Therapy with Mitochondria for Lung Diseases

Pulmonary endothelium dysfunction, with increased capillary permeability and mitochondrial impair, is a key aspect in the pathogenesis of acute respiratory distress syndrome (ARDS), which is a life-threatening condition with no effective treatment. The relevance of pulmonary endothelium for ARDS pathology has been more elucidated, showing a role in capillary permeability and mitochondrial dysfunction.  Additionally, it has been demonstrated that mesenchymal stromal cells (MSCs) can modulate the response of lung target cells through mitochondrial transfer. Although transplantation of healthy mitochondria is a promising approach for treating conditions underpinned by mitochondrial dysfunction, its therapeutic potential in ARDS is not sufficiently investigated. Herein, we tested the mitochondrial transplantation to restore the pulmonary endothelial cells function in in vitro and pre-clinical models of ARDS. Mitochondria derived from human bone-marrow mesenchymal stromal cells (hBMSC-mt) were isolated and immediately used for transplantation to primary human pulmonary microvascular endothelial cells (HPMECS), stimulated with E.coli lipopolysaccharides (LPS) or plasma samples from ARDS patients classified into hypo- and hyper-inflammatory phenotypes. The mitochondrial function and barrier integrity of HPMECs were accessed in a 24-hour timepoint. Mice were stimulated with lipopolysaccharide (LPS) intratracheally and treated with mitochondria intravenously. Further lung injury analysis was done in bronchoalveolar fluid lavage fluid (BALF) was evaluated. The stimulation with LPS or ARDS plasma generated an in vitro inflammatory microenvironment, with mitochondrial dysfunction and hyperpermeability. hBMSC-derived mitochondria were readily uptaken by HPMECs, with no cytotoxicity or inflammatory response, mitigating mitochondrial dysfunction and restoring barrier integrity. In vivo, mitochondria transplantation alleviated protein and neutrophil content in BALF, indicating restoration in the alveolar-capillary barrier integrity at some level. Taken together, our results showed mitochondria transplantation as a promising therapeutic approach in endothelial dysfunction, especially restoring the integrity of the pulmonary endothelial barrier in in vitro and in vivo preclinical models of ARDS.