title: Aryl hydrocarbon receptor is necessary to protect fetal human pulmonary microvascular endothelial cells against hyperoxic injury: Mechanistic roles of antioxidant enzymes and RelB.
abstract: Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. Activation of the aryl hydrocarbon receptor (AhR) protects adult and newborn mice against hyperoxic lung injury by mediating increases in the expression of phase I (cytochrome P450 (CYP) 1A) and phase II (NADP(H) quinone oxidoreductase (NQO1)) antioxidant enzymes (AOE). AhR positively regulates the expression of RelB, a component of the nuclear factor-kappaB (NF-κB) protein that contributes to anti-inflammatory processes in adult animals. Whether AhR regulates the expression of AOE and RelB, and protects fetal primary human lung cells against hyperoxic injury is unknown. Therefore, we tested the hypothesis that AhR-deficient fetal human pulmonary microvascular endothelial cells (HPMEC) will have decreased RelB activation and AOE, which will in turn predispose them to increased oxidative stress, inflammation, and cell death compared to AhR-sufficient HPMEC upon exposure to hyperoxia. AhR-deficient HPMEC showed increased hyperoxia-induced reactive oxygen species (ROS) generation, cleavage of poly(ADP-ribose) polymerase (PARP), and cell death compared to AhR-sufficient HPMEC. Additionally, AhR-deficient cell culture supernatants displayed increased macrophage inflammatory protein 1α and 1β, indicating a heightened inflammatory state. Interestingly, loss of AhR was associated with a significantly attenuated CYP1A1, NQO1, superoxide dismutase 1(SOD1), and nuclear RelB protein expression. These findings support the hypothesis that decreased RelB activation and AOE in AhR-deficient cells is associated with increased hyperoxic injury compared to AhR-sufficient cells.
authors.affiliation: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Shaojie
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ananddeep
authors.initials: A
authors.lastname: Patel
authors.affiliation: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Chu
authors.affiliation: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Weiwu
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Welty
authors.affiliation: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Bhagavatula
authors.initials: B
authors.lastname: Moorthy
authors.affiliation: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: shivanna@bcm.edu.
authors.forename: Binoy
authors.initials: B
authors.lastname: Shivanna
mesh_terms: D000328:Adult; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000187:drug effects* / Q000235:genetics; D002196:Capillaries / Q000187:drug effects / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology*; D005260:Female; D006801:Humans; D018496:Hyperoxia / Q000473:pathology*; D007249:Inflammation / Q000473:pathology; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects; D011247:Pregnancy; D011652:Pulmonary Circulation / Q000187:drug effects*; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000235:genetics; D051841:Transcription Factor RelB / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D051792:Basic Helix-Loop-Helix Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; D051841:Transcription Factor RelB; C111235:AHR protein, human; C497593:RELB protein, human
keywords: Antioxidant enzymes; Aryl hydrocarbon Receptor; Fetal human pulmonary microvascular endothelial cells; Hyperoxic injury; Oxidant stress; RelB
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