title: Asbestos-induced pulmonary fibrosis is augmented in 8-oxoguanine DNA glycosylase knockout mice.
abstract: Asbestos causes asbestosis and malignancies by mechanisms that are not fully established. Alveolar epithelial cell (AEC) injury and repair are crucial determinants of the fibrogenic potential of noxious agents such as asbestos. We previously showed that mitochondrial reactive oxygen species mediate asbestos-induced AEC intrinsic apoptosis and that mitochondrial human 8-oxoguanine-DNA glycosylase 1 (OGG1), a DNA repair enzyme, prevents oxidant-induced AEC apoptosis. We reasoned that OGG1 deficiency augments asbestos-induced pulmonary fibrosis. Compared with intratracheal instillation of PBS (50 μl) or titanium dioxide (100 μg/50 μl), crocidolite or Libby amphibole asbestos (100 μg/50 μl) each augmented pulmonary fibrosis in wild-type C57BL/6J (WT) mice after 3 weeks as assessed by histology, fibrosis score, lung collagen via Sircol, and type 1 collagen expression; these effects persisted at 2 months. Compared with WT mice, Ogg1 homozygous knockout (Ogg1(-/-)) mice exhibit increased pulmonary fibrosis after crocidolite exposure and apoptosis in cells at the bronchoalveolar duct junctions as assessed via cleaved caspase-3 immunostaining. AEC involvement was verified by colocalization studies using surfactant protein C. Asbestos increased endoplasmic reticulum stress in the lungs of WT and Ogg1(-/-) mice. Compared with WT, alveolar type 2 cells isolated from Ogg1(-/-) mice have increased mtDNA damage, reduced mitochondrial aconitase expression, and increased P53 and cleaved caspase-9 expression, and these changes were enhanced 3 weeks after crocidolite exposure. These findings suggest an important role for AEC mtDNA integrity maintained by OGG1 in the pathogenesis of pulmonary fibrosis that may represent a novel therapeutic target.
authors.affiliation: 1 Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown VA Medical Center, Chicago, Illinois.
authors.forename: Paul
authors.initials: P
authors.lastname: Cheresh
authors.forename: Luisa
authors.initials: L
authors.lastname: Morales-Nebreda
authors.forename: Seok-Jo
authors.initials: SJ
authors.lastname: Kim
authors.forename: Anjana
authors.initials: A
authors.lastname: Yeldandi
authors.forename: David B
authors.initials: DB
authors.lastname: Williams
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Gökhan M
authors.initials: GM
authors.lastname: Mutlu
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
authors.forename: Karen
authors.initials: K
authors.lastname: Ridge
authors.forename: Paul T
authors.initials: PT
authors.lastname: Schumacker
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
authors.forename: David W
authors.initials: DW
authors.lastname: Kamp
mesh_terms: D056809:Alveolar Epithelial Cells / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D017638:Asbestos, Crocidolite / Q000633:toxicity*; D004249:DNA Damage / Q000235:genetics; D045647:DNA Glycosylases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013997:Time Factors
chemical_list: D004272:DNA, Mitochondrial; D017638:Asbestos, Crocidolite; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse
keywords: 8-oxyguanosine DNA glycosylase; asbestosis; mitochondria; pulmonary fibrosis