## 3 Asthma and Nanovesicles in Asthma Pathogenesis  
Asthma is a chronic respiratory disease that presents several phenotypes. The global cases of asthma are estimated to be over 300 million by the World Health Organization (WHO) [30]. Asthma is commonly considered a childhood-onset disease; however, adults also can develop asthma later in life. Asthma is caused by both environmental factors such as house dust mites (HDM), particulate matter (PM), cigarette smoke (CS) [31] and genetic factors, among which allele 17q21 is the most studied [32]. Overall, the development of the disease is defined by increased mucus production, thickening of the subepithelial reticular basement membrane (RBM) of the lung mucosa, airway hyperresponsiveness and chronic inflammation [Figure 1]. All these events determine airway remodeling, which leads to the narrowing of the airways [31]. Recently, due to their high therapeutic potential, the emerging role of extracellular vesicles has been investigated in association with asthma pathogenesis [33; 34]. Within the respiratory system, several cell types are involved in the release of EVs: for instance, structural cells such as epithelial cells and fibroblasts [35; 36], resident immune cells such as dendritic cells (DCs) and alveolar macrophages (AMs) [28; 37] as well as recruited immune cells such as eosinophils [38]. The major producer of EVs within the lung are airway epithelial cells [35]. On their membrane, epithelial cell-derived EVs expose several mucins that can neutralize virus and bacteria [27]. Furthermore, it has been shown that EVs produced by epithelial cells can trigger the proliferation of macrophages upon IL-13 release by eosinophils, thereby promoting chronic inflammation [35]. A study by [PERSON] and colleagues [39] revealed the role in asthma pathogenesis of miRNAs present in epithelial-derived EVs. miR-34a, miR-92b, and miR-210 in EVs can potentially lead to Th2 responses and maturation of DCs in the early development of asthma. Aberrant deposition of extracellular matrix contributes to the RMB thickening in asthma pathogenesis. On their surface, EVs secreted by fibroblasts expose fibronectin, which can trigger invasion-associated signaling pathways [40]. An in vitro study showed that exosomes produced by the fibroblasts of severe asthmatics contain a low level of TGF2, which inhibits epithelial cells proliferation, contributing to the narrowing of the airways [37]. In order to trigger an allergic response, allergens must be presented to T cells by DCs. In humans, it has been shown how DC-derived exosomes can directly present antigen to T cells [41]. In mice, exosomes, rather than microc vesicles (MVs), overexpress allergens leading to the activation of allergen-specific T cells [37]. These findings highlight an important modulatory function of DC-derived exosomes in allergic responses. As epithelial cells, macrophages are a major source of EVs that display multiple functions. Macrophages-derived EVs can promote macrophage differentiation [42] via mRNA-223. During infections, both bacteria and macrophages release MVs, which have a strong proinflammatory effect. At the same time, these MVs can also induce tolerance and promote bacterial shedding [43]. EVs produced by macrophages can also activate toll-like receptors (TLRs) during infection as they contain heat-shock protein 70 (HSP70), which mediates the activation of nuclear factor kB (NFkB) [26]. Eosinophils play a major role in allergic asthma exacerbations [31]. Besides the release of potent Th2 cytokines, eosinophils release both MVs and exosomes [44]. Multiple  
Figure 1: Scheme of allergic asthma pathogenesis. Allergic asthma is triggered by inhaling allergens. (Allergens could have different origins such as dust mites, pet dander, pollen or mold.) During the different phases and chronicization of the pathology, the tissues undergo several modifications. Among these include hyperplasia, hypertrophy of mucous cells and an increase of their secretions, continuity loss of the epithelium and variation in EV content.