Mitochondrial DNA damage-associated molecular patterns mediate the response to bacteria-induced lung injury.

摘要

Treatment of patients with systemic inflammatory response syndrome (SIRS) becomes complicated if patients develop acute respiratory distress syndrome (ARDS) or more severe sequelae, such as multiple organ dysfunction syndrome (MODS). How an isolated injury can be propagated to distant tissues is unknown. Recently, elevated levels of mitochondrial DNA (mtDNA) were detected in severely-injured patients. mtDNA acts as a damage-associated molecular pattern (DAMP) following injury by binding to TLR9 on various immune cells to initiate an innate immune cascade. The stimulus for the release of mtDNA DAMPs was unknown. mtDNA is particularly sensitive to oxidative damage following an increase in reactive oxygen species. With this background, we used a stimulus known to create an oxidant stress, bacterial instillation in the trachea, to determine whether oxidative mtDNA damage is the trigger for subsequent release of mtDNA DAMPs. Outcomes measured included detection of mtDNA sequences in the circulating perfusate of isolated perfused rat lungs via quantitative real-time PCR analysis, changes in vascular permeability in isolated lungs as indicated by K f, and alterations in the oxidative mtDNA lesion densities of whole lungs challenged with Pseudomonas aeruginosa, a bacterium frequently implicated in nosocomial lung infections and ARDS. We found that P. aeruginosa caused increases in the levels of circulating mtDNA DAMPs, oxidative mtDNA damage, and vascular permeability. Upon addition of exogenous mtDNA DAMPs, increases in these three parameters were also detected, suggesting that mtDNA may initiate a feed-forward cycle of lung injury. This research is significant because it points to two novel targets for ARDS therapy: repair of oxidative mtDNA damage and degradation of released mtDNA DAMPs.