Abstract
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common critical diseases. Bone marrow mesenchymal stem cell (BMSC) transplantation is previously shown to effectively rescue injured lung tissues. The therapeutic mechanism of BMSC-derived exosomes is not fully understood. Here, we investigated the BMSC-derived exosomal microRNAs (miRNAs) on effecting lipopolysaccharide- (LPS-) induced ALI and its mechanism. In vitro, rat alveolar macrophages were treated with or without exosomes in the presence of 10 μg/ml LPS for 24 h. Cell viability was determined with Cell Counting Kit-8 assay. Apoptotic ratio was determined with TUNEL and Annexin V-FITC/PI double staining. The levels of miR-384-5p and autophagy-associated genes were measured by RT-qPCR and western blot. Autophagy was observed by TEM and assessed by means of the mRFP-GFP-LC3 adenovirus transfection assay. In vivo, we constructed LPS-induced ALI rat models. Exosomes were injected into rats via the caudal vein or trachea 4 h later after LPS treatment. The lung histological pathology was determined by H&E staining. Pulmonary vascular permeability was assessed by wet-to-dry weight ratio and Evans blue dye leakage assay, and inflammatory cytokines in serum and BALF were measured by ELISA. Furthermore, the therapeutic mechanism involved in miR-384-5p and Beclin-1 was determined. The results showed that BMSC-derived exosomes were taken up by the alveolar macrophages and attenuated LPS-induced alveolar macrophage viability loss and apoptosis. Exosomes effectively improved the survival rate of ALI rats within 7 days, which was associated with alleviating lung pathological changes and pulmonary vascular permeability and attenuating inflammatory response. Furthermore, this study for the first time found that miR-384-5p was enriched in BMSC-derived exosomes, and exosomal miR-384-5p resulted in relieving LPS-injured autophagy disorder in alveolar macrophages by targeting Beclin-1. Therefore, exosomal miR-384-5p could be demonstrated as a promising therapeutic strategy for ALI/ARDS.
Highlights
Acute lung injury (ALI) is a common critical disease that may develop into highly lethal acute respiratory distress syndrome (ARDS), with progressive respiratory failure and intractable hypoxemia as clinical characteristics [1]
Our findings indicated that Bone marrow mesenchymal stem cell (BMSC) secreted exosomes to transfer miR-384-5p into alveolar macrophages, which further protected against ALI by alleviating autophagy stress of alveolar macrophages via downregulation of Beclin-1
Fluorescenceactivated cell sorting (FACS) analysis illustrated that BMSCs expressed high levels of CD29, CD44, CD90, and CD105 (Figures 1(a)–1(d)) but were negative for CD11b/c, CD34, and CD45 (Figures 1(e)–1(g))
Summary
Acute lung injury (ALI) is a common critical disease that may develop into highly lethal acute respiratory distress syndrome (ARDS), with progressive respiratory failure and intractable hypoxemia as clinical characteristics [1]. The cellular pathology of ALI mainly involves the destruction of alveolar-capillary membrane barrier, a mass of neutrophil migration, and imbalances of proinflammatory and antiinflammatory cytokines in the lungs [2, 3]. Alveolar macrophages are described as a major component of airspace leukocytes and critically influence the development of ALI following infection and noninfectious stimuli [4]. Current clinical therapy for ALI includes pathogenesis removal, inflammation regulation, lung-protective ventilation, and organ supportive treatment as soon as possible to prevent the lung tissue injury [5, 6]. Searching for new and effective methods for the treatment of ALI/ARDS has become an urgent subject to be studied
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