Effects of hypercapnic acidosis on the primary cells relevant to ARDS pathophysiology and the therapeutic potential of mesenchymal stem cells

Abstract

Background: Inflammatory responses are central to injury and repair in Acute Respiratory Distress Syndrome (ARDS). Low tidal volume ventilation – the standard of care – is often associated with hypercapnic acidosis (HCA). Data on how HCA influences inflammation and repair in ARDS are controversial. Aim: To investigate the effects of HCA on the primary human cell types directly affected in ARDS, and on mesenchymal stem cells (MSCs) which are under clinical investigation as a potential therapy for the condition. Methods: Human pulmonary microvascular endothelial cells (HPMECs), small airway epithelial cells (SAECs), or MSCs were stimulated with cytomix (TNFα, IFNγ, IL1β). Cells were exposed to normocapnia (5% CO2) or HCA (15% CO2). The effects of HCA on inflammation, wound repair and the MSC secretome (through which MSCs exert their effects) were assessed. Results: HPMEC secretion of neutrophil chemoattractants IL8 and ENA-78, and expression of the adhesion molecule, ICAM-1, were significantly reduced in HCA. HCA did not affect the degree of cytomix-induced inhibition of wound closure. In SAECs, while IL8 secretion was reduced, wound closure was impaired by HCA in the inflammatory environment. HCA did not alter the MSC secretome or NFκB activation. Conclusion: While HCA reduces the contribution of HPMECs and SAECs to inflammation, it impairs wound repair, suggesting the potential for HCA to worsen epithelial barrier function. The MSC secretome and NFκB activation are unaffected by HCA, but functional studies utilising clinically relevant models are required to investigate whether the therapeutic effects of MSCs will persist in HCA.