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Gattazzo, Cristina (2009) Role of inflammation in the development of lung fibrosis and in the pathogenesis of pulmunary hypertension. [Tesi di dottorato]

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Abstract (inglese)

ABSTRACT
Background: The bleomycin is a glycopeptide with antitumor and antiviral activity utilized in clinical for chemotherapeutic treatment of several neoplasms. Unfortunately the 10% of treated patients develops interstitial pneumonia that progresses to fibrosis. The fibrogenesis is linked to develop of a Th2 cellular response with proinflammatory chemokines release.
Glycogen Synthase Kinase 3 (GSK-3) is a pivotal element for the control of immune response because modulates the inflammatory cytokines production. Since lung injury caused by bleomycin is characterized by an inflammatory response followed by a fibrotic degeneration, we postulated that blocking GSK-3 kinase activity with a specific inhibitor could affect the bleomycin-induced pulmonary inflammatory and pro-fibrotic cytokine network. Moreover it has been demonstrated that the develop of pathologies which elicit a Th2 inflammatory response could be mitigated by agents able to induce a Th1 immune response. Indeed administration of Neutrophil-Activating Protein of Helicobacter pylori (HP-NAP) was found to be able to down modulate the Th2 immune response in a asthma ovalbumin-induced model mouse by eliciting a Th1 immune response and resulted effective in preventing allergic asthma in the model mouse.
Purpose of the study: We investigated the effects of the specific and selective ATP-competitive GSK-3 inhibitor, SB216763, and the effects of HP-NAP administration on the onset and development of inflammation and fibrosis in a bleomycin-induced lung fibrosis mouse model.
Methods: We differently randomised cohorts of C57BL6 mice to receive intratracheal instillation of inhibitor SB216763, HP-NAP, bleomycin, bleomycin plus SB216763 or bleomycin plus HP-NAP and followed their health status for 28 days. Bronchoalveolar lavage (BAL) was performed and mice were sacrificed at different interval times (2, 7, 14 and 28 days). Histopathological analysis of the lungs, flow-cytometry studies and Cell Sorting of BAL pulmonary monocytes were then performed. Finally we examined cytokines gene expression levels in lung monocytes trough Real Time PCR analysis.
Results: SB216763 and HP-NAP administration prevented lung inflammation and the subsequent fibrosis when co-administrated with bleomycin. BALF analysis of mice revealed a significant reduction in bleomycin-induced alveolitis. SB216763 treatment was associated with a significantly lower production of inflammatory cytokines (TNF-α and CCL12) by macrophages. Moreover we observed that HP-NAP administration downmodulated the Th2 inflammatory response bleomycin-induced by eliciting a Th1 phenotype (downmodulating IL-4 chemokine and upregulating the IFN-γ).
Conclusions: These findings suggest that GSK-3 inhibition induces a protective effect on lung fibrosis triggered by bleomycin and candidate GSK-3 as a potential therapeutic target for preventing pulmonary fibrosis. Furthermore our results suggest that also HP-NAP, preventing lung fibrosis develop, might be a possible new tool for therapeutic strategies aimed to redirect Th2 into less aggressive Th1 response.

Abstract (italiano)

RIASSUNTO
Background: La bleomicina è un glicopeptite con attività antitumorale e antivirale utilizzata in clinica come chemio-terapico per il trattamento di diversi tumori. Sfortunatamente il 10% dei pazienti trattati sviluppa polmonite interstiziale che progredisce in fibrosi. La fibrogenesi è collegata allo sviluppo di una risposta immunitaria di tipo Th2 accompagnata dal rilascio di chemiochine pro-infiammatorie.
La Glicogeno Sintetasi Chinasi 3 (GSK-3, Glycogen Synthase Kinase 3)
è un fattore centrale per il controllo della risposta immunitaria poiché modula la produzione di citochine infiammatorie. Visto che il danno polmonare è caratterizzato da una risposta infiammatoria seguita da una degenerazione fibrotica, noi abbiamo ipotizzato che l’inibizione dell’attività di GSK-3, tramite uno specifico inibitore, potrebbe influenzare l’infiammazione del polmone ed il network di citochine pro-infiammatorie indotti dalla bleomicina. Recentemente è anche stato visto che lo sviluppo di patologie sostenute da un’infiammazione di tipo Th2 possono essere mitigate da agenti in grado di indurre una risposta infiammatoria di tipo Th1. In accordo con questi risultati la proteina attivante i neutrofili, prodotta dal batterio Helicobacter pylori (HP-NAP), stimolando una risposta immunitaria di tipo Th1, si è dimostrata capace di modulare la risposta immunitaria di tipo Th2 indotta dall’ ovalbumina in un modello murino di asma, risultando quindi efficace nel prevenire lo sviluppo dell’asma allergica.
Scopo dello studio: In questa ricerca abbiamo investigato gli effetti della somministrazione dell’inibitore SB216763, specifico per GSK-3, e della somministrazione della proteina HP-NAP nello sviluppo dell’infiammazione e della fibrosi nel modello murino di fibrosi polmonare indotta da bleomicina.
Metodi: Differenti coorti di topi C57BL6 sono state randomizzate per ricevere instillazione di SB216763, HP-NAP, bleomicina, bleomicina più SB216763 o bleomicina più HP-NAP, ed il loro stato di salute è stato monitorato per 28 giorni. I topi sono stati sacrificati ed i lavaggi broncho alveolari (BALs) eseguiti a diversi intervalli di tempo (a 2, 7, 14 e 28 giorni). Quindi sono stati eseguiti l’analisi istopatologia dei polmoni e valutazioni citoflurimetriche del BAL. Infine sono stati esaminati, tramite Real Time PCR, i livelli di espressione genica delle citochine nei monociti di polmone purificati dai BALs tramite sorting.
Risultati: La somministrazione dell’inibitore SB216763 e della proteina HP-NAP, quando co-somministrati con la bleomicina, sono stati in grado di prevenire l’instaurarsi dell’infiammazione e il conseguente sviluppo di fibrosi nel polmone. L’analisi dei BALs ha infatti rivelato una significativa riduzione dell’alveolite indotta dalla bleomicina. Il trattamento con l’SB216763 si è associato con una ridotta produzione, da parte di macrofagi, di citochine infiammatorie (TNF-α and CCL12), mentre la somministrazione di HP-NAP ha down-modulato la risposta infiammatoria di tipo Th2 indotta dalla bleomicina, stimolando il tipo Th1(diminuendo il livello di espressione delle chemiochina IL-4 ed aumentando invece quello di IFN-γ).
.Conclusioni: I risultati ottenuti in questo progetto di ricerca suggeriscono che l’inibizione di GSK-3 ha un effetto protettivo nella fibrosi polmonare indotta dalla bleomicina e candidano GSK-3 come potenziale target terapeutico per prevenire la fibrosi polmonare; inoltre suggeriscono che la proteina HP-NAP, prevenendo lo sviluppo della fibrosi polmonare tramite l’induzione di una risposta di tipo Th1, potrebbe essere una nuova strategia terapeutica per ridirezionare la risposta infiammatoria dal fenotipo Th2 verso quello meno aggressivo Th1.

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Tipo di EPrint:Tesi di dottorato
Relatore:Agostini, Carlo
Correlatore:Garbisa, Spiridione
Dottorato (corsi e scuole):Ciclo 21 > Corsi per il 21simo ciclo > IPERTENSIONE ARTERIOSA E BIOLOGIA VASCOLARE
Data di deposito della tesi:NON SPECIFICATO
Anno di Pubblicazione:13 Marzo 2009
Parole chiave (italiano / inglese):IPF, bleomycin, HP-NAP, lung fibrosis
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/11 Malattie dell'apparato cardiovascolare
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina Clinica e Sperimentale
Codice ID:2029
Depositato il:03 Lug 2009 10:48
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