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Mitochondrial DNA damage-associated molecular patterns mediate a feed-forward cycle of bacteria-induced vascular
Jamie L Kuck1, Boniface O Obiako1, Olena M Gorodnya1
1Department of Pharmacology, University of South Alabama, College of Medicine, Mobile, Alabama;
Abstract:
Fragments of the mitochondrial genome released into the systemic circulation after mechanical trauma, termed mitochondrial DNA damage-associated molecular patterns (mtDNA DAMPs), are thought to mediate the systemic inflammatory response syndrome. The close association between circulating mtDNA DAMP levels and outcome in sepsis suggests that bacteria also might be a stimulus for mtDNA DAMP release. To test this hypothesis, we measured mtDNA DAMP abundance in medium perfusing isolated rat lungs challenged with an intratracheal instillation of 5 × 10(7) colony-forming units of Pseudomonas aeruginosa (strain 103; PA103). Intratracheal PA103 caused rapid accumulation of selected 200-bp sequences of the mitochondrial genome in rat lung perfusate accompanied by marked increases in both lung tissue oxidative mtDNA damage and in the vascular filtration coefficient (Kf). Increases in lung tissue mtDNA damage, perfusate mtDNA DAMP abundance, and Kf were blocked by addition to the perfusion medium of a fusion protein targeting the DNA repair enzyme Ogg1 to mitochondria. Intra-arterial injection of mtDNA DAMPs prepared from rat liver mimicked the effect of PA103 on both Kf and lung mtDNA integrity. Effects of mtDNA and PA103 on Kf were also attenuated by an oligodeoxynucleotide inhibitor of Toll-like receptor 9 (TLR-9) by mitochondria-targeted Ogg1 and by addition of DNase1 to the perfusion medium. Collectively, these findings are consistent with a model wherein PA103 causes oxidative mtDNA damage leading to a feed-forward cycle of mtDNA DAMP formation and TLR-9-dependent mtDNA damage that culminates in acute lung injury.
Insights
Pseudomonas aeruginosa infection triggers mitochondrial DNA damage-associated molecular patterns (mtDNA DAMPs) release, causing acute lung injury. Repairing mitochondrial DNA damage with Ogg1 protein or blocking Toll-like receptor 9 (TLR-9) mitigates these effects.
Area of Science:
- Cellular and Molecular Biology
- Immunology
- Pathophysiology
Background:
- Mitochondrial DNA damage-associated molecular patterns (mtDNA DAMPs) released into circulation after trauma are implicated in systemic inflammation.
- Circulating mtDNA DAMP levels correlate with sepsis outcomes, suggesting bacterial stimuli may induce mtDNA DAMP release.
Purpose of the Study:
- To investigate whether Pseudomonas aeruginosa (PA103) instillation in rat lungs stimulates mtDNA DAMP release and contributes to acute lung injury.
- To explore the mechanisms underlying PA103-induced lung injury, focusing on oxidative mtDNA damage and Toll-like receptor 9 (TLR-9) activation.
Main Methods:
- Isolated rat lungs were challenged with intratracheal PA103, and mtDNA DAMPs in perfusate were measured.
- Lung tissue oxidative mtDNA damage and vascular filtration coefficient (Kf) were assessed.
- Interventions included mitochondria-targeted Ogg1, mtDNA DAMPs injection, TLR-9 inhibition, and DNase1 treatment.
Main Results:
- Intratracheal PA103 rapidly increased mtDNA DAMPs in lung perfusate, elevated lung tissue oxidative mtDNA damage, and increased Kf.
- Mitochondria-targeted Ogg1 blocked increases in mtDNA damage, mtDNA DAMPs, and Kf.
- Intra-arterial mtDNA DAMPs mimicked PA103 effects on Kf and mtDNA integrity; TLR-9 inhibition and DNase1 attenuated PA103 and mtDNA effects.
Conclusions:
- PA103 induces oxidative mtDNA damage, leading to mtDNA DAMP formation and a positive feedback loop involving TLR-9.
- This cycle of mtDNA damage and DAMP release culminates in acute lung injury.
- Targeting mitochondrial DNA repair or TLR-9 may offer therapeutic strategies for bacterial-induced lung injury.
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