Dual role and clinical application of extracellular vesicles in acute respiratory distress syndrome: Mechanism analysis and translational challenges

Table 1 Pro-inflammatory and anti-inflammatory mechanisms

	EVs type	Core molecule	Action mechanism	Clinical/experimental evidence	Ref.
Pro-inflammatory EVs	AT1-EVs	MiR155	Inhibiting SOCS1 in ALI and enhancing inflammatory response	AMO155c/CMNV and AMO155c/EV reduced miR155 Levels	[16]
		MiR-320a, miR-221	Hyperoxia-induced pulmonary epithelial MV	Promote macrophage activation	[18]
	Neutrophil-EVs	MiR-30d-5p	Enhanced NF-κB signaling induced polarization and pyrodeath of M1 macrophages	Decreased TNF-Exo or cecal ligation and puncture-induced M1 macrophage activation and macrophage death in the lung	[20]
	Bacteria-OMVs	LPS, flagellin	TLR2/4 double receptors activate alveolar macrophages	IL-1β, TNF-α, IL-6, and IFN-γ were elevated	[26]
		Tight junction protein ZO-1	Autophagosome degradation of OCLN was induced	TEER decreased, alveolar epithelial barrier dysfunction	[27]
	Virus-EVs	SARS-CoV-2, virus-RNA	Mediates bystander infection and down-regulates ACE2	Plasma spike + EVs was positively correlated with D-dimer	[36]
Anti-inflammatory EVs	MSC-EVs	Ang-1 mRNA, miR-146a	Inhibits NF-κB pathway, promotes M2 polarization and mitochondrial repair	Enhanced tissue recovery of damaged organs	[38,39]
	EC-EVs	MiR-223/RGS-1	Up-regulated STAT6 phosphorylation inhibited neutrophil migration	The plasma miR-223 Level was positively correlated with the proportion of CD45+ M2 macrophages	[42]
	Apoptosome	PS, IL-10	The MerTK/Rac1 pathway was activated to induce the amplification of Tregs	Decreased alveolar inflammatory factors	[44,45]

EVs: Extracellular vesicles; AT1: Alveolar type 1; SOCS1: Suppressing cytokine signaling suppressor 1; ALI: Acute lung injury; MV: Membrane vesicle; NF-κB: Nuclear factor-kappa B; TNF-Exo: Tumor necrosis factor-exosomes; OMVs: Outer membrane vesicles; LPS: Lipopolysaccharide; TLR2/4: Toll-like receptor 2/4; IL: Interleukin; TNF: Tumor necrosis factor; IFN: Interferon; ZO-1: Zonula occludens-1; OCLN: Occludin; TEER: Transendothelial electrical resistance; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; ACE2: Angiotensin-converting enzyme 2; MSC-EVs: Mesenchymal stem cell-derived extracellular vesicles; EC-EVs: Endothelial cell-derived extracellular vesicles; RGS-1: Regulator of G-protein signaling 1; STAT6: Signal transducer and activator of transcription 6; PS: Phosphatidylserine; MerTK: Macrophage c-mer tyrosine kinase; Treg: Regulatory T cells.