title: Mitochondrial DNA Damage Initiates Acute Lung Injury and Multi-Organ System Failure Evoked in Rats by Intra-Tracheal Pseudomonas Aeruginosa.
abstract: Although studies in rat cultured pulmonary artery endothelial cells, perfused lungs, and intact mice support the concept that oxidative mitochondrial (mt) DNA damage triggers acute lung injury (ALI), it has not yet been determined whether enhanced mtDNA repair forestalls development of ALI and its progression to multiple organ system failure (MOSF). Accordingly, here we examined the effect of a fusion protein construct targeting the DNA glycosylase, Ogg1, to mitochondria in a rat model intra-tracheal Pseudomonas aeruginosa (strain 103; PA103)-induced ALI and MOSF. Relative to controls, animals given PA103 displayed increases in lung vascular filtration coefficient accompanied by transient lung tissue oxidative mtDNA damage and variable changes in mtDNA copy number without evidence of nuclear DNA damage. The approximate 40% of animals surviving 24 h after bacterial administration exhibited multiple organ dysfunction, manifest as increased serum and tissue-specific indices of kidney and liver failure, along with depressed heart rate and blood pressure. While administration of mt-targeted Ogg1 to control animals was innocuous, the active fusion protein, but not a DNA repair-deficient mutant, prevented bacteria-induced increases in lung tissue oxidative mtDNA damage, failed to alter mtDNA copy number, and attenuated lung endothelial barrier degradation. These changes were associated with suppression of liver, kidney, and cardiovascular dysfunction and with decreased 24 h mortality. Collectively, the present findings indicate that oxidative mtDNA damage to lung tissue initiates PA103-induced ALI and MOSF in rats.
authors.affiliation: *Department of Surgery, College of Medicine, University of South Alabama, Mobile, Alabama †Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, Alabama ‡Department of Pharmacology, College of Medicine, University of South Alabama, Mobile, Alabama §Department of Cell Biology and Neuroscience, College of Medicine, University of South Alabama, Mobile, Alabama.
authors.forename: Yann-Leei
authors.initials: YL
authors.lastname: Lee
authors.forename: Boniface
authors.initials: B
authors.lastname: Obiako
authors.forename: Olena M
authors.initials: OM
authors.lastname: Gorodnya
authors.forename: Mykhaylo V
authors.initials: MV
authors.lastname: Ruchko
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Kuck
authors.forename: Viktor M
authors.initials: VM
authors.lastname: Pastukh
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Wilson
authors.forename: Jon D
authors.initials: JD
authors.lastname: Simmons
authors.forename: Mark N
authors.initials: MN
authors.lastname: Gillespie
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics* / Q000382:microbiology; D000818:Animals; D004249:DNA Damage / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D008297:Male; D009102:Multiple Organ Failure / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D014132:Trachea / Q000382:microbiology
chemical_list: D004272:DNA, Mitochondrial; D045647:DNA Glycosylases; C483741:OGG1 protein, rat