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 H2O2 levels. However, hyperoxia did not further augment H2O2 levels 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 HPMEC in vitro.
Highlights
Supplemental oxygen is commonly administered as a life-saving measure in patients with impaired lung function, it may exacerbate lung injury [1]
We investigated the impact of OM on acute hyperoxic injury in the human fetal lung derived human pulmonary microvascular endothelial cells (HPMEC) in vitro
We determined the effects of OM on NADP(H) quinone oxidoreductase 1 (NQO1) expression since our earlier study indicated that this enzyme was down-regulated in aryl hydrocarbon receptor (AhR)-deficient HPMEC [24]
Summary
Supplemental oxygen is commonly administered as a life-saving measure in patients with impaired lung function, it may exacerbate lung injury [1]. Excessive oxygen exposure leads to increased reactive oxygen species (ROS) production and expression of pro-inflammatory cytokines [2], which can react with nearby macromolecules (e.g., protein, lipids, DNA, and RNA) and modify their structure and function [3], resulting in both acute and chronic pulmonary toxicities. Despite significant advances in the management of premature neonates, broncho-pulmonary dysplasia (BPD) remains the most prevalent, and one of the most serious long-term sequelae of preterm birth, affecting approximately 14,000 preterm infants born each year in United States [6,7]. Hyperoxia-induced ROS generation is a major contributor to the development of BPD and its sequelae [8]. Infants with BPD are more likely to have long-term pulmonary problems, increased re-hospitalizations during the first year of life, and delayed neurodevelopment [6,9]. There is an urgent need for improved therapies in the prevention and treatment of BPD
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