Abstract

Acute respiratory distress syndrome (ARDS) is a devastating disorder characterized by diffuse inflammation and edema 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 the 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 the capacity of 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 the transfer of functional mitochondria; however, this proreparative effect of MSCs was lost in the setting of HCA. Therefore, HCA may adversely impact recovery from ARDS at the cellular level, whereas MSCs may not be therapeutically beneficial in patients with ARDS who develop HCA.—Fergie, N., Todd, N., McClements, L., McAuley, D., O’Kane, C., Krasnodembskaya, A. Hypercapnic acidosis induces mitochondrial dysfunction and impairs the ability of mesenchymal stem cells to promote distal lung epithelial repair.

Highlights

  • Acute respiratory distress syndrome (ARDS) is an acute inflammatory disorder in which the integrity of the alveolar epithelial2capillary endothelial barrier is compromised and ABBREVIATIONS: a-MEM, minimum essential medium with alpha modifications; Ang-1, angiopoietin-1; ARDS, acute respiratory distress syndrome; Bovine serum albumin (BSA), bovine serum albumin; CM, conditioned medium; CXCL, C-X-C motif chemokine ligand; Dulbecco’s phosphatebuffered saline (DPBS), Dulbecco’s phosphate-buffered saline; E-selectin, endothelial-selectin; FBS, fetal bovine serum; FCCP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone; HCA, hypercapnic acidosis; human pulmonary microvascular endothelial cells (HPMECs), human pulmonary microvascular endothelial cell; ICAM, intercellular adhesion molecule; IL-1ra, IL-1 receptor antagonist; JC-1, 5,59,6,69-tetrachloro-1,19,3,39-tetraethylbenzimidazolylcarbocyanine iodide; LDH, lactate dehydrogenase; LG, L-glutamine; MFI, median fluorescence intensity; Mesenchymal stem cells (MSCs), mesenchymal stem cell; pCO2, partial pressure of CO2; PS, penicillinstreptomycin; R6G, rhodamine 6G; SAEC, small airway epithelial cell

  • Low tidal volume ventilation is the mainstay of treatment, but it can be associated with the development of hypercapnic acidosis (HCA) [1, 2]

  • SAEC wound closure was diminished by cytomix stimulation in normocapnia, whereas a nonsignificant trend toward further worsening of the reparative response was observed in HCA (Fig. 2B)

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Summary

Introduction

Acute respiratory distress syndrome (ARDS) is an acute inflammatory disorder in which the integrity of the alveolar epithelial2capillary endothelial barrier is compromised and ABBREVIATIONS: a-MEM, minimum essential medium with alpha modifications; Ang-1, angiopoietin-1; ARDS, acute respiratory distress syndrome; BSA, bovine serum albumin; CM, conditioned medium; CXCL, C-X-C motif chemokine ligand; DPBS, Dulbecco’s phosphate-buffered saline; E-selectin, endothelial-selectin; FBS, fetal bovine serum; FCCP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone; HCA, hypercapnic acidosis; HPMEC, human pulmonary microvascular endothelial cell; ICAM, intercellular adhesion molecule; IL-1ra, IL-1 receptor antagonist; JC-1, 5,59,6,69-tetrachloro-1,19,3,39-tetraethylbenzimidazolylcarbocyanine iodide; LDH, lactate dehydrogenase; LG, L-glutamine; MFI, median fluorescence intensity; MSC, mesenchymal stem cell; pCO2, partial pressure of CO2; PS, penicillinstreptomycin; R6G, rhodamine 6G; SAEC, small airway epithelial cell Significant heterogeneity exists between macrovascular and microvascular cells with regard to protein expression profiles and barrier

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