Proton-pump inhibitor omeprazole attenuates hyperoxia induced lung injury.

Jute Richter,Jaan Toelen,Julio Jimenez,Jeroen Vanoirbeek,Paul Brady,Jan Deprest,Thomas Salaets,Taro Nagatomo,Flore Lesage

doi:10.1186/s12967-016-1009-3

Abstract

BackgroundThe 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.MethodsOmeprazole 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.ResultsDaily 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.ConclusionsNeonatal 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1009-3) contains supplementary material, which is available to authorized users.

Highlights

The administration of supplemental oxygen to treat ventilatory insufficiency may lead to the formation of reactive oxygen species and subsequent tissue damage
Increase in expression of Cytochrome P4501A1 (CYP1A1) after a single maternal dose of omeprazole (2 mg/kg IV) administered 8 h prior to delivery did not reach statistical significance compared to controls (p = 0.872)
Neonatal injections in hyperoxia exposed pups showed a dose-dependent rise in expression of CYP1A1 (Fig. 1) both at postnatal day 3 and 5

Summary

Introduction

The administration of supplemental oxygen to treat ventilatory insufficiency may lead to the formation of reactive oxygen species and subsequent tissue damage. 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. The use of excessive oxygen may lead to an increased production of reactive oxygen species (ROS) such as superoxide anion, hydroxyl radical and hydrogen peroxide [4,5,6] as well as the expression of pro-inflammatory cytokines [7]. Hyperoxia-induced production of ROS is recognized as a major contributor to the development of BPD [9] because the tissue damage and inflammation leads to a developmental arrest of the lung

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