Advances in the use of exosomes for the treatment of ALI/ARDS

Abstract

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a critical clinical syndrome with high morbidity and mortality. Currently, the primary treatment for ALI/ARDS is mainly symptomatic therapy such as mechanical ventilation and fluid management. Due to the lack of effective treatment strategies, most ALI/ARDS patients face a poor prognosis. The discovery of exosomes has created a promising prospect for the treatment of ALI/ARDS. Exosomes can exert anti-inflammatory effects, inhibit apoptosis, and promote cell regeneration. The microRNA contained in exosomes can participate in intercellular communication and play an immunomodulatory role in ALI/ARDS disease models. This review discusses the possible mechanisms of exosomes in ALI/ARDS to facilitate the development of innovative treatments for ALI/ARDS.

Keywords: acute lung injury; acute respiratory distress syndrome; exosomes; inflammation; treatment.

Figure 1

The source, formation process and surface markers of exosomes and the way of entering cells. Exosomes are derived from a variety of body fluids, such as saliva, breast milk, bronchoalveolar lavage fluid, urine, sweat, blood and plasma. CD9, CD63, CD81, TSG101, Alix and HSP70 are the most common exosome surface-specific protein markers. Early endosomes germinate to form multivesicular bodies containing multiple luminal vesicles, the binding of multivesicular bodies to lysosomes results in material degradation. In contrast, fusion with the cytoplasmic membrane leads to the release of intraluminal vesicles outside the cell. These intraluminal vesicles are called exosomes. Exosomes can directly fuse with the cell membrane of target cells, or uptaken by target cells through endocytosis. In addition, exosomes can also bind to specific receptors on the surface of target cells.

Figure 2

Biological effects of exosomes. The biological effects of exosomes include anti-inflammatory, anti-apoptotic and cell regeneration promoting effects. The anti-inflammatory effect of exosomes is reflected in the inhibition of the secretion of inflammatory cytokines such as TNF-α, IL-1β, IL-6, and MMP-9 and increased secretion of anti-inflammatory cytokines such as IL-10. In addition, exosomes can upregulate the expression of M2 macrophage markers such as CD206 and Arg-1, and then promote enhanced secretion of IL-10 and TSG-6 by macrophages. Moreover, MSCs-derived exosomes can inhibit the differentiation of T cells to Th17 cells and increase the level of Treg cells. They can also reduce neutrophil aggregation. Besides, exosomes can improve apoptosis of alveolar endothelial cells by inhibiting the expression of caspase-3, 8 and 9. MSCs-derived exosomes can also inhibit apoptosis of alveolar epithelial cells by inhibiting mitochondrial DNA damage and the activation of NLRP3 inflammasome, or by upregulating SIRT1 expression. Lastly, The pro-regenerative effects of exosomes were demonstrated promoting endogenous angiogenesis; promoting bone regeneration through activation of AKT/mTOR pathway and promoting fracture healing through HIF-1α-mediated angiogenesis. In addition, exosomes promoted hepatocyte proliferation, lung endothelial cell proliferation and alveolar epithelial cell barrier repair as well as the survival and proliferation of ATII cells and facilitate the re-epithelialization of damaged alveolar epithelial cells. These are the effects exosomes play in the in vitro and in vivo models.

Figure 3

Mechanisms by which exosomes attenuate ALI/ARDS and thus exert pulmonary protective effects. The potential therapeutic mechanisms of exosomes in the treatment of ALI/ARDS include transferring miRNA, participating in signal pathway transduction, and regulating mitochondrial function.