Table 3.

Summary of studies on the mechanism of EVs derived from other cell types in COPD

Mechanism—other cell types
Author, year [Ref.]	Title	Aim	Type	Conclusion
Benedikter et al., 2017 [25]	Cigarette smoke extract induced exosome release is mediated by depletion of exofacial thiols and can be inhibited by thiol-antioxidant	Investigate whether oxidative components of CSE are responsible for EV release and whether this could be prevented using the thiol antioxidants N-acetyl-l-cysteine (NAC) or glutathione (GSH)	In vitro	CSE exposure enhances the exosome release by airway epithelial cells (AEC) and this is mediated by thiol-reactive compounds like carbonyl acrolein, which may act by depleting extracellular free thiols
Moon et al., 2014 [26]	CCN1 secretion and cleavage regulate the lung epithelial cell functions after cigarette smoke	Investigate whether CCN1 is a potentially crucial factor for the pathogenesis of CS-induced emphysema	In vitro In vivo Mice	CS enhanced the release of exosomes containing full-length CCN1 (flCCN1) from lung epithelial cells. Exosome-mediated secretion of flCCN1 triggers inflammatory responses by mediating IL-8 release to distant portions of the lungs and subsequent neutrophil recruitment. Additionally, cleaved CCN1 (cCCN1) were generated from exosome-enriched CCN1 via secreted plasmin and promoted emphysematous changes
Genschmer et al., 2019 [27]	Activated PMN exosomes: pathogenic entities causing matrix destruction and disease in the lung	Investigate whether neutrophil elastase (NE) exists in exosomal form and whether such exosomes might bypass a1AT and contribute to inflammatory lung disease	In vitro Ex vivo human In vivo Mice	NE exists in an active, substrate-accessible form when associated with exosomes from activated PMN (polymorphonuclear leukocytes, i.e. neutrophils) and is resistant to a1AT. Activated PMN exosomes bind ECM via MAC-1 and degrade ECM via NE. CD66b+/NE+ PMN exosomes cause emphysema when administered to mice and when residing in COPD patients
Feller et al., 2018 [28]	Cigarette smoke-induced pulmonary inflammation becomes systemic by circulating extracellular vesicles containing Wnt5a and inflammatory cytokines	Demonstrate a potential mechanism for the systemic nature of COPD	In vitro Ex vivo human In vivo Mice	CS triggers release of EVs carrying pro-inflammatory cytokines and inflammation inducer Wnt5a, in turn triggering systemic inflammation and thus making COPD a complex disease that is hard to control
Qiu et al., 2020 [29]	Increased airway T lymphocyte microparticles in chronic obstructive pulmonary disease induces airway epithelial injury	Examine T lymphocyte microparticles (TLMP) subpopulations in BALF of patients with COPD and and explore the effects of MPs derived from different T cell subpopulations on airway epithelium	Ex vivo Human	The numbers of MPs derived from T lymphocytes in BALF were significantly upregulated in COPD patients compared with healthy volunteers. Isolated CD4+ and CD8+ TLMPs reduced cell viability and induced significant production of inflammatory cytokines including IL-6, MCP-1, MCP-2, MMP-9 and TNF-α in HBEs, while the levels of anti-inflammatory cytokine IL-10 were decreased. TLMPs in the airways may lead to airway epithelial injury and inflammation and serve essential roles in the pathophysiology of COPD
Zou et al., 2021 [30]	Release and actions of inflammatory exosomes in pulmonary emphysema: potential therapeutic target of acupuncture	Investigate if exosome-mediated release of NLRP3 inflammasome products instigates the inflammatory response in the lung during emphysema	In vivo Mice	NLRP3 inflammasome activation and associated inflammatory exosome release are critically implicated in the development of inflammation during PPE-induced emphysema
Wang et al., 2021 [31]	Cigarette smoke extract-treated airway epithelial cells-derived exosomes promote M1 macrophage polarization in chronic obstructive pulmonary disease	Investigate whether the exosomes derived from CSE-treated AECs regulate macrophage polarization and subsequently affect the progression of COPD by modulating TREM-1 expression	In vitro	Exosomes derived from CSE-treated AECs aggravate CS-induced lung inflammation and tissue injury in mice, which is associated with the promotion of M1 macrophage polarization by these exosomes through upregulation of TREM-1 expression
Song et al., 2021 [32]	Exosomal lncRNA TCONS_00064356 derived from injured alveolar epithelial type II cells affects the biological characteristics of mesenchymal stem cells	Investigate whether injured alveolar cells communicate with MSCs via secretion of exosomes and investigate the role of exosomal lncRNAs derived from injured alveolar cells to identify novel therapeutic targets for COPD	In vitro	Injured AEC-II cells can affect the biological characteristics of MSCs via secretion of exosomes and the dysregulated exosomal lncRNAs that may be involved in this process were screened out
Xia et al., 2022 [33]	The aberrant cross-talk of epithelium-macrophages via METTL3-regulated extracellular vesicle miR-93 in smoking-induced emphysema	Assess the role of EV miR-93 in bronchial epithelium exposed to cigarette smoke and the cross-talk between these cells and macrophages in smoking-induced emphysema	In vitro	CS exposure induces elevation of METTL3-promoted miR-93 maturation, and miR-93 is transferred from bronchial epithelial cells into macrophages by EVs. In macrophages, miR-93 activates the JNK pathway by targeting DUSP2, which increases the levels of MMP9 and MMP12, inducing elastin degradation. Therefore, CS induces emphysema by a mechanism in which METTL3-mediated EV miR-93 via m6A is involved in aberrant cross-talk of lung epithelial cells and macrophages
Margaroli et al., 2022 [34]	A novel in vivo model for extracellular vesicle-induced emphysema	Develop a mouse-to-mouse EV-transfer model to expand on neutrophil-derived EVs and further explore discrete disease-related mechanisms	In vivo Mice	This study highlights a rapid, novel neutrophil driven mechanism of emphysema mediated by mouse neutrophil derived EV-bound NE. EVs from in vivo LPS activated mouse neutrophils induced COPD-like disease in naive recipients through an alpha-1 antitrypsin resistant, NE-dependent mechanism
Nieri et al., 2021 [23]	Circulating extracellular vesicles are associated with disease severity and interleukin-6 levels in COPD: a Pilot study	Analyse endothelial-(E) and monocyte-derived (M) EV levels in COPD patients grouped according to the 2011 GOLD classification and analyse the relationship between EV and plasmatic markers of inflammation	Ex vivo Human	Circulating endothelial- and monocyte-derived extracellular vesicles increase along with COPD severity. The relationship among EEV and IL-6 suggests a biological link between inflammation and endothelial activation/damage