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Extracellular Vesicles and Lung Diseases
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This entry is adapted from the peer-reviewed paper 10.3390/ijms24010228

Although cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) stem from a different origin, one genetic and the other acquired, they share a similar pathophysiology, being the CF transmembrane conductance regulator (CFTR) protein implied in both disorders. Various subsets of EVs, comprised mainly of microvesicles (MVs) and exosomes (EXOs), are secreted by various cell types that are either resident or attracted in the airways during the onset and progression of CF and COPD lung disease, representing a vehicle for metabolites, proteins and RNAs (especially microRNAs), that in turn lead to events as such neutrophil influx, the overwhelming of proteases (elastase, metalloproteases), oxidative stress, myofibroblast activation and collagen deposition.

extracellular vesicles apoptotic bodies microvesicles exosomes

1. Biogenesis of EVs

Most prokaryotes and eukaryotic cells release extracellular vesicles (EVs) into the extracellular environment [1][2][3]. EVs consist of a phospholipid bilayer and have a role in cell-to-cell communication and disease pathogenesis [4][5]. As reported in the Minimal Information for Studies of Extracellular Vesicles (MISEV) guidelines, published by the International Society for Extracellular Vesicles (ISEV), depending on their size, density, composition (surface markers), biogenesis and secretory mechanisms [6], EVs can be distinguished into (1) apoptotic bodies, (2) microvesicles and (3) exosomes. Among these three structures, the apoptotic bodies are those with the largest size, in a range between 1000 and 5000 nm. Apoptotic bodies (ABs) derive from the fragmentation of the cell in the process of apoptosis and are released by budding from the plasma membrane. Apoptosis-derived EVs (ApoBDs) may contain cellular organelles, membranes, and cytosolic contents, but also noncoding RNAs and DNA fragments [5]. The density of ApoBDs is in the range between 1.18 and 1.28 g/mL [7]. Microvesicles (MVs), also known as microparticles (MPs) or ectosomes, are smaller than apoptotic bodies, ranging from 150–1000 nm. MVs originate from the outward budding of the plasma membrane and are subsequently released extracellularly [8]. These EVs are enriched with lipids, particularly phosphatidylserine (PS) [9][10]. The sucrose gradient density of MVs, lower than ApoBDs, is between 1.25 and 1.30 g/mL [11][12][13]. Exosomes (EXOs) are characterized by a double phospholipid layer and a diameter between 30 and 150 nm. The biogenesis of exosomes is a complex process that depends on mother-cell-stimulating signals [14] and begins with the formation of early endosomes [15][16][17]. The early sorting endosomes become late sorting endosomes [18] with the formation of intraluminal vesicles (ILVs) within the lumen of the endosome. Multivesicular bodies (MVBs) are formed thanks to ILVs which, during their development, randomly incorporate portions of the cytosol, as well as transmembrane and peripheral proteins, into the invaginating membrane [13]. Some MVBs are degraded in lysosomes by the endosomal sorting complex required for transports (ESCRTs)-dependent mechanism, while a good portion of these MVBs fuses with the plasma membrane and secretes exosomes via exocytosis into the extracellular space, using RAB GTPases (ESCRT-independent mechanism) [19][20].

The ESCRT mechanism, which is composed of the various ESCRT complexes (ESCRT-0, -I, -II, -III) and some proteins such as vacuolar protein sorting-associated protein 4 (Vps4), apoptosis-linked gene 2-interacting protein X (ALIX) and tumor susceptibility gene 101 protein (TSG101) [16][21], takes part in the process of the biogenesis/degradation of MVBs in a ubiquitination-dependent manner [22]. The ESCRT-0 complex is recruited to the endosomal membrane, while ESCRT-I and -II are required to cause the deformation of the membrane, allowing the sorting of cargo molecules in the MVBs. Subsequently, the ESCRT-III/Vps4 complex regulates the concentration of the components of the MVBs’ cargo and separates the vesicles from the plasma membrane [23][24].
Although the three main classes of EVs have been identified, as previously mentioned, as EXOs, MVs and ApoBDs, the issue of EV diversity has not been completely elucidated and is the subject of intense investigation by ISEV and independent researchers. Currently, it can be said that cells release a spectrum of heterogeneous populations of EVs with overlapping sizes [25]. Simply, it has been observed that EV subtypes can be differentiated according to: (1) physical characteristics, such as size or density; (2) biochemical composition; and (3) descriptions of conditions or cell of origin [26][27]. In terms of size, the researchers can define small EVs (S-EVs) as being <200 nm in diameter and large and/or medium EVs (m/l-EVs or L-EVs) as over 200 nm [6]. As for the molecular content, these EVs differ since L-EVs have more DNA, CD9, and Annexin A1, while S-EVs carry CD63 and CD81 [26]. Moreover, it has been proposed that, concerning miRNAs, there exist different EV subpopulations with unique characteristics and miRNA contents [25]. Finally, other EV subpopulations, called large oncosomes and originating directly from the plasma membrane, are released specifically by cancer cells, and they are larger than any other EV, i.e., between 1 and 10 μm [28].
Besides the inherent heterogeneity of EVs, complexity also concerns EXOs, which can include different subpopulations based on their size, content (cargo), functional impact on recipient cells, and cell of origin [29]. Three types of EXOs have been identified according to their size (40–75 nm, 75–100 nm, or 100–160 nm), their biomarker (tetraspanins CD63, CD9, or CD81) and their functional heterogeneity. In this last case, one EXO subtype can induce cell survival, while another set induces apoptosis, and a different set induces immunomodulation, etc., in different target cell types [29][30]. To illustrate this complex diversity, Zhang et al. [31], by using asymmetric flow field-flow fractionation, identified two exosome subpopulations (large exosome vesicles, Exo-L, 90–120 nm; small exosome vesicles, Exo-S, 60–80 nm) and discovered an abundant population of nonmembranous nanoparticles termed “exomeres” (~35 nm), and each of these subpopulations were associated with specific phenotypes and cargoes. The heterogeneity in terms of both the size and composition of EXOs is not surprising given the different protein complexes involved in ESCRT machinery and the existence of the ESCRT-independent pathway of EXO biogenesis.
The assessment of EV heterogeneity is the focus of several methods that capture EV populations and subpopulations, including ultrafiltration, differential ultracentrifugation, gradient ultracentrifugation, precipitation, size-exclusion chromatography, immune-affinity capture, mass spectrometric immunoassay, etc. [6][25][32][33][34]. An initial characterization of EV subpopulations, obtained after isolation, can be performed morphologically by scanning electron microscopy (SEM) [35], transmission electron microscopy (TEM) [36][37][38] or atomic force microscopy (AFM) [3][6][32][34].

2. EVs’ Cargo

The Bradford or micro-bicinchoninic acid (BCA) protein assay is used to quantify the vesicular proteins that are subsequently separated and specifically detected by Western blot analysis using different monoclonal antibodies, i.e., CD9, CD63, CD81, Hsp70 [35], MHC II, CD40, CD80, CD86, and CD54 [3][6][32][34].
Purified EVs can thus undergo characterization with respect to their cargoes, such as metabolites and lipids [39][40][41], proteins [40][42], transcripts (prevalently mRNAs, miRNAs and long noncoding (lnc) RNAs, but also small nuclear RNA, small nucleolar RNA, noncoding RNA, long intergenic noncoding RNA, piwi-interacting RNA) [40][43][44], and genetic material (single-strand DNA, double-strand DNA, mitochondrial DNA) [40][45]. The vesicles’ cargo depends on the source from which the EVs originate and on their biological state (e.g., transformed, differentiated, stimulated, and stressed) [15][46]. Furthermore, based on the molecular content of EVs, it is possible to understand the physiological and pathological state of the cells [47][48][49].
Exosomes consist of a lipophilic shell with lipids and intramembrane ligands and receptors [50]. These vesicles are detected in biological fluids such as blood [51], sputum [52], cerebrospinal fluid [53], bronchial alveolar lavage fluid (BALF) [54], and urine [55], but they can also be secreted by various cell types such as bronchial epithelial cells [56], mesenchymal stem cells [57], macrophages [58], dendritic cells [59], natural killer (NK) cells [60], T cells [61], and B cells [62]. Exosomes are released into the extracellular environment and directed to different organs such as the lung, liver, kidney, pancreas, spleen, gastrointestinal tract, etc. [63][64][65]. Thanks to EXOs’ amphiphilic properties, hydrophobic and hydrophilic bioactive molecules can be incorporated into them [66].
EXOs have a very complex composition. They are characterized by a high and specific protein content (~4563 proteins) [67][68] derived from the plasma membrane, the cytosol, and the endocytosis pathway. Particularly, EXOs are rich in the most common proteins CD9, CD81, CD82, CD63, CD106 of the tetraspanin family [15][29][69], which act as specific membrane markers [70] and play an important role in cell penetration, invasion and fusion; the heat shock proteins HSP60, HSP70, HSP90, which allow the peptide to be loaded onto MHC I; Alix, Flotillin-1 and TSG101 proteins [15][29][69], which are necessary during the biogenesis of exosomes and useful for the trafficking and release through the MVB formation [29]. Among the various proteins that are part of the exosomes’ cargo there are those located on the surface of the vesicles that can induce intracellular signaling by interacting with the target cells’ receptors. Furthermore, EXOs carry other proteins such as annexins (I, II, V e VI) and Ras proteins that promote the docking of vesicles and membrane transport and fusion [68], cell-specific class II proteins of the myosin heavy chain, which are incorporated only in exosomes isolated from APC cells [71], GTPases (EEF1A1, eEF2) and cytoskeletal proteins (actin, sinenin and moesin), enzymes and signal transduction proteins as well as lipids (approximately 194) [29][68][72], and functionally active genetic material including DNA, messenger RNA (mRNA), microRNAs (miRNAs), noncoding RNA (tRNAs, rRNAs), and metabolites [73][74].
miRNAs are small noncoding RNAs ranging in size from 20 to 22 nucleotides and are the most abundant component of the exosome’s cargo. Their internalization in exosomes is regulated by the presence of RNA-binding proteins via specific conserved miRNA motifs. For example, there are various RNA-binding proteins, such as SUMO protein (hnRNBA1), that can recognize GAGAG motifs of miRNA [75], or the synaptotagmin-binding cytoplasmic RNA-interacting protein that identifies the GGCU motif [76]. Previously, several studies have shown the presence of large amounts of extracellular miRNAs outside EXOs and MVs, which are often associated with Argonaute (Ago) proteins. These miRNAs could result from the death of many cells, remaining stable in the extracellular environment thanks to binding with the Ago-2 protein [77]. miRNAs, specifically those incorporated in exosomes, are actively secreted and thus involved in unidirectional intracellular trafficking, causing phenotypic changes of the recipient cells [78]. EXO miRNAs can regulate gene expression at the translational and post-translational levels [79]. All body fluids are rich in exosomes and therefore in the miRNAs packed inside the vesicles. For this reason, exosomes are utilized as noninvasive biomarkers [80], especially in cancer prognosis. For example, EXO miR-451a, miR-21 and miR-4257 are altered in lung cancer and thus associated with tumor progression and poor prognosis [81].
The intercellular signaling and the structural stability and rigidity of exosomes is normally guaranteed by several components such as cholesterol, arachidonic acid, diglycerides, sphingolipids (i.e., sphingomyelin and ceramide), phospholipids, glycerophospholipids including PS, phosphatidylcholine (PC), phosphatidylinositol (PI), and phosphatidylethanolamine (PE), but also bioactive lipids such as prostaglandins and leukotrienes [82]. Exosomes have a lipid content comparable to that present in the parental cell [83], but sometimes even higher for specific lipids (PS, PC, PI, cholesterol). This latter aspect increases the rigidity of the exosome membrane.
There are not many studies on the molecular composition of MVs, but the presence of lipids, proteins and nucleic acids similar to those of exosomes has been identified. The proteomic cargo of MVs is characterized by various molecules, already mentioned in EXOs, including Alix, TSG101, the tetraspanins CD9, CD81, CD63, CD86, CD40, integrins, selectins, and glycoproteins, e.g., GPIb [11][84], but also matrix metalloproteinases (MMPs) [11][85] and cytoskeletal proteins, e.g., β-actin [86]. From a lipidomic point of view, MVs’ membranes are enriched with different lipids, mostly PC (59.2%), but also sphingomyelin (SM), PE, PS, cholesterol and diacylglycerol [87][88][89][90][91][92]. Instead, ApoBDs, based on their origin, are composed of a myriad of proteins such as heat shock proteins, e.g., HSPB6, RAB11A, Annexins, e.g., ANXA6 or ANXA5, histones and cytosolic proteins [91][93]. Moreover, these vesicles are rich in PS [94]. In addition to exosomes, both MVs and ApoBDs are also characterized by the presence of nucleic acids including DNA, mRNA, miRNA and rRNA [95][96].

3. EVs in Lung Homeostasis

Epithelia are characterized by a higher turnover rate in comparison to other tissue compartments, as old cells are continually replaced by new cells derived from differentiation into the staminal niche. However, as compared to other organs (e.g., skin, gut), in physiological conditions, lungs are characterized by a very slow cellular turnover [97]. It is well known that lungs are daily exposed to noxious stimuli such as environmental pollutants and microorganisms, which can give rise to an inflammatory process. When damaged, lungs are able to regenerate and repair its different tissues. In the “steady state”, the cell renewal is very low, while after injury a regenerative response takes place thanks to interactions between stem cells and the surrounding environment [98]. Lungs are characterized by regenerative processes that respond to a kind of “regionalization”. Indeed, in the proximal airways, the progenitor compartment is represented by basal cells that self-renew and, in the presence of tissue injury, can differentiate into different cytotypes such as secretory, goblet, ciliated and neuroendocrine cells so as to guarantee the integrity of airway structures. Apart from basal cells, secretory cells possess self-renewing properties and a good differentiative activity [99][100][101]. Alveoli, which are representative of the distal region, are composed of alveolar type 1 (AT1) and alveolar type 1 (AT2), with the latter having a staminal/progenitor behavior, which is particularly important both during the formation of alveoli and after cell damage in adult lungs [102][103][104]. In addition, during lung regeneration, the stromal components supporting the epithelial staminal niche, e.g., mesenchymal and immune cells, seems to be very important [105].
In recent years, it has been demonstrated that EVs regulate the lungs’ homeostasis as well as their functions [106][107][108][109]. Many types of respiratory cells can release EVs (MVs and EXOs), including alveolar epithelial cells, alveolar macrophages, pulmonary vascular endothelial cells, airway and vascular smooth muscle cells, fibroblasts, stromal cells, and immune cells [19]. Recently, it has been demonstrated that EVs derived from airway epithelial cells are fundamental for both the communication among different epithelial cells and the homeostasis of airways and alveoli. When airway epithelial cells take up EVs derived from different airway cell populations, many molecules with important roles in cell life, such as proteins and miRNAs, are differently expressed or regulated. Recently, Kadota et al. [110] published a paper concerning the role EVs in the modulation of cell signaling involved in IPF, a disease in which the lung parenchyma is deeply compromised, resulting in poor patient prognosis. When given intratracheally in a mouse model of bleomycin-induced lung fibrosis, bronchial epithelial cell-derived EVs can attenuate WNT signaling, thereby suppressing the differentiation of myofibroblasts and epithelial cell senescence. The antifibrotic activity of bronchial epithelial cell EVs is higher as compared to that of mesenchymal stem cell EVs. It is interesting to point out that this effect is partly due to the miRNA cargo, which is able to negatively regulate the WNT–TGF-β crosstalk. In addition to the attenuation of the profibrotic cell phenotype and experimental lung fibrosis in vivo, they observed a negative modulation of myofibroblast differentiation and cellular senescence in lung fibroblasts (LFs). These results indicate that the direct administration of bronchial epithelial cell-derived EVs into the trachea may be a potential therapeutic approach to treat IPF by targeting the TGF-β–WNT crosstalk. As described above, another important source of EVs are alveolar epithelial cells. In normal conditions, these structures are characterized by a very slow cellular turnover, but murine models have demonstrated how in the presence of cell damage, AT2 cells acquire significant regenerative properties characterized by their intense cell proliferation and differentiation into AT1 cells. It is well established that EVs represent the way by which AT2 cells communicate with one another in orchestrating the maintenance or repair of damaged alveoli. Quan et al. [111] showed that EXOs derived from A549 cells (an AT2 cell line) could induce the proliferation of AT2 cells via miR-371b-5p, but not differentiation into pluripotent-stem-cell (PSC)-derived cultures. Interestingly, in the same study, it was observed that both bleomycin-treated human-induced PSC (hiPSC)-differentiated AT2 cells (hiPSC-AT2) and primary human AT2 cells were able to secrete miR-371b-5p in EVs. These results are indicative of the potential role of miR-371b-5p as an inducer of re-epithelization in the alveolar niche when lung injury takes place. Another recent study concerning the possible beneficial role of AT2-cell-derived EXOs was carried out by Mitchell and colleagues using a murine model of hyperoxia-induced lung injury [112]. Exosomes were isolated from both hiPSCs and hiPSC-AT2 (alveolar-like phenotype) and bound to magnetic beads before being administrated to mice. It was demonstrated that in the mice that were administered the exosome/beads, the level of tissue injury was lower as compared with that observed in the control mice.
Currently, the roles of EVs derived from mesenchymal cells in epithelial stem/progenitor cells function during regeneration remain unclear. Some studies carried out using mesenchymal cells, such as LFs obtained from lung tissue of patients, have shown that EVs derived from these cells can induce abnormal epithelial regeneration. Haj-Salem et al. have demonstrated that LF-derived EXOs are central in the crosstalk between fibroblasts and epithelial cells [113]. Epithelial cells were challenged with EVs obtained from fibroblasts residing in the bronchi of severe eosinophilic asthma patients, and the effect was that they proliferated abnormally. This hyper-proliferation was due to the lower levels of the antiproliferative mediator TGF-β2.
In a study concerning IPF, Kadota et al. [114] have demonstrated that LF EXOs from patients can be taken up by epithelial cells, causing damage in their mitochondria as well as the induction of senescence. IPF LF EVs induce an overproduction of ROS by the mitochondria, which in turn causes mitochondrial damage, the activation of DNA damage response, and results in senescence. In IPF pathogenesis, it is very important to observe how the interstitial LFs differentiate into contractile myofibroblasts, which are characterized by a high proliferation and an excessive secretion of the extracellular matrix. It is also worth mentioning that some lipidic mediators, such as prostaglandins (PGs), can inhibit myofibroblast differentiation. Some researchers showed that the stimulation of primary human LFs with IL-1β inhibited the differentiation into contractile myofibroblasts of both themselves (autocrine signal) and adjacent naive LFs in co-cultures (paracrine signal). Interestingly, the same study demonstrated for the first time that the effects of the antifibrotic properties of activated fibroblasts on fibroblasts close to them are mediated by EXOs and other EVs, the content of which is represented by several PGs, including the antifibrotic PGE2.
Another important source of EVs in the lungs is represented by resident immune cells with multiple subclasses of dendritic cells, innate lymphoid cells and interstitial and alveolar macrophages. Macrophage-derived EVs can induce regenerative processes in lung epithelia. SOCS1 and SOCS3 (suppressors of cytokine signaling) are two anti-inflammatory mediators contained in EVs that are secreted by alveolar macrophages (AM). They inhibit Janus kinase–STAT signaling, which represents an important pathway activated by many cytokines [115]. Moreover, SOCS3 contained within human alveolar macrophage EVs can exert antitumoral effects and decrease the production of some cytokines involved in allergic response, such as IL-4, IL-13 and thymic stromal lymphopoietin, from airway epithelial cells [116]. Furthermore, in the presence of LPS, macrophages secrete EVs. Moreover, in the early phases of LPS stimulation, these EVs are mostly ABs, which contain miRNAs such as miR-221 and miR-222. Functionally, ABs produced upon the LPS stimulation of macrophages are able to induce the proliferation of malignant and/or normal lung epithelial cells. miR-221/222 deletion in ABs significantly reduces the AB-mediated proliferation, demonstrating that the AB-shuttling of miR-221/222 itself promotes cell growth [117]. Moreover, an important study was carried out with the purpose of evaluating the impact of some miRNAs on the fibrosis associated with IPF progression. Interestingly, the results of this study demonstrated that macrophages isolated from sputum are rich in exosomal miR-142-3p, and that macrophage-derived exosomes inhibit pulmonary fibrosis progression via the delivery of miR-142-3p [118]. It is noteworthy that macrophage EXOs exert an important role as promoters of epithelial cell maintenance.
Resident MSCs represent another important source of EVs in the lung. Several in vivo models have demonstrated the beneficial role of MSC-derived EVs and MVs in inflammatory conditions caused by bacteria and viruses [119][120][121][122]. Silva et al. [123] demonstrated that MSC-EVs were able to improve the alveolar–capillary barrier in experimental models of ARDS (acute respiratory distress syndrome). Even if it is still not clear how dysfunctional mitochondria contribute to the compromised alveolar–capillary barrier, this study demonstrates that MSC-EVs can restore the functionality of mitochondria. The dysfunctional mitochondria respiration, caused by stimulation with LPS of primary human distal lung epithelial cells, is restored by the transfer of mitochondria contained in MSC-EVs. Moreover, in a murine model of an LPS-injured lung, treatment with MSC-EVs reduced lung injury and restored mitochondrial respiration. In another study [124], it was demonstrated how the uptake of MSC-derived EXOs can down-regulate the expression of SAA3 (serum amyloid A3), an important mediator of the acute phase of inflammation. It is noteworthy to specify that this effect has been observed with EVs obtained from miR-30b-3p-overexpressing MSCs. A further demonstration of the anti-inflammatory activity of miRNAs contained within MSC-EVs has been obtained [125][126]. The treatment of murine bone-marrow-derived MSCs with hypoxia increased miR-21-5p concentration in MSC-EXOs, which in turn attenuated ischemia/reperfusion injury in a mouse lung [125].
It has been also demonstrated that autophagy may have an important role in tissue regeneration mediated by MSCs [126][127]. A study by Wei et al. [128] further elaborated on the relationship between autophagy, inflammation and lung damage as exerted by MSC-EXOs. MiR-377-3p contained in EXOs from human umbilical cord MSCs protected lungs from acute injury induced by LPS. This beneficial effect was due to the down-regulation of RPTOR (target regulatory-associated protein of mTOR) mediated by miR-377-3p.

4. Dysregulation of EVs’ Cargo in the Pathogenesis of COPD and CF

EVs, containing a specific cargo of lipids, proteins, metabolites and nucleic acids, regulate the intercellular communication in both health and disease, influencing physiological and pathological processes (i.e., immune responses [129], tissue repair [130][131], stem cell maintenance [132], cardiovascular diseases [133][134], neurodegeneration and demyelinating diseases [135][136], cancer [137] and inflammation [138]). EXOs can trigger signaling and thus release their content in target cells in different ways: (1) at the cellular level through the interaction of the EXO membrane ligands with specific membrane receptors of recipient cells; (2) by a mechanism in which the membrane proteins of the exosomes are cleaved by the proteases and act as ligands for the target cell receptors; (3) by the direct fusion of the EXO membrane with target cells, resulting in its content being secreted into the cytosol of the recipient cell [139]; (4) at the intracellular level via the process of EXO endocytosis (i.e., clathrin-mediated endocytosis, caveolin-mediated endocytosis, micropinocytosis and phagocytosis) [140] by different types of cells including gastric epithelial cells [141], macrophages [142], cardiomyocytes [143], etc.
EVs, released from almost all cell types in the lung, play an important role in the pathogenesis of chronic respiratory diseases such as COPD and CF [144][145]. They mediate intercellular communication in the lungs and hence are involved in pulmonary homeostasis [146] and cellular response to stimuli and lung disease [145][147]. A dysregulation of the protein, lipid and nucleic acid (especially miRNA) content of exosomes has been highlighted in respiratory diseases that also involve inflammation, especially following exposure to various stimuli [148][149][150]. Several studies have shown that bronchial epithelial cells, which normally regulate airway homeostasis, release more extracellular vesicles than other cells [148]. These EVs are characterized on the surface by some mucins (MUC1, MUC4 and MUC16) [147] that protect against pathogens [151], maintain the structure of the vesicles [147], and allow the interaction of the vesicles with the inhaled substances or with the receiving cells. Epithelial EVs transport pro-inflammatory cytokines and are rich in miRNA-210, whose levels further increase after exposure to cigarette smoke extract (CSE) [152]. Xu et al. showed that CSE increased the levels of miRNA-21 in the EVs released by human bronchial epithelial cells in COPD patients [153]. Moreover, the lengthy exposure to cigarette smoke extract increased cellular communication network factor 1 (flCCN1) levels in EVs, which regulated the lung homeostasis [154]. Alipoor et al. highlighted the importance of airway epithelial cell exposure to tobacco smoke extract in increasing the miRNA content of exosomes such as miRNA-101 and miRNA-144, which inhibit CFTR protein expression in the pathogenesis of COPD [149].
Lung resident macrophage-derived exosomes also play a pivotal role in inflammation, immune function and tissue injury in the lung tissue microenvironment [155]. Macrophage EXOs are enriched with miRNA-223, which is targeted to recipient cells by activating the differentiation of monocytes into macrophages [156], and in MHC II molecules, they are important for antigen presentation and immune activation [157][158]. It has been previously shown that CSE exposition increased the secretion of macrophage MVs with pro-inflammatory activity in lung diseases [159]. Li et al. showed that CSE caused an alteration of the content of macrophage-derived MVs, leading to an up-regulation of MMP14 [85]. Furthermore, Cordazzo et al. showed that mycobacterium infection also increased the protein content of alveolar-macrophage (AM)-derived exosomes, especially HSP-70 [159], with pro-inflammatory activity mediated by NK cell activation [160].
EVs released by endothelial cells, particularly circulating microparticles (EMPs), are increased in patients with several diseases such as COPD [161] or in response to various stresses such as cigarette smoke extract [162]. CSE reduced the trafficking of α1AT mediated by endothelial-cell-derived EVs to lung epithelial cells [163]. Numerous studies showed an increase in CD31+/CD42b- or CD31+CD62E+ EMPs [164][165][166][167] in COPD patients and in healthy smokers, which decreased in smokers who stopped smoking, suggesting the important role of EVs in inducing apoptosis and endothelial damage with poor repair capacity [164]. On the other hand, studies using mouse models investigated the EVs’ cargo following prolonged exposure over time to the cigarette smoke extract, discovering an increase in CD31+/42b- EMPs [168].
EVs also have great potential in CF lung disease. Exosomes derived from CF epithelial cells of the lung airways have a different protein content than the EVs released by healthy cells [169]. EVs mediate inflammation by regulating the migration and activation of neutrophilic leukocytes in the CF airways. This is allowed by the rich content of the CF airway bronchial-epithelial-cell (CFBE41o-)-derived exosomes in the integrin proteins, such as VCAM1 [169], with consequent migration of neutrophils to inflammatory sites [170], and in the ligand S100 A12 [169], which can bind the RAGE receptor placed on the surface of the receiving neutrophils, causing their activation [171].
Differences in EVs’ cargoes between healthy individuals and CF/COPD patients are highlighted in Figure 1.
Figure 1. Molecular cargo of healthy EVs and vesicles released by various cell types in the pathogenesis of chronic obstructive pulmonary disease (EVs in COPD) and cystic fibrosis (EVs in CF). The increase in some vesicle’s components, involved in certain respiratory diseases, is indicated by an upward arrow. The exposure to various stimuli such as cigarette smoke extract leads to changes in the content of EVs released by the various cell types in the lung. In COPD, MMP4 and miRNA-223 levels increase in the vesicles released by macrophages; epithelial-cell-derived EVs show an overexpression of miRNA-101, miRNA-21, miRNA-210, miRNA-144 and an increase in the cellular communication network factor 1 (flCCN1) levels; endothelial cells secrete exosomes and microparticles (MPs) rich in CD31+/CD42b- or CD31+/CD62E+ and with reduced levels of α1-antitrypsin. In CF, the expression of the integrin protein VCAM1 and the ligand S100A12 is enhanced in the EVs released by the airway bronchial epithelial cells. Created with BioRender.com.

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Subjects: Respiratory System
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Sante Di Gioia
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Valeria Daniello
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Massimo Conese
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Update Date: 05 Jan 2023
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