title: Time-dependent and somatically acquired mitochondrial DNA mutagenesis and respiratory chain dysfunction in a scleroderma model of lung fibrosis.
abstract: Reactive oxygen species (ROS) have been implemented in the etiology of pulmonary fibrosis (PF) in systemic sclerosis. In the bleomycin model, we evaluated the role of acquired mutations in mitochondrial DNA (mtDNA) and respiratory chain defects as a trigger of ROS formation and fibrogenesis. Adult male Wistar rats received a single intratracheal instillation of bleomycin and their lungs were examined at different time points. Ashcroft scores, collagen and TGFβ1 levels documented a delayed onset of PF by day 14. In contrast, increased malon dialdehyde as a marker of ROS formation was detectable as early as 24 hours after bleomycin instillation and continued to increase. At day 7, lung tissue acquired significant amounts of mtDNA deletions, translating into a significant dysfunction of mtDNA-encoded, but not nucleus-encoded respiratory chain subunits. mtDNA deletions and markers of mtDNA-encoded respiratory chain dysfunction significantly correlated with pulmonary TGFβ1 concentrations and predicted PF in a multivariate model.
authors.affiliation: 1] Dept. of Pulmonary Medicine University Hospital Bern, Bern Switzerland [2] Dept. of Clinical Research, University of Bern, Bern Switzerland [3].
authors.forename: Amiq
authors.initials: A
authors.lastname: Gazdhar
authors.affiliation: 1] Dept. of Rheumatology & Clinical Immunology, University Hospital Freiburg, Freiburg, Germany [2].
authors.forename: Dirk
authors.initials: D
authors.lastname: Lebrecht
authors.affiliation: Pulmonary Cell Research, Biomedicine, University Basel; Pneumology, Internal Medicine, University Hospital Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Roth
authors.affiliation: Pulmonary Cell Research, Biomedicine, University Basel; Pneumology, Internal Medicine, University Hospital Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Tamm
authors.affiliation: Dept. of Rheumatology & Clinical Immunology, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Venhoff
authors.affiliation: Division of Rheumatology, Dept. of Medicine, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Chingching
authors.initials: C
authors.lastname: Foocharoen
authors.affiliation: 1] Dept. of Pulmonary Medicine University Hospital Bern, Bern Switzerland [2] Dept. of Clinical Research, University of Bern, Bern Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Geiser
authors.affiliation: 1] Dept. of Rheumatology & Clinical Immunology, University Hospital Freiburg, Freiburg, Germany [2] Dept. of Rheumatology at Basel University, Basel, Switzerland.
authors.forename: Ulrich A
authors.initials: UA
authors.lastname: Walker
mesh_terms: D000818:Animals; D001761:Bleomycin; D015153:Blotting, Western; D004272:DNA, Mitochondrial / Q000235:genetics*; D004195:Disease Models, Animal; D004579:Electron Transport / Q000235:genetics; D003576:Electron Transport Complex IV / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D016296:Mutagenesis; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D003576:Electron Transport Complex IV