Acute Respiratory Distress Syndrome (ARDS) is a devastating disorder characterised by diffuse inflammation and oedema formation. The main management strategy - low tidal volume ventilation - can be associated with the development of hypercapnic acidosis (HCA). Mesenchymal stem cells (MSCs) are a promising therapeutic candidate currently in early-phase clinical trials. The effects of HCA on the alveolar epithelium and capillary endothelium are not well established. The therapeutic efficacy of MSCs has never been reported in HCA. In the present study we evaluated effects of HCA on inflammatory response and reparative potential of the primary human small airway epithelial and lung microvasculature endothelial cells as well as on capacity of the bone marrow-derived MSCs to promote wound healing in vitro. We demonstrate that HCA attenuates the inflammatory response and reparative potential of primary human small airway epithelium and capillary endothelium and induces mitochondrial dysfunction. It was found that MSCs promote lung epithelial wound repair via transfer of functional mitochondria, however this pro-reparative effect of MSCs was lost in the setting of HCA. Therefore, 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.
Author contribution description: Senior Author. In this manuscript, we demonstrate the effects of Hypercapnic Acidosis (HCA), (condition often associated with low tidal volume ventilation of critically ill patients) on primary human cells of the pulmonary capillary endothelium (HPMECs), the small airway epithelium (SAECs) and Mesenchymal Stem/Stromal Cells (MSCs). We have found that although HCA attenuates inflammatory responses in primary human pulmonary cells, it simultaneously impairs their reparative capacities and induces induces significant mitochondrial dysfunction. For the first time, we demonstrate that transfer of functional mitochondria is responsible for the ability of MSCs to promote lung epithelial repair, thus revealing the novel mechanism of MSC therapeutic effects in ARDS, although this effect is lost in HCA. 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. This may subsequently allow for appropriate stratification of patients with ARDS (or other lung diseases) who are most likely to respond to MSC-based therapies. I supervised PhD student (Fergie) conducting this work and contributed to the design, interpretation of evidence, manuscript writing, final approval of the manuscript and provision of funding. Biotechnolgy,24/246 IF 5.595, SNIP 1.2