title: The NRF2 activation and antioxidative response are not impaired overall during hyperoxia-induced lung epithelial cell death.
abstract: Lung epithelial and endothelial cell death caused by pro-oxidant insults is a cardinal feature of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) patients. The NF-E2-related factor 2 (NRF2) activation in response to oxidant exposure is crucial to the induction of several antioxidative and cytoprotective enzymes that mitigate cellular stress. Since prolonged exposure to hyperoxia causes cell death, we hypothesized that chronic hyperoxia impairs NRF2 activation, resulting in cell death. To test this hypothesis, we exposed nonmalignant small airway epithelial cells (AECs) to acute (1-12 h) and chronic (36-48 h) hyperoxia and evaluated cell death, NRF2 nuclear accumulation and target gene expression, and NRF2 recruitment to the endogenous HMOX1 and NQO1 promoters. As expected, hyperoxia gradually induced death in AECs, noticeably and significantly by 36 h; ~60% of cells were dead by 48 h. However, we unexpectedly found increased expression levels of NRF2-regulated antioxidative genes and nuclear NRF2 in AECs exposed to chronic hyperoxia as compared to acute hyperoxia. Chromatin Immunoprecipitation (ChIP) assays revealed an increased recruitment of NRF2 to the endogenous HMOX1 and NQO1 promoters in AECs exposed to acute or chronic hyperoxia. Thus, our findings demonstrate that NRF2 activation and antioxidant gene expression are functional during hyperoxia-induced lung epithelial cell death and that chronic hyperoxia does not impair NRF2 signaling overall.
authors.affiliation: Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Haranatha R
authors.initials: HR
authors.lastname: Potteti
authors.forename: Narsa M
authors.initials: NM
authors.lastname: Reddy
authors.forename: Tom K
authors.initials: TK
authors.lastname: Hei
authors.forename: Dhananjaya V
authors.initials: DV
authors.lastname: Kalvakolanu
authors.forename: Sekhar P
authors.initials: SP
authors.lastname: Reddy
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D018496:Hyperoxia / Q000378:metabolism* / Q000473:pathology*; D008168:Lung / Q000473:pathology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human