Oxidatively Damaged Mitochondrial DNA Induces Inflammation in Lung Epithelial Cells

Pulmonary epithelial cells are key effectors and targets in the pathogenesis of inflammatory lung diseases such as asthma, and chronic obstructive pulmonary disease, among others. Oxidative stress has been implicated at the earliest step in development of lung inflammation, but the molecular mechanisms of how oxidative injury to epithelial cells develops inflammatory response remain unclear. While investigating the mechanisms responsible for activating inflammation in response to prolonged, low-level oxidative stress, we identified a role for an active and selective cellular extrusion of damaged mitochondrial DNA, that did not affect cellular viability. Selective release of damaged mitochondrial DNA, first into the cytoplasm where it binds to intracellular DNA sensor and subsequently into the extracellular space, triggers autocrine and paracrine modes of the inflammatory response. In vivo, intratracheal administration of the isolated mtDNA induces production of pro-inflammatory mediators in lungs of naive mice without tissue injury. Extrusion of mtDNA also occurs in vivo into the bronchoalveolar lavage fluid of mice subjected to cigarette smoke injury. We proposed that inflammation triggered by mtDNA-specific damage contribute to development of inflammatory lung diseases.