Abstract
Alveolar epithelial-capillary barrier disruption is a hallmark of Acute Respiratory Distress Syndrome (ARDS). Contribution of mitochondrial dysfunction to the compromised alveolar-capillary barrier in ARDS remains unclear. Mesenchymal stromal cells-derived extracellular vesicles (MSC EVs) are considered as a cell free therapy for ARDS. Mitochondrial transfer was shown to be important for the therapeutic effects of MSCs and MSC EVs. Here we investigated the contribution of mitochondrial dysfunction to the injury of alveolar epithelial and endothelial barriers in ARDS and the ability of MSC EVs to modulate alveolar-capillary barrier integrity through mitochondrial transfer.
Primary human small airway epithelial and pulmonary microvascular endothelial cells and human precision cut lung slices (PCLSs) were stimulated with endotoxin or plasma samples from patients with ARDS and treated with MSC EVs, barrier properties and mitochondrial functions were evaluated. LPS-injured mice were treated with MSC EVs and degree of lung injury and mitochondrial respiration of the lung tissue were assessed.
Inflammatory stimulation resulted in increased permeability coupled with pronounced mitochondrial dysfunction in both types of primary cells and PCLSs. EVs derived from normal MSCs restored barrier integrity and normal levels of oxidative phosphorylation while EV preparation which did not contain mitochondria was not effective.In vivo, presence of mitochondria was critical for EV ability to reduce lung injury and restore mitochondrial respiration in the lung tissue.
In the ARDS environment MSC-EVs improve alveolar-capillary barrier properties through restoration of mitochondrial functions at least partiallyviamitochondrial transfer.
Footnotes
This manuscript has recently been accepted for publication in theEuropean Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of theERJonline. Please open or download the PDF to view this article.
Conflict of interest: Dr. Silva has nothing to disclose.
Conflict of interest: Dr. Su has nothing to disclose.
Conflict of interest: Dr. Calfee reports grants from NIH, during the conduct of the study; grants and personal fees from Roche/Genentech, grants and personal fees from Bayer, personal fees from Quark Pharmaceuticals, personal fees from Prometic, personal fees from Gen1e Life Sciences, personal fees from Vasomune, outside the submitted work;.
Conflict of interest: Dr. Delucchi has nothing to disclose.
Conflict of interest: Dr. Weiss has nothing to disclose.
Conflict of interest: Outside the submitted work, Dr. McAuley reports personal fees from consultancy for GlaxoSmithKline, Boehringer Ingelheim and Bayer. In addition his institution has received funds from grants from the UK NIHR, Wellcome Trust and others. In addition, Dr. McAuley has a patent issued to his institution for a treatment for ARDS. DFM is a Director of Research for the Intensive Care Society and NIHR EME Programme Director.
Conflict of interest: Dr. O'Kane reports Bayer, grants from Wellcome Trust,, MRC and NI HSC R&D, and that spouse has received consultancy fees from GlaxoSmithKline, Boehringer Ingelheim and Bayer, outside the submitted work;.
Conflict of interest: Dr. Krasnodembskaya reports grants from Medical Research Council, UK, during the conduct of the study;.
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- ReceivedAugust 3, 2020.
- AcceptedDecember 2, 2020.
- Copyright ©ERS 2020