic diplegia (7.8 vs. 4.1%) and quadriplegia (3.9 vs. 0.9%) phenotypes as well as cognitive (12.8 vs. 4.6%) and language scores<70 (24.2 vs. 12.3%) were significantly more frequent in those with BPD compared to those without BPD. BPD was independently associated (adjusted OR 2.4; 95% CI 1.40-4.13) with cognitive impairment. Rates of adverse neurodevelopmental outcomes in early childhood were significantly higher in those with BPD. BPD by the physiologic definition was independently associated with cognitive impairment using Bayley Scales III. These findings have implications for targeted post-discharge surveillance and early intervention. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Bronchopulmonary dysplasia-oxidative stress and antioxidants.

               Ola Saugstad (2003)
              There is increasing evidence that oxidative stress is implicated in the development of bronchopulmonary dysplasia. Several important factors contribute to augmented oxidative stress in the newborn and especially the preterm infant: first, because of its immaturity, the lung of preterm infants is frequently exposed to oxygen therapy and hyperoxia. Second, the antioxidant defense and its ability to be induced during an hyperoxic challenge are impaired. Third, the preterm infant has an increased susceptibility to infection and inflammation, which increases oxidative stress. Fourth, free iron, which catalyzes the production of toxic reactive oxygen species, can be detected in preterm infants. The molecular and cellular mechanisms for free radical-induced injury are now understood in more detail, and it is clear that oxidative stress plays an important role in triggering apoptosis, in serving as second messenger and in signal transduction. This new insight might lead to novel and efficient therapies. So far, there has been no significant breakthrough regarding antioxidant therapies. Care should, however, be exercised in supplementing the preterm infant with antioxidants since this may affect growth and development.
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                Author and article information

                Contributors
                +32 16 342288 , jute.richter@uzleuven.be
                juliojimenez@gmail.com
                ctnagatomo@gmail.com
                jaan.toelen@uzleuven.be
                paul.brady@med.kuleuven.be
                salaetst@gmail.com
                flore.lesage@med.kuleuven.be
                jeroen.vanoirbeek@med.kuleuven.be
                jan.deprest@uzleuven.be
                Journal
                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central (London )
                1479-5876
                27 August 2016
                27 August 2016
                2016
                : 14
                : 1
                Affiliations
                [1 ]Department of Development and Regeneration, Faculty of Medicine, KU Leuven, Leuven, Belgium
                [2 ]Division Woman and Child, University Hospitals Leuven, Leuven, Belgium
                [3 ]Departamento Ginecología y Obstetricia, Clínica Alemana, Santiago, Chile
                [4 ]Department of Neonatology, Ehime Prefectural Central Hospital, Matsuyama, Japan
                [5 ]Centre for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
                [6 ]Laboratory of Occupational and Environmental Toxicology, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium
                [7 ]Clinical Department of Obstetrics and Gynaecology and Academic Department of Development and Regeneration, Organ System Cluster, University Hospitals of Leuven, Herestraat 49, 3000 Leuven, Belgium
                Article
                1009
                10.1186/s12967-016-1009-3
                5002203
                © The Author(s) 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: Marie Curie Industria-Academia Partnership Program grant
                Award ID: PIAP-GA-2009-251356
                Award Recipient :
                Funded by: Erasmus Mundi Doctoral grant
                Award ID: 2013-0040
                Award Recipient :
                Funded by: Fonds Wetenschappelijk Onderzoek Vlaanderen
                Award ID: 1801207
                Award Recipient :
                Funded by: Klinische Opleidings- en Onderzoeks- Raad
                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                Medicine

                bronchopulmonary dysplasia, omeprazole, cyp1a1, rabbit, preterm

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