Hyperoxia contributes to lung injury in experimental animals and bronchopulmonary dysplasia (BPD) in preterm infants. Cytochrome P450 (CYP) 1A 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 C57BL/6J (WT) 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 contrary, 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 pulmonary and hepatic CYP1A enzymes. These studies have important implications for the prevention and/or treatment of hyperoxia-induced disorders like BPD in infants and acute respiratory distress syndrome (ARDS) in older children and adults.
- Received April 14, 2011.
- Revision received July 14, 2011.
- Accepted July 15, 2011.
- The American Society for Pharmacology and Experimental Therapeutics