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Cinetto, Francesco (2015) Glycogen synthase kinase-3 (GSK-3) in the pathogenesis of pulmonary fibrosis: what we know from the mouse model. [Tesi di dottorato]

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Abstract (inglese)

Introduction: Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by an aberrant interstitial deposition of collagen in the lung parenchyma, leading to progressive lung function impairment. Repeated injuries to the alveolar epithelium are believed to lead to an imbalance of the extracellular matrix (ECM) turnover supported by metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). The kinase GSK-3 is a mediator of the cytokine homeostasis and favors the production of pro-inflammatory mediators. Its specific inhibitor, SB216763, displayed anti-inflammatory and anti-fibrotic properties of in a mouse model of Bleomycine (BLM)-induced pulmonary fibrosis. Furthermore, GSK-3 seems to be involved in the epithelial to mesenchimal transition (EMT). The purpose of this study was to assess the expression of MMP9, TIMP1, MMP2 and and TIMP2 in the early inflammatory response and in the late fibrosis induced by BLM in a mouse model of pulmonary fibrosis. Next goal was to elucidate whether the in vivo treatment with SB216763 could modulate MMPs activity and their balance with TIMPs. Moreover, in vitro experiments were aimed to identify the signal pathways through which GSK-3 can modulate MMPs and TIMPs.
Methods: Cohorts of C57BL6 mice (12 weeks old) were randomized to receive intratracheal instillation of either saline (PBS), or BLM alone, or BLM in association with SB216763. The inhibitor was administered intraperitoneally the day after BLM and every 48 hours up to the sacrifice on day 7 (inflammatory phase) or 28 (fibrotic phase), when bronchoalveolar lavage (BAL) was performed and lungs harvested. MMP9 and MMP2 activity was measured by gel zymography in BAL fluid (BALF). MMPs and TIMPs expression levels were evaluated by Real Time-PCR and Western Blotting. Their tissue localization was evaluated by IHC analysis. In vitro experiments were performed using A549 cells as epithelial model, assessing expression and activity of MMPs downstream of TNFα, with and without GSK-3 silencing by siRNA.
Results: MMP9 and MMP2 levels were elevated in BALF from BLM-treated mice at day 7. At this time point, the inflammatory cells recruited in the intra-alveolar spaces were alveolar macrophages (AMs), lymphocytes and neutrophils. Furthermore, the lung IHC staining indicated a strong positivity for MMP9, MMP2, TIMP1 and TIMP2 in interstitial AM (iAM) and, specifically, in injured and cuboidalized epithelium. BLM-treated mice sacrificed at day 28 presented high levels of MMP2 and TIMP1 and low levels of MMP9 in the BALF. Interestingly, in vivo GSK-3 inhibition reduced MMP9, MMP2 and TIMP1 levels in the BALF and their positivity in iAMs and in epithelium. Moreover, in vitro experiments performed with A549 cells, as epithelial model, demonstrated that GSK-3α and GSK-3β silencing increased MMP9 expression after stimulation with the pro-inflammatory cytokine TNFα. This effect was achieved by the interaction of GSK-3 with NF-kB and ERK signalling transduction pathway.
Conclusions: Our mouse model of BLM-induced pulmonary fibrosis clearly showed an imbalance between MMPs and TIMPs during inflammation and fibrosis. Importantly, we proposed GSK-3 as a crucial mediator of their expression in AMs and in damaged epithelium. Next, in vitro results with A549 cells suggested that GSK-3 silencing induce MMP-9 secretion, downstream of TNFα, in a p65-mediated and ERK1,2 dependent manner.

Abstract (italiano)

Introduzione: La fibrosi polmonare idiopatica (IPF) è un'interstiziopatia caratterizzata da un decorso fatalmente progressivo, che conduce alla completa compromissione della funzione polmonare. Pur essendo la sua patogenesi non pienamente compresa, il primum movens sembra essere un danno epiteliale ripetuto che induce l'aberrante deposizione di matrice extracellulare (ECM), il cui turnover non viene più garantito da metalloproteasi (MMPs) e loro inibitori tissutali (TIMPs). La chinasi GSK-3 è nota per il suo ruolo cardine nella modulazione di citochine pro-infiammatorie ed in diverse vie del segnale e processi cellulari verosimilmente coinvolti nella patogenesi della IPF. La sua inibizione in vivo, in un modello murino di fibrosi polmonare indotta da bleomicina (BLM), si è dimostrata in grado di modulare sia la risposta infiammatoria precoce che la fase fibrotica tardiva. Il ruolo della chinasi nella modulazione dell'equilibrio fra MMPs e TIMPs nella fibrogenesi polmonare non è ad oggi chiarito.
Metodi: Diverse coorti di topi C57BL6 sono state sottoposte all'instillazione endotracheale di BLM o PBS e trattate o meno, per via intraperitoneale, con l'inibitore di GSK-3 SB216763. Per misurare attività, espressione proteica e genica delle MMPs sono stati utilizzati, rispettivamente, zimografia, WB analysis e RT-PCR del liquido di lavaggio bronco alveolare (BALF) di topi sacrificati a 7 o 28 giorni dalla somministrazione di BLM. L'espressione proteica e genica delle TIMPs è stata valutata con WB e RT-PCR. E' stata inoltre eseguita l'analisi istologica ed immunoistochimica dei polmoni, ai due intervalli di tempo. L'effetto in vitro del silenziamento di GSK-3 è stato infine studiato su una linea di cellule epiteliali alveolari umane (A549).
Risultati: Il trattamento con BLM ha dimostrato di aumentare la cellularità ed i livelli di MMP2 e MMP9 nel BALF al giorno +7. Si è inoltre registrato un significativo aumento dell'espressione di MMP2, MMP9, TIMP1 e TIMP2, all'analisi immunoistochimica, a livello di macrofagi alveolari (iAMs) e cellule epiteliali alveolari cuboidalizzate (CEACs). I topi sacrificati al giorno +28 hanno mostrato un incremento dei livelli di MMP2 e TIMP1, ma non di MMP9, nel BALF. L'inibizione in vivo di GSK-3 mediante SB216763 si è dimostra in grado di ridurre il reclutamento di cellule infiammatorie e la secrezione di MMPs al giorno +7, a livello del BALF; ha inoltre ridotto i livelli di MMP2 al giorno +28. Anche l'espressione di MMPs e TIMPs è stata modulata dall'inibizione di GSK-3, a livello di iAMs e CEACs, ad entrambi gli intervalli di tempo. Gli esperimenti in vitro su A549 hanno invece dimostrato che il silenziamento di GSK-3 è in grado di potenziare la secrezione di MMP9 indotta dallo stimolo proinflammatorio con TNFa, che attiva la via di NF-kB.
Conclusioni: Il nostro lavoro dimostra un ruolo di GSK-3 nella modulazione dell'espressione di MMPs e TIMPs in un modello murino di fibrosi polmonare indotta da BLM, che interessa sia la fase infiammatoria precoce che quella fibrotica tardiva. L'effetto dell'inibizione di GSK-3 sembra esplicarsi, in particolare, a livello di iAMs e CEACs. I dati in vitro, pur preliminari, indicano un effetto opposto del silenziamento di GSK-3 sulla secrezione di MMP9 in una linea di cellule epiteliali alveolari (A549); il silenziamento di GSK-3 potenzia l’effetto di TNFα sulla secrezione di MMP-9, tramite un meccanismo che coinvolge p65 ed è ERK1,2-dipendente

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Tipo di EPrint:Tesi di dottorato
Relatore:Agostini, Carlo
Dottorato (corsi e scuole):Ciclo 27 > corsi 27 > Ipertensione Arteriosa e Biologia Vascolare
Data di deposito della tesi:30 Aprile 2015
Anno di Pubblicazione:28 Aprile 2015
Parole chiave (italiano / inglese):IPF, MMPs, TIMPs, GSK-3, BLM mouse model
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/09 Medicina interna
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina
Codice ID:8763
Depositato il:16 Nov 2015 11:51
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