Abstract
The mitochondrial targeted DNA repair enzyme, 8-oxoguanine DNA glycosylase 1, was previously reported to protect against mitochondrial DNA (mtDNA) damage and ventilator induced lung injury (VILI). In the present study we determined whether mitochondrial targeted endonuclease III (EndoIII) which cleaves oxidized pyrimidines rather than purines from damaged DNA would also protect the lung. Minimal injury from 1 h ventilation at 40 cmH2O peak inflation pressure (PIP) was reversed by EndoIII pretreatment. Moderate lung injury due to ventilation for 2 h at 40 cmH2O PIP produced a 25-fold increase in total extravascular albumin space, a 60% increase in W/D weight ratio, and marked increases in MIP-2 and IL-6. Oxidative mtDNA damage and decreases in the total tissue glutathione (GSH) and the GSH/GSSH ratio also occurred. All of these indices of injury were attenuated by mitochondrial targeted EndoIII. Massive lung injury caused by 2 h ventilation at 50 cmH2O PIP was not attenuated by EndoIII pretreatment, but all untreated mice died prior to completing the two hour ventilation protocol, whereas all EndoIII-treated mice lived for the duration of ventilation. Thus, mitochondrial targeted DNA repair enzymes were protective against mild and moderate lung damage and they enhanced survival in the most severely injured group.
Highlights
There is general acceptance that ventilator induced lung injury (VILI) contributes significantly to the mortality in the acute respiratory distress syndrome (ARDS) because a large scale clinical trial reducing tidal volume from 12 mL/kg to 6 mL/kg improved ARDS survival by 22% [1,2]
Respiratory rate was reduced in the groups ventilated with higher peak inflation pressures (PIP) levels to maintain minute ventilation near normal levels, but hypocapnia was present in the high PIP ventilation groups indicating a level of hyperventilation
PaCO2 values were significantly lower in the endonuclease III (EndoIII) treated groups ventilated at 40 and 50 cmH2O PIP, compared to non-ventilated mice a significant alkalosis was not present
Summary
There is general acceptance that ventilator induced lung injury (VILI) contributes significantly to the mortality in the acute respiratory distress syndrome (ARDS) because a large scale clinical trial reducing tidal volume from 12 mL/kg to 6 mL/kg improved ARDS survival by 22% [1,2]. Even using a low tidal volume, mechanical ventilation can magnify the injurious effect of pre-existing damage or infection [3,4,5]. This means a further improvement in survival from ARDS during mechanical ventilation will require a pharmacologic intervention which will protect against injury due to a variety of insults that may activate multiple signal pathways. Mitochondrial DNA (mtDNA) is some 10 to 100-fold more sensitive to oxidative damage than nuclear DNA [6] These damaged mitochondria can leak increased amounts of superoxide into the cytoplasm and activate NADPH oxidases [7,8]. Repair of mtDNA damage can interrupt the progression of oxidant production, mitochondrial failure and cell death
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