title: Omeprazole attenuates hyperoxic lung injury in mice via aryl hydrocarbon receptor activation and is associated with increased expression of cytochrome P4501A enzymes.
abstract: Hyperoxia contributes to lung injury in experimental animals and bronchopulmonary dysplasia (BPD) in preterm infants. Cytochrome P4501A (CYP1A) enzymes, which are regulated by the aryl hydrocarbon receptor (AhR), have been shown to attenuate hyperoxic lung injury in rodents. Omeprazole, a proton pump inhibitor, used in humans to treat gastric acid-related disorders, induces hepatic CYP1A in vitro. However, the mechanism by which omeprazole induces CYP1A and its impact on CYP1A expression in vivo and hyperoxic lung injury are unknown. Therefore, we tested the hypothesis that omeprazole attenuates hyperoxic lung injury in adult wild-type (WT) C57BL/6J mice by an AhR-mediated induction of pulmonary and hepatic CYP1A enzymes. Accordingly, we determined the effects of omeprazole on pulmonary and hepatic CYP1A expression and hyperoxic lung injury in adult WT and AhR dysfunctional (AhRd) mice. We found that omeprazole attenuated lung injury in WT mice. Attenuation of lung injury by omeprazole paralleled enhanced pulmonary CYP1A1 and hepatic CYP1A2 expression in the omeprazole-treated mice. On the other hand, omeprazole failed to enhance pulmonary CYP1A1 and hepatic CYP1A2 expression and protect against hyperoxic lung injury in AhRd mice. In conclusion, our results suggest that omeprazole attenuates hyperoxic lung injury in mice by AhR-mediated mechanisms, and this phenomenon is associated with induction of CYP1A enzymes. These studies have important implications for the prevention and/or treatment of hyperoxia-induced disorders such as BPD in infants and acute respiratory distress syndrome in older children and adults.
authors.affiliation: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Binoy
authors.initials: B
authors.lastname: Shivanna
authors.forename: Weiwu
authors.initials: W
authors.lastname: Jiang
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.forename: Xanthi I
authors.initials: XI
authors.lastname: Couroucli
authors.forename: Bhagavatula
authors.initials: B
authors.lastname: Moorthy
mesh_terms: D055371:Acute Lung Injury / Q000473:pathology* / Q000517:prevention & control*; D000818:Animals; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018496:Hyperoxia / Q000473:pathology*; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology; D008168:Lung / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D009853:Omeprazole / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism; D011654:Pulmonary Edema / Q000473:pathology; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D018336:Receptors, Aryl Hydrocarbon; D003577:Cytochrome P-450 Enzyme System; D009853:Omeprazole