title: DNA Repair Interacts with Autophagy To Regulate Inflammatory Responses to Pulmonary Hyperoxia.
abstract: Oxygen is supplied as a supportive treatment for patients suffering from acute respiratory distress syndrome. Unfortunately, high oxygen concentration increases reactive oxygen species generation, which causes DNA damage and ultimately cell death in the lung. Although 8-oxoguanine-DNA glycosylase (OGG-1) is involved in repairing hyperoxia-mediated DNA damage, the underlying molecular mechanism remains elusive. In this study, we report thatogg-1-deficient mice exhibited a significant increase of proinflammatory cytokines (TNF-α, IL-6, and IFN-γ) in the lung after being exposed to 95% oxygen. In addition, we found thatogg-1deficiency downregulated (macro)autophagy when exposed to hyperoxia both in vitro and in vivo, which was evident by decreased conversion of LC3-I to LC3-II, reduced LC3 punctate staining, and lower Atg7 expression compared with controls. Using a chromatin immunoprecipitation assay, we found that OGG-1 associated with the promoter of Atg7, suggesting a role for OGG1 in regulation of Atg7 activity. Knocking down OGG-1 decreased the luciferase reporter activity of Atg7. Further, inflammatory cytokine levels in murine lung epithelial cell line cells were downregulated following autophagy induction by starvation and rapamycin treatment, and upregulated when autophagy was blocked using 3-methyladenine and chloroquine.atg7knockout mice and Atg7 small interfering RNA-treated cells exhibited elevated levels of phospho-NF-κB and intensified inflammatory cytokines, suggesting that Atg7 impacts inflammatory responses to hyperoxia. These findings demonstrate that OGG-1 negatively regulates inflammatory cytokine release by coordinating molecular interaction with the autophagic pathway in hyperoxia-induced lung injury.
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203.|State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, The Third Military Medical University, Chongqing 400042, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Lin
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203.
authors.forename: Weidong
authors.identifier: 0000-0003-2941-4285
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203.
authors.forename: Shirui
authors.identifier: 0000-0001-6740-880X
authors.initials: S
authors.lastname: Tan
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203.|State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Xikun
authors.identifier: 0000-0001-6768-2382
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203.|Key Laboratory of Biotechnology for Medicinal Plants of Jiangsu Province, Jiangsu Normal University, Xuzhou, Jiangsu 2211116, People's Republic of China.
authors.forename: Rongpeng
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203.
authors.forename: Qinqin
authors.initials: Q
authors.lastname: Pu
authors.affiliation: Department of Medicine, Yale University, New Haven, CT 06510.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Koff
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203.
authors.forename: Archana
authors.initials: A
authors.lastname: Dhasarathy
authors.affiliation: Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu 100005, People's Republic of China; and mafeng@hotmail.co.jp hellojjx@126.com xindeng@cityu.edu.hk.
authors.forename: Feng
authors.identifier: 0000-0002-1594-6064
authors.initials: F
authors.lastname: Ma
authors.affiliation: Department of Biomedical Sciences, City University of Hong Kong, Hong Kong 999077, People's Republic of China mafeng@hotmail.co.jp hellojjx@126.com xindeng@cityu.edu.hk.
authors.forename: Xin
authors.initials: X
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, The Third Military Medical University, Chongqing 400042, People's Republic of China; mafeng@hotmail.co.jp hellojjx@126.com xindeng@cityu.edu.hk.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203; mafeng@hotmail.co.jp hellojjx@126.com xindeng@cityu.edu.hk.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001343:Autophagy; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D020552:Comet Assay; D016207:Cytokines / Q000096:biosynthesis; D045647:DNA Glycosylases / Q000378:metabolism*; D004260:DNA Repair; D004195:Disease Models, Animal; D018496:Hyperoxia / Q000378:metabolism / Q000473:pathology*; D047468:Immunoprecipitation; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D016207:Cytokines; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse