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Scarpa, Maria Cristina (2016) INTERAZIONE FRA DANNO POLMONARE CRONICO E INVECCHIAMENTO, MICROBIOMA POLMONARE ED ESPOSIZIONE AGLI INQUINANTI INALATORI. [Tesi di dottorato]

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Abstract (inglese)

Our research project was designed to analyze the inter-play between aging, chronic lung injury, lung microbiome and exposure to air pollutants. The project was divided into four parts:
1) systematic review of the literature about the role of non-invasive biomarkers in detecting the acute respiratory effects of traffic-related air pollution;
2) retrospective/prospective study of the possible predictors of carbon particles accumulation in the airways macrophages;
3) prospective evaluation of the effect of smoking and/or disease (COPD) on microbial colonization of the lung;
4) prospective study about the effects of traffic-related air pollution and cigarette smoke on lung aging.
The first part was a systematic review of the literature on the use of samples obtained in a non-invasive way aimed to study the short-term effects of urban traffic-related air pollution on the respiratory system. Although subjects with COPD have been generally considered to be at higher risk for the adverse effects of air pollutants, these patients have been recruited only in a few studies [1-4]. According Manney et al. [1], an increase of nitrates and nitrites in exhaled breath condensate (EBC) is associated with a large exposure to particles in subjects with COPD and asthma, with no differences between the two diseases. FeNO measurements yielded conflicting results: one study found a association with PM2.5 in subjects with COPD, but not with asthma [2], while in another study [3], FeNO levels resulted to be associated with PM pollution in participants with asthma but not in those with COPD. According to Gong et al. [4] cellularity of induced sputum in COPD patients is not affected by particles exposure. More research is thus required to clarify the effect of air pollution related to acute traffic in people who suffer from lung diseases other than asthma. The acute effects on respiratory disease are difficult to be attributed to a particular pollutant in most surveys with environmental exposure [5]. Further research are warranted to promote a better standardization of methods for pollutants monitoring. In real life conditions, 'unexposed' subjects do not exist and the difference between the minimum and maximum levels of air pollution is often less than three times [6]. When planning observational studies, a baseline for levels of inflammatory markers in individuals exposed to low levels of pollutants should be established to be able to detect an effect at higher exposures.
The second part of our project aimed to investigate the determinants of the accumulation of carbon particles in the cytoplasm of airway macrophages obtained from induced sputum. Three groups of subjects were enrolled: patients suffering from COPD, healthy smokers and non-smoking healthy controls. Exposure to cigarette smoke, to indoor and outdoor air pollution, and occupational exposure was quantified with a dedicated questionnaire. This analysis aimed to control potential confounders to make a correct evaluation of the personal exposure to air pollution. The most important predictors of the black carbon (BC) load in airway macrophages resulted to be the presence of COPD and urban traffic exposure, while smoking did not show any significant association. Traffic exposure in the previous year of the visit (measured as the number of equivalent vehicles) was correlated with the carbon load. In addition, in COPD the carbon particles accumulation did not resulted to be correlated with the degree of obstruction nor with the degree of neutrophilic inflammation of the airways. In conclusion , quantification of BC in macrophages is suitable for assessing traffic exposure, although further studies are needed to assess macrophage function in patients with and without disease and to evaluate the biological effects of the individual carbon load. The third part aimed to non-invasively assess the differential role of cigarette smoke and smoke-associated chronic airflow limitation on airways bacterial colonization. The molecular identification of the pulmonary microbiota in three groups of subjects was carried out. Phyla and genera present in each subject and in each group were identified. It was then calculated α and β diversity index to evaluate the differences in bacterial composition intra sample and between samples of the same group, respectively. The composition of phyla in stable COPD patients was similar to that found in earlier research based on the use of bronchial brushing and bronchoalveolar lavage with the advantage that our number of sequence reading was much higher than those previously analyzed. It was also observed that subjects with COPD who received corticosteroids showed a lower abundance of bacteria of genus Prevotella and greater abundance of Veillonella genus compared to untreated subjects. Smokers have an increased relative number of Neisseria and Bergeyella genera, and a decreased relative number of Streptococcus and Rothia genera compared to non-smokers. Our results suggested that cigarette smoking may cause a decrease in the relative abundance of species, regardless of the development of chronic airflow limitation, thus influencing the composition of the lung microbiome. Molecular analysis proved to be indispensable to compare different niches and to identify the most abundant organisms present in different groups. Indeed, traditional culture tests and biochemical assays did not allows phenotypic identification of bacteria. The analysis of the resident microbiota in patients with stable COPD compared to smokers and non-smokers suggested the richness of the microbiota is important for lung health.
In the fourth part of the research a feasibility study of DNA extraction from sputum cells and the respective quantification was performed. The evaluation of lung aging due to urban pollution and cigarette smoke was carried out on both samples of blood and induced sputum and the telomere length will be measured. We expected that the rate of decline in lung function would be associated with the rate of biological aging. We also assumed that aging in white blood cells reflects that of cells coming from induced sputum. We expected that cigarette smoking accelerates the aging of cells in induced sputum when inflammation and exposure to environmental pollution are constant.
In conclusion, the presence of COPD affects both the lung carbon load linked to urban traffic (with the same external exposure of the subjects), and the biodiversity of lung microbial colonization. On the other hand, cigarette smoking has no effect on the content of carbon particles, but acts on the composition of the microbiota.

Abstract (italiano)

Il progetto di ricerca nel suo insieme si proponeva di analizzare l’interazione tra danno polmonare cronico, invecchiamento, microbioma polmonare ed esposizione agli inquinanti inalatori. Il proggetto era articola in quattro parti:
1) revisione sistematica della letteratura sul ruolo dei biomarcatori non invasivi nello studio degli effetti respiratori acuti dell’inquinamento associato a traffico;
2) studio retrospettivo/prospettico dei determinanti dell’accumulo delle particelle carboniose nei macrofagi delle vie aree;
3) valutazione prospettica dell’effetto del fumo e/o della malattia (BPCO) sulla colonizzazione microbica a livello polmonare;
4) studio prospettico dell’effetto dell’inquinamento urbano e del fumo di sigaretta sull’invecchiamento polmonare.
La prima parte era un’analisi sistematica della letteratura sull’uso di campioni ottenuti in modo non invasivo per studiare degli effetti a breve termine sul sistema respiratorio dell'inquinamento atmosferico dovuto a traffico urbano. Da questa emerge che, sebbene i soggetti con broncopneumopatia cronica ostruttiva (BPCO) siano stati generalmente considerati a più alto rischio per gli effetti negativi degli inquinanti atmosferici, questi pazienti sono stati reclutati solo in pochi studi [1-4]. Secondo Manney et al. [1], l'aumento di nitrati e nitriti nel condensato dell’aria esalata (EBC) è stato associato con una grossa esposizione di particelle nei soggetti con BPCO e asmatici, senza differenze significative tra le due malattie. Le misure di ossido nitrico esalato (FeNO) in altri due studi hanno dato risultati opposti: uno ha trovato un rapporto con PM2.5 in soggetti con BPCO, ma non con asmatici [2], mentre nell’altro [3], il FeNO è stato associato con livelli di inquinamento da PM nei partecipanti con asma ma non in quelli con BPCO. Secondo Gong et al. [4] la cellularità dell’espettorato indotto in soggetti con BPCO non è influenzata dall’esposizione a particolato. Sono quindi necessarie nuove ricerche volte a chiarire l’effetto dell’inquinamento atmosferico acuto legato al traffico in soggetti che soffrono di malattie polmonari diverse dall’asma. Tuttavia, gli effetti acuti sulla salute sono difficili da attribuire ad un particolare inquinante nella maggior parte delle indagini con esposizione ambientale [5]. Ulteriori ricerche dovrebbero essere dirette a promuovere una migliore standardizzazione dei metodi per monitorare gli inquinanti da traffico. Va ricordato che, in condizioni di vita reale, i soggetti veramente 'non esposti' non esistono e la differenza tra i livelli minimi e massimi di inquinamento atmosferico è spesso meno di tre volte [6]. Dovrebbe essere stabilita, in particolare quando si pianificano studi osservazionali, una base di riferimento per i livelli di marcatori infiammatori in soggetti esposti a bassi livelli di sostanze inquinanti per essere in grado rilevare un effetto con esposizioni più elevate.
Nella seconda parte l’obbiettivo era di indagare i determinanti dell’accumulo di particelle carboniose nel citoplasma dei macrofagi delle vie aeree ottenuti dall’espettorato indotto. A tale scopo si sono arruolati tre gruppi di soggetti: affetti da BPCO, fumatori sani e controlli non fumatori sani. Tramite questionario è stata valutata la loro esposizione a fumo passivo di sigaretta, a inquinamento indoor, a inquinamento dell’aria negli spostamenti quotidiani e all’esposizione professionale. Questa analisi ha permesso di controllare i potenziali fattori confondenti per poter eseguire una corretta analisi dell’esposizione personale a inquinamento dell’aria. Si è osservato come i maggiori determinanti del contenuto di black carbon (BC) nei macrofagi delle vie aeree siano la presenza di BPCO e l'esposizione al traffico urbano, mentre non è stato dimostrato un ruolo dell'abitudine al fumo di sigaretta. L’esposizione a traffico (misurato come numero di veicoli equivalenti) era correlata con il carico di particelle carboniose. Inoltre, per quanto concerne la BPCO, l'accumulo di particelle carboniose non risulta correlato con il grado di ostruzione né con il grado di infiammazione neutrofila delle vie aeree. La quantificazione di BC nei macrofagi risulta adatta a valutare l’esposizione a traffico, anche se sono necessari ulteriori studi sulla funzionalità dei macrofagi nei soggetti con e senza malattia e una valutazione degli effetti biologici sul singolo individuo dovuti all’accumulo di BC.
Nella terza parte si è proposto di valutare, in modo non invasivo, il ruolo differenziale del fumo di sigaretta e della limitazione cronica del flusso aereo associata a fumo sulla colonizzazione batterica delle vie aeree. È stata quindi effettuata l’identificazione molecolare del microbiota polmonare residente nei 3 gruppi di soggetti. Sono stati identificati i phyla e i generi presenti in ciascun soggetto e in ogni gruppo. Sono stati poi calcolati gli indici di diversità α e β per valutare rispettivamente le differenze di composizione batterica intra campione e tra campioni dello stesso gruppo. La composizione in phyla nei pazienti BPCO stabili è risultata essere simile a quella trovata nelle precedenti ricerche basate sull'utilizzo di brushing bronchiale e broncolavaggio, con il vantaggio che il nostro numero di letture di sequenza è molto più alto di quelli precedentemente analizzati. Inoltre si è osservato che i soggetti con BPCO che ricevevano corticosteroidi mostravano una scarsa abbondanza di batteri di genere Prevotella e un’abbondanza maggiore di batteri di genere Veillonella rispetto ai soggetti non trattati. I fumatori rispetto ai non fumatori hanno un numero relativo aumentato dei generi Neisseria e Bergeyella, mentre è diminuito per i generi Streptococcus e Rothia. I risultati suggeriscono che il fumo di sigaretta possa indurre una diminuzione dell’abbondanza relativa di specie, indipendentemente dallo sviluppo della limitazione cronica al flusso aereo, influenzando così la composizione del microbioma polmonare. L’analisi molecolare si è rivelata indispensabile per confrontare nicchie diverse e identificare organismi più abbondanti presenti in un gruppo rispetto ad un altro, cosa che l’identificazione fenotipica dei batteri, ottenuta tramite i tradizionali esami colturali e saggi biochimici non consentiva. L'analisi del microbiota residente nei pazienti con BPCO stabile rispetto ai fumatori e soggetti non fumatori suggerisce che la ricchezza del microbiota è importante per la salute polmonare.
Per svolgere l’ultima parte della ricerca è stato fatto uno studio di fattibilità dell’estrazione del DNA da cellule dell’espettorato e relativa quantificazione. La valutazione dell’invecchiamento polmonare dovuto ad inquinamento urbano e a fumo di sigaretta sarà effettuata sia su campioni di sangue che di espettorato misurando la lunghezza dei telomeri. Ci si aspetta che il tasso di declino della funzione polmonare sia associato al tasso di invecchiamento biologico. Tra risultati attesi ipotizziamo anche che l'invecchiamento nei leucociti del sangue rispecchi quello delle cellule dell'espettorato indotto. A parità di infiammazione e di esposizione all'inquinamento ambientale, ci si aspetta che il fumo di sigaretta acceleri l'invecchiamento delle cellule dell'espettorato indotto.
In conclusione, la presenza di BPCO influenza sia il carico di particelle carboniose nel polmone legate al traffico urbano (a parità di esposizione esterna dei soggetti), sia la biodiversità della colonizzazione microbica polmonare. Viceversa, il fumo di sigaretta non ha effetti sul contenuto di particelle carboniose, ma agisce sulla composizione del microbiota.

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Tipo di EPrint:Tesi di dottorato
Relatore:Lotti, Marcello
Correlatore:Maestrelli, Piero
Dottorato (corsi e scuole):Ciclo 28 > Scuole 28 > TERRITORIO, AMBIENTE, RISORSE E SALUTE
Data di deposito della tesi:27 Gennaio 2016
Anno di Pubblicazione:27 Gennaio 2016
Parole chiave (italiano / inglese):BPCO macrofagi microbioma particolato telomeri
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/44 Medicina del lavoro
Struttura di riferimento:Dipartimenti > Dipartimento Territorio e Sistemi Agro-Forestali
Codice ID:9089
Depositato il:07 Nov 2016 16:29
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