Transplantation of Viable Allogeneic Mitochondria Improves Gas Exchange and Alveolar-Capillary Permeability in Rats with Endotoxin-Induced Acute Lung Injury

Background: Acute lung injuries (ALI) cause disruption of the alveolar-capillary barrier and remains as the leading cause of death in critically ill patients. This study tested the hypothesis that the administration of freshly isolated viable allogeneic mitochondria can prevent injury of the alveolar-capillary barrier at the endothelial level, as mitochondrial dysfunction of the pulmonary endothelium is a critical aspect of ALI progression.Methods: ALI was induced by intratracheal lipopolysaccharide instillation (LPS, 1mg/kg) in anesthetized rats. Mitochondria (100 μg) were isolated from the freshly harvested soleus muscles of naïve rats and stained with a green fluorescence MitoTracker™ dyne. A mitochondria or placebo solution was randomly administered into the jugular veins of the rats at 2 h and 4 h after ALI induction. An arterial blood gas analysis was done 20 h later. The animals were then sacrificed, and lung tissues were harvested for analysis.Results: An IVIS Spectrum imaging system was used to obtain ex vivo heart-lung block images and demonstrated the enhancement of MitoTracker™ fluorescence in the lungs. Mitochondria transplantation significantly improved arterial oxygen contents (PaO2 and SaO2), while reduced CO2 tension in rats with ALI. Animals with mitochondrial transplants had significantly increased ATP concentration in lung tissues. Allogeneic mitochondria transplantation preserved alveolar-capillary barrier function, as shown by a reduction in protein levels in the bronchoalveolar lavage fluid, and decrease of extravasated Evans blue dyne and hemoglobin content in lung tissues. Relaxation responses to acetylcholine and eNOS expression were potentiated in injured pulmonary arteries, and inflammatory cells infiltration into lung tissue was also reduced following mitochondrial transplantation.Conclusions: Transplantation of viable mitochondria protects the integrity of endothelial lining of the alveolar-capillary barrier, thereby improving gas exchange during the acute stages of endotoxin-induced ALI. However, the longer-term effects of mitochondrial transplantation on pulmonary function recovery after ALI requires further investigation.