Basi Molecolari delle Patologie Polmonari

Chronic Obstructive Pulmonary Disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF) are severe lung diseases that share a common trigger represented by chronic smoking exposure, which causes lung epithelial injury and a subsequent immune-inflammatory response. Despite this common trigger, their pathological patterns and disease progressions differ markedly. COPD is characterized by a not fully reversible airflow obstruction and abnormal inflammation, and its clinical progression is influenced by different factors and comorbidities among which chronic bronchitis is key. A prompt diagnosis of "early disease" and an appropriate assessment of chronic bronchitis are fundamental in the clinical management of COPD patients. Their role has been the focus of two studies (Studies 1 and 2) conducted on an ongoing cohort of smokers with and without COPD, showing that the presence of chronic bronchitis significantly affects symptoms, quality of life, and survival, highlighting the importance of recognizing and managing this condition. Additionally, the Maximal Mid-Expiratory Flow (MMEF 25-75%), a simple lung function test, can be an easy and important step for detecting existing lung abnormalities, able to identify symptomatic individuals with early pathological changes that might lead to COPD. The immune-inflammatory response induced by cigarette smoking may be modulated by several factors including coagulation factors, particularly Factor XIII (FXIII), which is also involved in the modulation of inflammation by stabilizing fibrin deposits and influencing inflammatory cells activity. This concept led us to investigate (in study 3) the expression of FXIII in alveolar macrophages, from lungs obtained at surgery in smokers with and without COPD. This study showed that FXIIIA is significantly expressed in alveolar macrophages of smokers with COPD suggesting that it could play an important role in the adaptive inflammatory reaction characteristic of the disease. A crucial aspect of inflammation is cell-cell communication mediated by extracellular vesicles (EVs). EVs, which are lipid bilayer membrane-delimited particles that carry biomolecules such as miRNA and cytokines, play a significant role in modulating the inflammatory response. Our research group had previously shown the presence of EVs in broncho-alveolar lavage (BAL) in COPD. We now investigated whether in COPD patients EVs in BAL reflect those in blood. In study 4 we showed that significant differences in epithelial and macrophage-derived EVs can be clearly detected between non-smokers, smokers without COPD, and smokers with COPD in BAL, but not in plasma. This suggests that BAL could be a better medium than blood to study EVs in lung diseases. We therefore examined, in study 5, whether EVs from BAL could also actively modulate lung inflammation in COPD examining the anti-inflammatory proteins SOCS3 (Suppressor of Cytokine Signalling 3). We found that COPD patients had high levels of SOCS3 in alveolar macrophages-derived EVs, indicating a possible role in the modulation of lung inflammation. Differently from COPD, IPF, a chronic fibrotic lung disease, leads to progressive replacement of normal lung tissue with extracellular matrix, driven by pro-fibrotic polarized macrophage activation, with fibroblasts’ derived TGF-β playing a central role. In study 6 we developed an in vitro model of macrophage polarization into M1 (pro-inflammatory) and M2 (pro-repair) phenotypes, to investigate how polarized macrophages-derived EVs and their miRNA cargo influence TGF-β production by human lung fibroblasts. We reported that EVs derived from cultured M1 polarized macrophages, but not M2 macrophages, stimulated the production of TGF-β by cultured human lung fibroblast, and that target miRNAs also delivered by EVs are involved in the modulation of TGF-β release.