Hypercapnic acidosis induces mitochondrial dysfunction and impairs the ability of mesenchymal stem cells to promote distal lung epithelial repair

What is it about?

Acute Respiratory Distress Syndrome (ARDS) is a severe clinical syndrome that affects 20% of all critically ill patients and has very high mortality rate around 30-50% . There is no effective treatments for this condition at this time. ARDS is characterised by an excessive and dysregulated inflammation in the lung that results in the failure to maintain its main function - breathing. In order to breath these patients require mechanical ventilation. Very frequently low tidal volume ventilation can be associated with the development of hypercapnic acidosis (HCA). The effect of HCA on primary human lung cells still remains unclear. Mesenchymal stem cells (MSCs) are a promising therapeutic candidate for ARDS currently in early-phase clinical trials. The therapeutic efficacy of MSCs has never been reported in HCA. In this manuscript, we demonstrate the effects of HCA on primary human cells of the pulmonary capillary endothelium, the small airway epithelium and MSCs. We have found that although HCA attenuates inflammatory responses in endothelial and epithelial cells, it simultaneously impairs their reparative capacities. We also demonstrate that HCA induces significant mitochondrial dysfunction in all three primary human cell types. In addition, for the first time, we demonstrate that transfer of functional mitochondria is responsible for the ability of MSCs to promote epithelial repair, although this effect is lost in HCA. _x000D_ These findings suggest that HCA may adversely impact recovery from ARDS at the cellular level, while MSCs may not be therapeutically beneficial in patients with ARDS who develop HCA.

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