Mitochondrial DNA damage-associated molecular patterns mediate a feed-forward cycle of bacteria-induced vascular injury in perfused rat lungs

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.

The pulmonary endothelium in acute respiratory distress syndrome: insights and therapeutic opportunities

“…In this context, they are potent inducers of the inflammasome via toll-like receptor 9 (TLR9),70 activating leucocyte-mediated lung injury when injected in vivo71 and endothelial barrier disruption in vitro . 72 A bacterial challenge in isolated mouse lungs induced mtDNA release which was associated with endothelial hyperpermeability; this effect was replicated with exogenous mtDNA and attenuated by blockade of TLR9 73. Further elucidation of mechanisms of mtDNA release and their interplay with ROS as well as intracellular signalling pathways are required but this represents an intriguing line of investigation, if not a potential therapeutic target.…”

Early Diagnosis of Sepsis: Is an Integrated Omics Approach the Way Forward?

“…Recently, a number of predictive biomarkers directly related to mitochondrial proteins and metabolites has been associated with patient outcomes. These include cardiolipin [89, 90], mitochondrial DNA (mtDNA) damage-associated molecular patterns (DAMPs) [91–93] and the previously described carnitine esters [35, 37]. Interestingly, mtDNA has been reported to induce immune paralysis in septic patients [94].…”

Preeclampsia and health risks later in life: an immunological link

“…Recent observations clearly suggest that shed nuclear and mitochondrial products can facilitate effector immune responses [78][79][80][81][82][83][84]. It is proposed that cell death and injury can lead to release of nuclear and mitochondrial DNA (mtDNA) which can act as a damage-associated molecular pattern and interact with Toll-like receptor 9 (TLR9) [39].…”

“…The preeclampsia placenta, particularly associated with intrauterine growth restriction, exhibits high content of mtDNA DAMPS [70][71][72][73][74][75][76][77][78][79]. Recent evidence clearly suggests that circulating mtDNA DAMPS cause inflammatory responses via activation of TLR9 signaling pathway [80,81]. Taking a cue from these studies, it can be proposed that poor placentation and trophoblast cell death result in production of mitochondrial milieu containing mtDNA DAMPS which can utilize TLR9 to mount a potent systemic inflammatory response, vascular deficiency, and preeclampsia-like features associated with IUGR [39,82].…”