Omeprazole Attenuates Pulmonary Aryl Hydrocarbon Receptor Activation and Potentiates Hyperoxia-Induced Developmental Lung Injury in Newborn Mice.
Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in human preterm infants and a similar lung phenotype characterized by alveolar simplification in newborn mice. Omeprazole (OM) is a proton pump inhibitor that is used to treat humans with gastric acid related disorders. OM-mediated aryl hydrocarbon receptor (AhR) activation attenuates acute hyperoxic lung injury (HLI) in adult mice. Whether OM activates pulmonary AhR and protects C57BL/6J newborn mice against hyperoxia-induced developmental lung (alveolar and pulmonary vascular simplification, inflammation, and oxidative stress) injury (HDLI) is unknown. Therefore, we tested the hypothesis that OM will activate pulmonary AhR and mitigate HDLI in newborn mice. Newborn mice were treated daily with i.p. injections of OM at doses of 10 (OM10) or 25 (OM25) mg/kg while being exposed to air or hyperoxia (FiO2 of 85%) for 14 days, following which their lungs were harvested to determine alveolarization, pulmonary vascularization, inflammation, oxidative stress, vascular injury, and AhR activation. To our surprise, hyperoxia-induced alveolar and pulmonary vascular simplification, inflammation, oxidative stress, and vascular injury were augmented in OM25-treated animals. These findings were associated with attenuated pulmonary vascular endothelial growth factor receptor 2 expression and decreased pulmonary AhR activation in the OM25 group. We conclude that contrary to our hypothesis, OM decreases functional activation of pulmonary AhR and potentiates HDLI in newborn mice. These observations are consistent with our previous findings, which suggest that AhR activation plays a protective role in HDLI in newborn mice.
Section of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030 shivanna@bcm.edu.
Binoy
B
Shivanna
Section of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030.
Shaojie
S
Zhang
Section of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030.
Ananddeep
A
Patel
Section of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030.
Weiwu
W
Jiang
Section of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030.
Lihua
L
Wang
Section of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030.
Stephen E
SE
Welty
Section of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030.
Bhagavatula
B
Moorthy
D000818:Animals; D000831:Animals, Newborn; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000009:adverse effects; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001997:Bronchopulmonary Dysplasia / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D007231:Infant, Newborn; D007274:Injections, Intraperitoneal; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D009853:Omeprazole / Q000008:administration & dosage / Q000009:adverse effects*; D018384:Oxidative Stress / Q000187:drug effects; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D011650:Pulmonary Alveoli / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D000897:Anti-Ulcer Agents; D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D009853:Omeprazole; D054328:Proton Pump Inhibitors; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse
aryl hydrocarbon receptor; hyperoxia; inflammation; lung development; omeprazole; oxidative stress