*Purpose: Mitochondrial transplantation therapy is an innovative strategy for the treatment of mitochondrial dysfunction. The approach has shown efficacy in the treatment of cardiac ischemic reperfusion injuries in clinical trials. However, to date no studies have addressed its efficacy in lung transplantation (LTx).

*Methods: Here, we investigate the efficacy of mitochondrial transplantation in a murine donation after cardiac death (DCD) allogenic orthotopic lung transplant model. Balb/c DCD left lungs were cold stored for 18hrs prior to implantation into C57Bl/6 recipients. Upon reperfusion LTx recipients received either vehicle or vehicle-containing mitochondria via tracheal nebulization. Twenty-four hours post-transplant lung function, histopathology, edema, and immunological parameters were assessed. Lung graft uptake of nebulized mitochondria was assessed by flow cytometry. Increased levels of circulating mitochondrial DNA (mtDNA) fragments are associated with poor LTx outcomes and thus were quantified in each group.

*Results: Compared to controls, LTx recipients treated with nebulized mitochondria had significantly reduced evidence of histological injury and significantly improved graft oxygenation. Neutrophil infiltration, interstitial edema, and pro-inflammatory cytokines (KC, MCP-1, IL-6) were also significantly decreased in the mitochondria treatment group. Flow cytometric analysis of nebulized mitochondria uptake demonstrated localization to lung graft macrophages, epithelial and endothelial cells. Quantitative PCR of recipient serum from both groups revealed no difference in the levels of circulating mtDNA fragments at 24hrs post-transplant.

*Conclusions: Taken together these results conclude that mitochondrial transplantation by nebulization is an effective delivery mechanism to localize mitochondria to the lung graft, improve LTx outcomes, and reduce lung inflammation, without causing an increase in systemic levels of fragmented mtDNA.

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