Abstract
BackgroundThe acute respiratory distress syndrome (ARDS) is characterized by disruption of the alveolar-capillary barrier resulting in accumulation of proteinaceous edema and increased inflammatory cells in the alveolar space. We previously found that endothelial progenitor cell (EPC) exosomes prevent endothelial dysfunction and lung injury in sepsis in part due to their encapsulation of miRNA-126. However, the effects of EPC exosomes in acute lung injury (ALI) remain unknown.MethodsTo determine if EPC exosomes would have beneficial effects in ALI, intratracheal administration of lipopolysaccharide (LPS) was used to induce ALI in mice. Lung permeability, inflammation, and the role of miRNA-126 in the alveolar-epithelial barrier function were examined.ResultsThe intratracheal administration of EPC exosomes reduced lung injury following LPS-induced ALI at 24 and 48 h. Compared to placebo, intratracheal administration of EPC exosomes significantly reduced the cell number, protein concentration, and cytokines/chemokines in the bronchoalveolar lavage fluid (BALF), indicating a reduction in permeability and inflammation. Further, EPC exosomes reduced myeloperoxidase (MPO) activity, lung injury score, and pulmonary edema, demonstrating protection against lung injury. Murine fibroblast (NIH3T3) exosomes, which do not contain abundant miRNA-126, did not provide these beneficial effects. In human small airway epithelial cells (SAECs), we found that overexpression of miRNA-126-3p can target phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2), while overexpression of miRNA-126-5p inhibits the inflammatory alarmin HMGB1 and permeability factor VEGFα. Interestingly, both miR-126-3p and 5p increase the expression of tight junction proteins suggesting a potential mechanism by which miRNA-126 may mitigate LPS-induced lung injury.ConclusionsOur data demonstrated that human EPC exosomes are beneficial in LPS-induced ALI mice, in part through the delivery of miRNA-126 into the injured alveolus.
Highlights
The acute respiratory distress syndrome (ARDS) is characterized by disruption of the alveolar-capillary barrier resulting in accumulation of proteinaceous edema and increased inflammatory cells in the alveolar space
Using a combination of the murine intratracheal lipopolysaccharide (LPS)induced acute lung injury (ALI) model, in vitro transfection assays, and next-generation sequencing, we demonstrated that miR126-containing endothelial progenitor cell (EPC) exosomes decrease the severity of ALI whereas NIH3T3 exosomes with barely detectable levels of miR-126 do not
EPC exosomes decreased cell counts, protein concentration, and cytokines/chemokines of bronchoalveolar lavage fluid (BALF) in LPSinduced acute lung injury Increased BALF cell number and protein concentration are representative of augmented endothelial and epithelial permeability
Summary
The acute respiratory distress syndrome (ARDS) is characterized by disruption of the alveolar-capillary barrier resulting in accumulation of proteinaceous edema and increased inflammatory cells in the alveolar space. The acute lung injury (ALI) associated with ARDS is characterized by damage and disruption of the epithelial and endothelial layers at the alveolar-capillary barrier and recruitment of inflammatory cells into the alveolar space. The integrity of these layers is, in part, governed by tight junction proteins including claudins and occludins [5] while the activation of endothelial cells and recruitment of inflammatory cells are governed by inflammatory cytokines and chemokines [6]. Therapies which enhance claudin and occludin stability or mitigate local inflammatory cytokine release could reduce the severity of lung injury and improve the patient outcomes
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