## 5 Microbiome Extracellular Vesicles and Chronic Respiratory Diseases  
Human cells are not the only ones to produce microvesicles that affect the status of the respiratory system. Above the respiratory mucosa is a mucous layer in which all the microorganisms that make up the airway microbiota are settled [73]. The main  
Figure 2: Scheme of COPD pathogenesis. Chronic external stimuli generate massive deregulation of lower airways. Chronic external stimuli generate massive deregulation or lower airways. EVs mediate these tissue changes directly and indirectly. Their production is also increased by the perennially present phlogistic status established with the progress of the pathology. The immune cell component contributes greatly to the release of EVs that affect all cell populations of the respiratory mucosa.  
communication pathway between the cells of our body and the microbiota is via EV [18]. Communication via EV guarantees an interaction between host and microbiome without direct contact and in a bidirectional manner. This interaction is physiologically present in a state of health, and its alteration can trigger pathogenetic processes [74]. Commensal bacterial species that constitute our microbiome are not the only EV users, but also the pathogenic infectious species could exploit this communication pathway [75]. Among the most significant aspects affected by EVs is that of immunomodulation [76; 77]. One of the most studied interactions is between _Pseudomonas aeruginosa_ and airway epithelial cells. _P. aeruginosa_ releases outer membrane vesicles (OMVs) in the mucus layer; OMVs fuse with cellular membranes on the epithelial cells apical side and deliver a 23-nucleotide tRNA (sRNA-52320). sRNA-2320 reduces IL-8 secretion and the migration of neutrophils into the lungs and suppresses the immune response to bacterial infection by targeting several genes in the LPS-stimulated MAPK signaling pathway [76; 78; 79]. In recent years, specific interactions between microbiome EVs and chronic diseases have been shown. In patients with asthma, _Sphingomonas_, _Akkermansia_, _Methylophaga_, _Acidocella_, and _Marinobacter_ were significantly more abundant. It is interesting to note how this notion was obtained indirectly by analyzing the EVs released by these bacterial species. Thus, microcusicles can be used for diagnostic purposes (in integration with other specific examinations) [80]. Urine-released microbial extracellular vesicles can be potential and novel biomarkers for chronic respiratory diseases. The analysis of EVs is, in fact, also possible through an investigation of the urine of patients [81]. By this analytic method, the different microbiome composition of asthmatic patients has been detected. The diversity also appears to correlate with IgE levels and eosinophil % [82]. These findings suggest that they may play important roles in allergic-based airway diseases. The analysis and monitoring of COPD also benefit EVs studies. Altered miRNA profiles in COPD have been discovered analyzing EVs. [PERSON] et al. used different EV isolation and purification methods to characterize the plasma-derived EV miRNAs from nonsmokers, smokers, and patients with COPD [83]. They analyzed plasma-derived EVs from smokers, nonsmokers and patients with COPD, discovering how EVs vary in their dimensions, distribution, concentration and phenotypic characteristics. They concluded that plasma-derived EV miRNAs are novel circulating pulmonary disease biomarkers. miR-21 to miR-181a levels have been monitored by [PERSON] et al. In particular, heavy smokers without diagnosed COPD were taken into consideration. The levels of the two miRNAs have a dichotomous pattern: the levels of miR-21 were significantly higher in the COPD patients and asymptomatic heavy smokers than in the healthy controls (HC), while miR-18a levels were significantly lower in the COPD patients and asymptomatic heavy smokers than in the HC [84]. The ratio of these miRNA levels could be used as a potential biomarker of early COPD pathogenesis.