TABLE 2.
Contribution of EVs to the pathogenesis of ARDS.
| In vitro models | |||
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| Source (Cell/Fluid/Tissue) | EV type | Effects | References |
| Macrophages | MVs and apoptotic bodies | Monocyte differentiation into macrophages (EV cargo: miR-223) and epithelial cell growth promotion (EV cargo: mir-221 and miR-222). | Ismail et al., 2013; Zhu et al., 2017 |
| EVs | Endothelial inflammation (via NFκB activation), endothelial barrier disruption (via VCAM-1, ICAM-1 and E-selectin upregulation), exacerbation of endothelial thrombogenicity (via TF EV-mediated transfer), and endothelial apoptosis (via p20 EV-mediated transfer). | Aharon et al., 2008; Wang et al., 2011; Mitra et al., 2015 | |
| Endothelial cells | EVs | Monocyte adhesion and recruitment via upregulating IL-6, IL-8, CXCL-1, MCP-1, CCL4, and CCL5 (EV cargo: CXCL-10 and CCL-5). | Hosseinkhani et al., 2018 |
| MVs | Upregulation of ICAM-1 expression mediated by activation of EGFR and PARP-1. Caveolae-dependent mechanism. | Andrews and Rizzo, 2016 | |
| Neutrophils | MVs | Antimicrobial effect (EV cargo: CR1, MPO and elastase). | Hess et al., 1999 |
| EVs | Anti-inflammatory effects (via decreasing IL-6, IL-8, IL-10, IL-1β, TNF-α, and CXCL-1, and TGF-β enhancement) and reduction of alveolar permeability (via PAR-1 inhibition) (EV cargo: miR-223, miR-126, miR-150, miR-451a). | Gasser and Schifferli, 2004; Eken et al., 2010, 2013; Neudecker et al., 2017; Youn et al., 2021 | |
| EVs | Macrophage inflammation (EV cargo: miR-1260, miR-1285, miR-4454, miR-7975). | Youn et al., 2021 | |
| EVs | Endothelial cell activation via increasing TF, ICAM-1, MCP-1, IL-6, and IL-8 production. | Mesri and Altieri, 1998, 1999 | |
| EVs | Oxidative stress induction on endothelial cells (via MPO EV-mediated transfer) and platelets (via arachidonic acid EV-mediated transfer). | Pitanga et al., 2014 | |
| EVs | Vascular permeability increase (EV cargo: cathepsin, S100A-8, S100A-9). | Dalli et al., 2013 | |
| Exosomes | ECM degradation (via elastase EV-mediated transfer). | Mammoto et al., 2013; Genschmer et al., 2019 | |
| Platelets | EVs | Monocyte activation and recruitment (via increasing CD11b, LFA-1 and Mac-1), and oxidative stress induction on monocytes and endothelial cells (via arachidonic acid EV-mediated transfer). | Barry et al., 1997; Nomura et al., 2001 |
| EVs | Vascular permeability via inflammasome activation (EV cargo: IL-1β) and increased endothelial adhesiveness via ICAM-1 upregulation (EV cargo: miR-320b and CCL5). | Nomura et al., 2001; Mause et al., 2005; Gidlof et al., 2013; Hottz et al., 2013 | |
| EVs | Endothelial cell apoptosis via repressing BCL2L1 and BCLAF1 genes (EV cargo: miR-142-3p). | Bao et al., 2017 | |
| E. coli induced-ALI in ex vivo human lungs | Lung perfusate EVs | Pulmonary edema, impaired of fluid clearance, neutrophilic infiltration, and elevated concentrations of TNF-α in BALF. | Liu et al., 2019 |
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| In vivo models | |||
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| Model | EV type and source | Effects | References |
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| LPS-induced ALI in mice | BALF-derived | Inflammasome activation and induction of IL-1β production in macrophages (EV cargo: miR-466g, miR-466m-5p, miR-155, and miR-146a). | Shikano et al., 2019 |
| Inflammation and ECM degradation via induction of MMP1 and IL-6 production (EV cargo: CCN1). | Shi et al., 2018 | ||
| Macrophage derived-EVs, mainly produced by infectious stimuli, induced inflammation in macrophages via TLR6. | Lee et al., 2018b | ||
| BALF-derived exosomes | Inflammation induction and alteration of TJs in alveolar epithelial cells (EV cargo: miR-155 and miR-146a). | Yuan et al., 2018 | |
| ICAM-1, IL-8 and MCP1 upregulation in alveolar epithelial cells (EV cargo: TNF-α, IL-1β, and IL-6). | Soni et al., 2016; Zhang D. et al., 2019 | ||
| Endothelial cell-derived MVs | Neutrophil recruitment and increases in IL-1β and MPO in BALF. | Buesing et al., 2011; Li et al., 2015 | |
| Impairment in vasodilatation via eNOS activation and reducing levels of NO. | Densmore et al., 2006 | ||
| ALI induced by sterile stimuli (oxidative stress, acid aspiration or mechanical ventilation) in rodents | BALF-derived EVs | Epithelium derived-EVs, mainly produced by sterile stimuli, induced inflammation in macrophages via TLR2 activation. | Lee et al., 2018b |
| BALF-derived MVs | Macrophage activation via MMP9, and TNF-α production and NFκB activation in macrophages (EV cargo: miR-320a, miR-22, miR-342), and macrophage migration through integrin β1 expression (EV cargo: miR-17 and mir-221). | Lee et al., 2017 | |
| Epithelial cell-derived EVs Endothelial cell-derived MVs | Macrophage inflammation via induction of IL-6, TNF-α, and MIP-2 production (EV cargo: caspase-3). | Moon et al., 2015 | |
| Increased levels associated with pulmonary edema, inflammatory infiltrates, deterioration of gas exchange following ventilator-induced lung injury. | Cabrera-Benitez et al., 2015; Pan et al., 2017 | ||
| Sepsis-induced ALI in mice | Alveolar epithelial cell-derived exosomes | Macrophage activation via NFκB (EV cargo: miR-92a-3p). | Liu et al., 2021 |
| Endothelial cell-derived MVs | Endothelial permeability (via MLC and VE-cadherin phosphorylation) and neutrophil activation (via CD11b overexpression) and NETs formation (EV cargo: c-Src kinase). | Chatterjee et al., 2020a | |
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| Clinical studies | |||
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| ARDS patients | BALF-derived EVs | Inflammation and ECM degradation via induction of MMP1 and IL-6 production (EV cargo: CCN1). | Shi et al., 2018; Morrell et al., 2020 |
| BALF-derived exosomes | Hydrolysis of lung surfactant phospholipids and inflammation induction (EV cargo: sPLA2). | Papadopoulos et al., 2020 | |
| Cystic fibrotic patients | BALF-derived EVs | Neutrophil chemotaxis and recruitment into alveolar space (EV cargo: S100A). | Useckaite et al., 2020 |
Summary of the effects induced by EVs in experimental models of ALI. The type of EV described in each study is specified in the second column and is included only for comparison purposes. Please, note that current methods are unable to separate these vesicles efficiently.
ALI, acute lung injury; Ang-1, angiopoetin-1; ARDS, acute respiratory distress syndrome; BALF, bronchoalveolar lavage fluid; BCL2L1, B-cell lymphoma 2-like protein 1; BCLAF1, B-cell lymphoma 2-associated transcription factor 1; CCL, chemokine (C-C motif) ligand; CCN1, cellular communication network factor 1; CD, cluster of differentiation; c-Src, cellular Src; CXCL, chemokine (C-X-C motif) ligand; ECM, extracellular matrix; eNOS, endothelial nitric oxide synthase; EV, extracellular vesicles; HGF, hepatocyte growth factor; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; LFA-1, lymphocyte function-associated antigen 1; LPS, lipopolysaccharide; Mac-1, macrophage-1 antigen or macrophage integrin; MCP-1, monocyte chemotactic protein 1; MIP-2, macrophage inflammatory protein 2; MLC, myosin light chain; MMP, matrix metalloprotease; MPO, myeloperoxidase; NETs, neutrophil extracellular traps; NFκB, nuclear factor kappa B; NO, nitric oxide; MCP-1, monocyte chemotactic protein 1; PAR-1, protease-activated receptor 1; sPLA2, secretory phospholipase A2; TGF-β, transforming growth factor β; TF, tissue factor; TJs, tight junctions; TLR, toll-like receptor; TNF-α, tumor necrosis factor α; VCAM-1, vascular cell adhesion molecule 1; VE-cadherin, vascular endothelial-cadherin.