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Biondini, Davide (2019) From cigarette smoking to Chronic Obstructive Pulmonary Disease or Idiopathic Pulmonary Fibrosis. Why? [Ph.D. thesis]

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Abstract (italian or english)

Chronic Obstructive Pulmonary Disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF) are two chronic lung diseases with distinct clinical, pathological and epidemiologic features. In both disorders cigarette smoking represents a major risk factor; indeed, it causes a repetitive alveolar damage that elicit inflammatory response and may enhance the establishment of the disease. During my PhD, we investigated the role of innate and adaptive immune response in COPD and IPF, and how it may be related to different clinical outcomes.
In COPD, the role of inflammation is consolidated; alveolar macrophages (AM), which are one of the main actors of innate immune response, were firstly recognized to play a key role in the pathogenesis of the disease, by releasing protease that damage lung parenchyma. In our studies, we investigated how AM may be involved in the development of COPD with alternative mechanisms; for example, we analyzed AM polarization, classic (M1) and alternative (M2), in lung tissue and how it may be influenced by smoking and disease severity. The model of COPD as a disease caused only by an antiprotease-protease imbalance has been overtaken; indeed, not all subjects with α1-Antitrypsin (AAT) deficiency (AATD) develop disease, meaning that other immune regulatory factors are involved. In fact, we investigated α1AT polymerization in AM as a pro-inflammatory trigger, due to its abnormal accumulation in AM endoplasmatic reticulum. Moreover, we performed a genome wide analysis in siblings with AATD, with extreme phenotypes of the disease (emphysema/no emphysema), searching for genes variants that may modulate or promote inflammatory response, possibly explain these opposite manifestations.
Since the study of biomarkers is becoming of great interest in the field, we focused our research on adaptive immune cells in the blood, examining blood eosinophils (BE) and lymphocytes (BL), to investigate whether they can be predictor of clinical outcomes, and if they reflect what is happening in the lung. In addition, we have started to unravel the possible role of the peripheral BL in the development or prevention of cancer. Then we moved from peripheral blood to the lung tissue, examining how lymphocyte and eosinophil counts in the lung may change after the introduction of an anti-inflammatory treatment with Roflumilast, adding some clues on its mechanisms of action. Indeed, the study of lung infiltrate is mandatory to better understand the pathogenesis of the disease, and we are currently developing new techniques to deeply analyze the immune cells in COPD lung, and the presence of markers of immunomodulation.
In IPF, the role of inflammation is more debated than COPD. Our idea that an inflammatory reaction could be an important part of IPF has lead us to investigate the possible role of innate and adaptive immune response in the pathogenesis of the disease, not only in explanted lungs of end-stage IPF, but also in the surgical lung biopsies of patients with mild disease. The pathological evidences we found were then correlated to clinical outcomes, as disease progression, to study if they may account for the variability in lung function decline. Moreover, we also explored whether different lung tissue inflammatory profiles may impact on the response to Pirfenidone treatment, which exerts also an anti-inflammatory effect. Finally, we investigated HRCT as a possible non-invasive predictor of disease behavior and treatment response in IPF.
The results of the studies we have conducted so far, highlights how inflammatory response, and especially the immune regulation, is pivotal in COPD and IPF, adding novel findings to previous knowledge in the areas of innate and adaptive inflammation, and putting the basis for future research in these smoking-induced diseases.

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EPrint type:Ph.D. thesis
Tutor:Saetta, Marina
Data di deposito della tesi:01 December 2019
Anno di Pubblicazione:01 December 2019
Key Words:Chronic Obstructive Pulmonary Disease Idiopathic Pulmonary Fibrosis
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/10 Malattie dell'apparato respiratorio
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari
Codice ID:12265
Depositato il:02 Feb 2021 10:54
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