This study tested the hypothesis that oxidative mitochondrial-targeted
DNA (
mtDNA) damage triggered
ventilator-induced lung injury (VILI). Control mice and mice infused with a fusion
protein targeting the
DNA repair enzyme, 8-oxoguanine-DNA glycosylase 1 (OGG1) to mitochondria were mechanically ventilated with a range of peak inflation pressures (PIP) for specified durations. In minimal VILI (1 h at 40 cmH(2)O PIP), lung total extravascular
albumin space increased 2.8-fold even though neither
lung wet/dry (W/D) weight ratios nor bronchoalveolar lavage (BAL)
macrophage inflammatory protein (MIP)-2 or
IL-6 failed to differ from nonventilated or low PIP controls. This increase in
albumin space was attenuated by OGG1. Moderately severe VILI (2 h at 40 cmH(2)O PIP) produced a 25-fold increase in total extravascular
albumin space, a 60% increase in W/D weight ratio and marked increases in BAL MIP-2 and
IL-6, accompanied by oxidative
mitochondrial DNA damage, as well as decreases in the total tissue
glutathione (GSH) and GSH/GSSH ratio compared with nonventilated lungs. All of these injury indices were attenuated in OGG1-treated mice. At the highest level of VILI (2 h at 50 cmH(2)O PIP), OGG1 failed to protect against massive lung
edema and BAL
cytokines or against depletion of the tissue GSH pool. Interestingly, whereas untreated mice died before completing the 2-h protocol, OGG1-treated mice lived for the duration of observation. Thus mitochondrially targeted OGG1 prevented VILI over a range of ventilation times and pressures and enhanced survival in the most severely injured group. These findings support the concept that oxidative
mtDNA damage caused by high PIP triggers induction of acute
lung inflammation and injury.