title: Hyperoxia and interferon-γ-induced injury in developing lungs occur via cyclooxygenase-2 and the endoplasmic reticulum stress-dependent pathway.
abstract: We noted a marked increase in cyclooxygenase-2 (Cox2) and the activation of the endoplasmic reticulum (ER) stress pathway in newborn murine lung on exposure to hyperoxia and IFN-γ. We sought to evaluate Cox2-mediated ER stress pathway activation in hyperoxia-induced and IFN-γ-mediated injury in developing lungs. We applied in vivo genetic gain-of-function and genetic/chemical inhibition, as well as in vitro loss-of-function genetic strategies. Hyperoxia-induced and IFN-γ-mediated impaired alveolarization was rescued by Cox2 inhibition, using celecoxib. The use of small interfering RNA against the ER stress pathway mediator, the C/EBP homologous protein (CHOP; also known as growth arrest and DNA damage-inducible gene 153/GADD153), alleviated cell death in alveolar epithelial cells as well as in hyperoxia-induced and IFN-γ-mediated murine models of bronchopulmonary dysplasia (BPD). In addition, CHOP siRNA also restored alveolarization in the in vivo models. Furthermore, as evidence of clinical relevance, we show increased concentrations of Cox2 and ER stress pathway mediators in human lungs with BPD. Cox2, via CHOP, may significantly contribute to the final common pathway of hyperoxia-induced and IFN-γ-mediated injury in developing lungs and human BPD.
authors.affiliation: Division of Perinatal Medicine, Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Rayman
authors.initials: R
authors.lastname: Choo-Wing
authors.forename: Mansoor A
authors.initials: MA
authors.lastname: Syed
authors.forename: Anantha
authors.initials: A
authors.lastname: Harijith
authors.forename: Brianne
authors.initials: B
authors.lastname: Bowen
authors.forename: Gloria
authors.initials: G
authors.lastname: Pryhuber
authors.forename: Cecilia
authors.initials: C
authors.lastname: Janér
authors.forename: Sture
authors.initials: S
authors.lastname: Andersson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Homer
authors.forename: Vineet
authors.initials: V
authors.lastname: Bhandari
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000378:metabolism / Q000473:pathology; D000068579:Celecoxib; D016923:Cell Death; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D018496:Hyperoxia / Q000473:pathology*; D007150:Immunohistochemistry; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011720:Pyrazoles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; C497250:Ddit3 protein, mouse; D011720:Pyrazoles; D034741:RNA, Small Interfering; D013449:Sulfonamides; D051742:Transcription Factor CHOP; D007371:Interferon-gamma; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000068579:Celecoxib