title: Down-regulation of 8-oxoguanine DNA glycosylase 1 expression in the airway epithelium ameliorates allergic lung inflammation.
abstract: Allergic airway inflammation is characterized by increased expression of pro-inflammatory mediators, inflammatory cell infiltration, mucus hypersecretion, and airway hyperresponsiveness, in parallel with oxidative DNA base and strand damage, whose etiological role is not understood. Our goal was to establish the role of 8-oxoguanine (8-oxoG), a common oxidatively damaged base, and its repair by 8-oxoguanine DNA glycosylase 1 (Ogg1) in allergic airway inflammatory processes. Airway inflammation was induced by intranasally administered ragweed (Ambrosia artemisiifolia) pollen grain extract (RWPE) in sensitized BALB/c mice. We utilized siRNA technology to deplete Ogg1 from airway epithelium; 8-oxoG and DNA strand break levels were quantified by Comet assays. Inflammatory cell infiltration and epithelial methaplasia were determined histologically, mucus and cytokines levels biochemically and enhanced pause was used as the main index of airway hyperresponsiveness. Decreased Ogg1 expression and thereby 8-oxoG repair in the airway epithelium conveyed a lower inflammatory response after RWPE challenge of sensitized mice, as determined by expression of Th2 cytokines, eosinophilia, epithelial methaplasia, and airway hyperresponsiveness. In contrast, 8-oxoG repair in Ogg1-proficient airway epithelium was coupled to an increase in DNA single-strand break (SSB) levels and exacerbation of allergen challenge-dependent inflammation. Decreased expression of the Nei-like glycosylases Neil1 and Neil2 that preferentially excise ring-opened purines and 5-hydroxyuracil, respectively, did not alter the above parameters of allergic immune responses to RWPE. These results show that DNA SSBs formed during Ogg1-mediated repair of 8-oxoG augment antigen-driven allergic immune responses. A transient modulation of OGG1 expression/activity in airway epithelial cells could have clinical benefits.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA. bacsi.attila@gmail.com
authors.forename: Attila
authors.initials: A
authors.lastname: Bacsi
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Aguilera-Aguirre
authors.forename: Bartosz
authors.initials: B
authors.lastname: Szczesny
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Radak
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Hazra
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Sur
authors.forename: Xueqing
authors.initials: X
authors.lastname: Ba
authors.forename: Istvan
authors.initials: I
authors.lastname: Boldogh
mesh_terms: D031164:Ambrosia / Q000276:immunology; D000818:Animals; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D053904:DNA Breaks, Single-Stranded; D045647:DNA Glycosylases / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair; D015536:Down-Regulation; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D011058:Pollen / Q000276:immunology; D034741:RNA, Small Interfering; D012130:Respiratory Hypersensitivity / Q000201:enzymology* / Q000235:genetics; D020545:Respiratory Mucosa / Q000201:enzymology* / Q000276:immunology
chemical_list: D034741:RNA, Small Interfering; C024829:8-hydroxyguanine; D006147:Guanine; D004247:DNA; D045647:DNA Glycosylases; C481347:Neil1 protein, mouse; C502613:Neil2 protein, mouse; C485990:Ogg1 protein, mouse