title: Cigarette smoke induces nucleic-acid oxidation in lung fibroblasts.
abstract: Oxidative stress is widely proposed as a pathogenic mechanism for chronic obstructive pulmonary disease (COPD), but the molecular pathway connecting oxidative damage to tissue destruction remains to be fully defined. We suggest that reactive oxygen species (ROS) oxidatively damage nucleic acids, and this effect requires multiple repair mechanisms, particularly base excision pathway components 8-oxoguanine-DNA glycosylase (OGG1), endonuclease III homologue 1 (NTH1), and single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1), as well as the nucleic acid-binding protein, Y-box binding protein 1 (YB1). This study was therefore designed to define the levels of nucleic-acid oxidation and expression of genes involved in the repair of COPD and in corresponding models of this disease. We found significant oxidation of nucleic acids localized to alveolar lung fibroblasts, increased levels of OGG1 mRNA expression, and decreased concentrations of NTH1, SMUG1, and YB1 mRNA in lung samples from subjects with very severe COPD compared with little or no COPD. Mice exposed to cigarette smoke exhibited a time-dependent accumulation of nucleic-acid oxidation in alveolar fibroblasts, which was associated with an increase in OGG1 and YB1 mRNA concentrations. Similarly, human lung fibroblasts exposed to cigarette smoke extract exhibited ROS-dependent nucleic-acid oxidation. The short interfering RNA (siRNA)-dependent knockdown of OGG1 and YB1 expression increased nucleic-acid oxidation at the basal state and after exposure to cigarette smoke. Together, our results demonstrate ROS-dependent, cigarette smoke-induced nucleic-acid oxidation in alveolar fibroblasts, which may play a role in the pathogenesis of emphysema.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, School of Medicine, Washington University, St. Louis, Missouri 63110, USA.
authors.forename: Gaetan
authors.initials: G
authors.lastname: Deslee
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Adair-Kirk
authors.forename: Tomoko
authors.initials: T
authors.lastname: Betsuyaku
authors.forename: Jason C
authors.initials: JC
authors.lastname: Woods
authors.forename: Carla H
authors.initials: CH
authors.lastname: Moore
authors.forename: David S
authors.initials: DS
authors.lastname: Gierada
authors.forename: Susan H
authors.initials: SH
authors.lastname: Conradi
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Atkinson
authors.forename: Holly M
authors.initials: HM
authors.lastname: Toennies
authors.forename: John T
authors.initials: JT
authors.lastname: Battaile
authors.forename: Dale K
authors.initials: DK
authors.lastname: Kobayashi
authors.forename: G Alexander
authors.initials: GA
authors.lastname: Patterson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Holtzman
authors.forename: Richard A
authors.initials: RA
authors.lastname: Pierce
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D045647:DNA Glycosylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D043224:Deoxyribonuclease (Pyrimidine Dimer) / Q000378:metabolism; D015536:Down-Regulation; D004646:Emphysema / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008168:Lung; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009696:Nucleic Acids / Q000378:metabolism*; D010084:Oxidation-Reduction; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D051981:Uracil-DNA Glycosidase / Q000378:metabolism; D051840:Y-Box-Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D009696:Nucleic Acids; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D043224:Deoxyribonuclease (Pyrimidine Dimer); C468347:NTHL1 protein, human; D045647:DNA Glycosylases; C498095:SMUG1 protein, human; D051981:Uracil-DNA Glycosidase; C479058:oxoguanine glycosylase 1, human