Fig. 5.

Proposed feed-forward cycle linking oxidative mtDNA damage and DAMP formation to injury propagation. Proposed model linking oxidant stress induced by bacteria, trauma, or ischemia-reperfusion injury to oxidative mtDNA damage, mtDNA DAMP formation, and regenerative mtDNA damage in a feed-forward cycle culminating in inflammation and tissue damage. The model, if valid, explains why treatment of the initial insult, regardless of its specific etiology, often fails to prevent propagation of the insult to distant organs and the occurrence of delayed organ dysfunction. The model also points to two new isolated targets for pharmacological intervention. Both inhibition (A) of oxidative mtDNA damage and enhanced degradation (B) of mtDNA DAMPs would be expected to forestall injury progression. Note that the model fails to consider the potentially complex interactions between alveolar macrophages, resident neutrophils, and vascular endothelial cells in driving the postulated feed-forward pathway. See text for additional details.