title: Omeprazole attenuates hyperoxic injury in H441 cells via the aryl hydrocarbon receptor.
abstract: Hyperoxia contributes to the development of bronchopulmonary dysplasia in premature infants. Earlier we observed that aryl hydrocarbon receptor (AhR)-deficient mice are more susceptible to hyperoxic lung injury than AhR-sufficient mice, and this phenomenon was associated with a lack of expression of cytochrome P450 1A enzymes. Omeprazole, a proton pump inhibitor used in humans with gastric acid-related disorders, activates AhR in hepatocytes in vitro. However, the effects of omeprazole on AhR activation in the lungs and its impact on hyperoxia-induced reactive oxygen species (ROS) generation and inflammation are unknown. In this study, we tested the hypothesis that omeprazole attenuates hyperoxia-induced cytotoxicity, ROS generation, and expression of monocyte chemoattractant protein-1 (MCP-1) in human lung-derived H441 cells via AhR activation. Experimental groups included cells transfected with AhR small interfering RNA (siRNA). Hyperoxia resulted in significant increases in cytotoxicity, ROS generation, and MCP-1 production, which were significantly attenuated with the functional activation of AhR by omeprazole. The protective effects of omeprazole on cytotoxicity, ROS production, and MCP-1 production were lost in H441 cells whose AhR gene was silenced by AhR siRNA. These findings support the hypothesis that omeprazole protects against hyperoxic injury in vitro via AhR activation that is associated with decreased ROS generation and expression of MCP-1.
authors: Division of Neonatal–Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. shivanna@bcm.edu
authors: Binoy
authors: B
authors: Shivanna
authors: Chun
authors: C
authors: Chu
authors: Stephen E
authors: SE
authors: Welty
authors: Weiwu
authors: W
authors: Jiang
authors: Lihua
authors: L
authors: Wang
authors: Xanthi I
authors: XI
authors: Couroucli
authors: Bhagavatula
authors: B
authors: Moorthy
mesh_terms: D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000009:adverse effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D018496:Hyperoxia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000473:pathology; D055370:Lung Injury / Q000517:prevention & control; D009853:Omeprazole / Q000008:administration & dosage* / Q000009:adverse effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000276:immunology / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; D009853:Omeprazole