title: Proton-pump inhibitor omeprazole attenuates hyperoxia induced lung injury.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: Department of Development and Regeneration, Faculty of Medicine, KU Leuven, Leuven, Belgium. jute.richter@uzleuven.be.|Division Woman and Child, University Hospitals Leuven, Leuven, Belgium. jute.richter@uzleuven.be.|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. jute.richter@uzleuven.be.
authors: Jute
authors: J
authors: Richter
authors: Department of Development and Regeneration, Faculty of Medicine, KU Leuven, Leuven, Belgium.|Departamento Ginecología y Obstetricia, Clínica Alemana, Santiago, Chile.
authors: Julio
authors: J
authors: Jimenez
authors: Department of Development and Regeneration, Faculty of Medicine, KU Leuven, Leuven, Belgium.|Department of Neonatology, Ehime Prefectural Central Hospital, Matsuyama, Japan.
authors: Taro
authors: T
authors: Nagatomo
authors: Department of Development and Regeneration, Faculty of Medicine, KU Leuven, Leuven, Belgium.|Division Woman and Child, University Hospitals Leuven, Leuven, Belgium.
authors: Jaan
authors: J
authors: Toelen
authors: Centre for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
authors: Paul
authors: P
authors: Brady
authors: Department of Development and Regeneration, Faculty of Medicine, KU Leuven, Leuven, Belgium.|Division Woman and Child, University Hospitals Leuven, Leuven, Belgium.
authors: Thomas
authors: T
authors: Salaets
authors: Department of Development and Regeneration, Faculty of Medicine, KU Leuven, Leuven, Belgium.
authors: Flore
authors: F
authors: Lesage
authors: Laboratory of Occupational and Environmental Toxicology, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium.
authors: Jeroen
authors: J
authors: Vanoirbeek
authors: Department of Development and Regeneration, Faculty of Medicine, KU Leuven, Leuven, Belgium.|Division Woman and Child, University Hospitals Leuven, Leuven, Belgium.
authors: Jan
authors: J
authors: Deprest
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D018496:Hyperoxia / Q000150:complications*; D007150:Immunohistochemistry; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D055370:Lung Injury / Q000188:drug therapy* / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D009853:Omeprazole / Q000494:pharmacology / Q000627:therapeutic use*; D054328:Proton Pump Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D012129:Respiratory Function Tests; D016019:Survival Analysis; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D054328:Proton Pump Inhibitors; D019363:Cytochrome P-450 CYP1A1; D009853:Omeprazole
keywords: Bronchopulmonary dysplasia; CYP1A1; Omeprazole; Preterm; Rabbit