## 2 Nanoviscles: Exosomes and Outer Membrane Vesicles  
The paracrine communication system regulated by extracellular vesicles (EVs) and exosomes plays a key role in the communication of the EMTU, in the maintenance of tissue homeostasis of the airways as well as in many pathogenetic processes affecting the apparatus [13]. The intimate interconnection that interfaces the epithelial layer to the connective layer, synching them in their biological activities, is favored by the vesicular system that traffics nucleic acids (miRNA, siRNA) [14], growth factors, tissue-specific receptors as well as proteases [15]. As with [PERSON] and [PERSON]'s EMTU studies, extracellular vesicles and exosomes have long been erroneously considered as results of \"garbage disposal\" whose sole purpose was to eliminate waste substances from cells [16; 17]. They are actively secreted by all eukaryotic and prokaryotic cells and are part of an articulated cell-to-cell communication system, both in physiological and pathological conditions [18]. In recent decades, several scientific works demonstrated the roles of EVs in a plethora of physiological processes. EVs are involved in cellular homeostasis and signaling. They can act as carriers of an enormous variety of molecules, and they express numerous signal proteins on their surface [19]. EVs are classified according to their size as (1) microcusicles (100-1000 nm in diameter); (2) apoptotic blebs (1000-5000 nm in diameter); and (3) exosomes (diameter 20-150 nm) [20]. On one side, microcusicles and apoptotic blebs originate from the outward budding of the cell membrane, unlike exosomes, which result from the invagination of endosomal membranes [21]. The understanding of the different originative pathways and the sortingmechanisms spotlighting transport, cargo packing and vesicle exocytosis find practical utility in the isolation studies of EVs for diagnostic and therapeutic purposes. Therefore, the role of the proteins belonging to the endosomal sorting complex required for transport (ESCRT -0, -I, -II and -III), responsible for the control of the biogenic and cargo loading processes of the EVs, is crucial [22]. As previously mentioned, the load of the EVs is tissue-specific and related to the function they can perform, i.e., EVs produced by tumor cells have a decisive impact on paracrine signaling mechanisms in support of tumor growth [23; 24; 25]; however, under physiological conditions, other EVs perform diametrically opposite roles, such as protection from traumatic tissue events or promoting the tissue healing itself [26]. A determining example might be the EVs produced in the lung microenvironment [26]. In homeostasis conditions, a broad range of cell types, such as fibroblasts, epithelial cells and endothelial cells, also actively secrete EVs: those EVs have been largely characterized, showing that epithelial cells are the main characters on the production of EVs, enriched with secretory and membrane-anchored mucins, which contribute to the mucociliary defense and boosting of innate immune defenses [27]. Not only epithelial cells but also macrophages that are present in BAL fluid play a pivotal role in the inflammatory modulation. It has been demonstrated that alveolar macrophages secrete SOCS-1 and -3 within nanoparticles, which are uptaken by lung epithelial cells. Both SOCS-1 and -3 are negative modulators of cytokine 1 and 3 biogenesis (through the STAT pathway inhibition) [28]. In normal conditions, this can modulate the inflammatory response, but at the same time, this negative modulation of IL-1 and -3 biogenesis seems to be lost in cigarette-smoking subjects, presenting a new model for the control of inflammatory response during inflammation or stress tissue [28]. Thus, with the importance of pulmonary EVs in maintaining homeostasis being confirmed, it is not difficult to think how dysregulations in this sense are closely related to the pathogenesis of various lung diseases [29].