Alveolar macrophage-derived microvesicles mediate acute lung injury

Abstract

BackgroundMicrovesicles (MVs) are important mediators of intercellular communication, packaging a variety of molecular cargo. They have been implicated in the pathophysiology of various inflammatory diseases; yet, their role in acute lung injury (ALI) remains unknown.ObjectivesWe aimed to identify the biological activity and functional role of intra-alveolar MVs in ALI.MethodsLipopolysaccharide (LPS) was instilled intratracheally into C57BL/6 mice, and MV populations in bronchoalveolar lavage fluid (BALF) were evaluated. BALF MVs were isolated 1 hour post LPS, assessed for cytokine content and incubated with murine lung epithelial (MLE-12) cells. In separate experiments, primary alveolar macrophage-derived MVs were incubated with MLE-12 cells or instilled intratracheally into mice.ResultsAlveolar macrophages and epithelial cells rapidly released MVs into the alveoli following LPS. At 1 hour, the dominant population was alveolar macrophage-derived, and these MVs carried substantive amounts of tumour necrosis factor (TNF) but minimal amounts of IL-1β/IL-6. Incubation of these mixed MVs with MLE-12 cells induced epithelial intercellular adhesion molecule-1 (ICAM-1) expression and keratinocyte-derived cytokine release compared with MVs from untreated mice (p<0.001). MVs released in vitro from LPS-primed alveolar macrophages caused similar increases in MLE-12 ICAM-1 expression, which was mediated by TNF. When instilled intratracheally into mice, these MVs induced increases in BALF neutrophils, protein and epithelial cell ICAM-1 expression (p<0.05).ConclusionsWe demonstrate, for the first time, the sequential production of MVs from different intra-alveolar precursor cells during the early phase of ALI. Our findings suggest that alveolar macrophage-derived MVs, which carry biologically active TNF, may play an important role in initiating ALI.

Lung Epithelial Cell–Derived Microvesicles Regulate Macrophage Migration via MicroRNA-17/221–Induced Integrin β1 Recycling

“…Whereas the release of MVs is continuous, and stimulated by a variety of cell stressor, ABs are only generated as a result of cell death. In contrast MVs and Exos are continuously released by live cells (7, 8) in either the absence or presence of noxious stimuli (9, 10). Recent studies have shown that both proteins and nucleic acids are differentially sorted into the three types of EVs reflecting their functional diversity (3, 9).…”

“…Accumulating evidence further suggest that in addition to EV surface antigens, EV can shuttle microRNAs (miRNAs) that may play an essential role in mediating intercellular communication (11–13). It is now generally accepted that single miRNAs have diverse targets and can up- or down-regulate hundreds of genes (14), MVs and Exos therefore act in part as messengers in the coordination of innate immune responses to noxious stimuli (7, 9, 10). …”

“…Common features of ALI/ARDS include an intense inflammatory response in the lung parenchyma, severe injury to the epithelial and endothelial cell barriers leading to alveolar edema, decreased lung compliance, impaired gas exchange and hypoxemia (17, 18). This can occur in the presence of a broad range of agents including oxidative stress, acid aspiration and infection (7, 10). The alveolar epithelium functions as a first-line defense against noxious insults and as such is critical in maintaining the integrity and function of the lung during development of ALI (17–20).…”

Extracellular Vesicles in ARDS: New Insights into Pathogenesis with Novel Clinical Applications

“…Different alveolar cell types release extracellular vesicles in sequential order following murine intratracheal LPS lung injury [14]. Alveolar macrophage-derived extracellular vesicles are rapidly released first, followed by endothelial extracellular vesicles and then neutrophil extracellular vesicles.…”

Macrophage-derived microvesicles’ pathogenic role in acute lung injury

“…When instilled intratracheally in naive mice, MVs isolated from macrophages primed with LPS induced ALI with an increase in influx of neutrophils and cytokines/chemokines (eg, KC), in lung protein permeability and in the expression of ICAM-1 on alveolar epithelial type I and II cells ( Figure 8). 7 There are several important findings in the manuscript by Soni et al 7 with clinical relevance. First, the clear demonstration that MVs released into the injured alveolus early in ALI were biologically active, with the capability to induce an inflammatory response.…”