title: Omeprazole does not Potentiate Acute Oxygen Toxicity in Fetal Human Pulmonary Microvascular Endothelial Cells Exposed to Hyperoxia.
abstract: Hyperoxia contributes to the pathogenesis of broncho-pulmonary dysplasia (BPD), which is a developmental lung disease of premature infants that is characterized by an interruption of lung alveolar and pulmonary vascular development. Omeprazole (OM) is a proton pump inhibitor that is used to treat humans with gastric acid related disorders. Earlier we observed that OM-mediated aryl hydrocarbon receptor (AhR) activation attenuates acute hyperoxic lung injury in adult mice and oxygen toxicity in adult human lung cells. However, our later studies in newborn mice demonstrated that OM potentiates hyperoxia-induced developmental lung injury. Whether OM exerts a similar toxicity in primary human fetal lung cells is unknown. Hence, we tested the hypothesis that OM potentiates hyperoxia-induced cytotoxicity and ROS generation in the human fetal lung derived primary human pulmonary microvascular endothelial cells (HPMEC). OM activated AhR as evident by a dose-dependent increase in cytochrome P450 (CYP) 1A1 mRNA levels in OM-treated cells. Furthermore, OM at a concentration of 100 μM (OM 100) increased NADP(H) quinone oxidoreductase 1 (NQO1) expression. Surprisingly, hyperoxia decreased rather than increase the NQO1 protein levels in OM 100-treated cells. Exposure to hyperoxia increased cytotoxicity and hydrogen peroxide (H2O2) levels. Interestingly, OM 100-treated cells exposed to air had increased H2O2levels. However, hyperoxia did not further augment H2O2levels in OM 100-treated cells. Additionally, hyperoxia-mediated oxygen toxicity was similar in both vehicle- and OM-treated cells. These findings contradict our hypothesis and support the hypothesis that OM does not potentiate acute hyperoxic injury in HPMECin vitro.
authors.affiliation: Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Ananddeep
authors.initials: A
authors.lastname: Patel
authors.affiliation: Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Shaojie
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Bhagavatula
authors.initials: B
authors.lastname: Moorthy
authors.affiliation: Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Binoy
authors.initials: B
authors.lastname: Shivanna
keywords: Aryl hydrocarbon receptor; Cytochrome P450 1A1; Human pulmonary microvascular endothelial cells; Hyperoxia; NADP(H) quinone oxidoreductase 1; Omeprazole; Oxidant stress