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Marulli, Giuseppe (2009) Detection of Squamos Cell Carcinoma Antigen (SCCA) in early and end stage Idiopathic Pulmonary Fibrosis (IPF): molecular substrates and clinico-pathological correlations. [Tesi di dottorato]

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Abstract (inglese)

BACKGROUND
Idiopathic pulmonary fibrosis (IPF), morphologically characterized by usual interstitial pneumonia (UIP), represents a progressive disease of unknown aetiology that continues to be associated with poor prognosis. The cardinal pathological features are the epithelial damage/activation, fibroblastic/myofibroblastic foci formation and extracellular matrix remodelling. The current paradigm suggests a pivotal role of the epithelium in the disease pathogenesis. Epithelial injury and subsequent deregulated repair results in profibrogenic cytokines (like TGF-?1) release with consequent abnormal mesenchymal cell activation and proliferation. Therefore, epithelial instability seems a crucial step in the development and progression of the disease, including neoplastic transformation. Few molecular tissue markers have been studied in IPF in order to clarify the pathogenetic mechanisms leading to the disease. Squamous cell carcinoma antigen (SCCA) is a serine protease inhibitor (serpin) physiologically found in the normal squamous epithelium and typically expressed by dysplastic and neoplastic epithelial cells of various origin, more often in squamous cell tumours. No information is actually available on its expression in IPF.
MATERIAL AND METHODS
In this study we analysed SCCA and TGF-b1 expression in surgical open-lung biopsies from 22 IPF patients with early-stage disease (GROUP A), in native lungs from 48 IPF patients with end-stage disease (GROUP B) who underwent to lung transplantation and in 20 control cases (GROUP C, 10 normal lungs from cadaveric donors, 10 lungs from patients with other interstitial diseases).
In vitro study using A549 pneumocytes was also conducted to investigate the relationship between SCCA and TGFb1 expression. SCCA and TGFb1 epithelial expression were evaluated by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). Time course analysis of TGF-b1 expression in A549 pneumocytes incubated with different SCCA concentrations was assessed by real time RT-PCR. The quantitative immunohistochemical assessment of SCCA and TGF-?1 was undertaken in each IPF sample by counting at least 500 cuboidal cells. A quantitative assessment of different pathological parameters (fibrosis, fibroblast foci and honeycombing changes) have been also considered in each samples. Clinical data including lung function and cardiovascular parameters were correlated to pathological features. In GROUP A lung function tests were re-evaluated at 8-12 months after biopsy.
RESULTS
Alveolar SCCA expression was present in IPF patients, but was not detected in alveolar cells in any of control cases. In GROUP A SCCA was positively correlated with the extension of fibroblastic foci (r=0.49, p=0.02), expression of TGF-b1 (r=0.78, p<0.0001) and with DLCO decline at follow-up (r=0.59, p=0.01). In vitro experiments showed that incubation of cultured cells with SCCA induced TGF-b1 expression, with a peak at 24 hours. In GROUP B SCCA and TGF-b1 values were high and positively correlated (r=0.45, p<0.001), while an inverse correlation was found between SCCA and DLCO (r=-0.43, p=0.005) and TGF-b1 and DLCO (r=-0.42, p=0.04). Interestingly, among metaplastic alveolar epithelial cells, a significant difference in SCCA expression was found between cuboidal, bronchialized and squamous cells, with increased expression for squamous cells that also presented a significant higher grade of dysplasia.
CONCLUSION
The over-expression of SCCA and TGF-?1 in the alveolar epithelium corroborates the hypothesis that disturbed epithelial alveolar regeneration and abnormal secretion of the cytokines are important steps in the pathogenesis of remodelling and fibrosis of IPF. SCCA could have a double role influencing the epithelial proliferation (autocrine action) and promoting fibroblast proliferation/fibrosis through increased TGF-?1 secretion (paracrine action). SCCA may be considered a potential marker of disease activity being strictly correlated with impairing lung function.

Abstract (italiano)

INTRODUZIONE
La fibrosi polmonare idiopatica (FPI), caratterizzata morfologicamente dal correlato patologico di polmonite interstiziale usuale (UIP), rappresenta una malattia ad eziologia sconosciuta, ad andamento progressivo e prognosi infausta.
Gli elementi anatomo-patologici cardine sono il danno/attivazione epiteliale, la formazione di foci fibroblastici/miofibroblastici ed il rimodellamento della matrice extracellulare. La teoria patogenetica più accreditata attribuisce un ruolo determinante alla disfunzione epiteliale alveolare. Il danno epiteliale ed i successivi meccanismi deregolati di riparo portano al rilascio di citochine pro-fibrogenetiche (come il TGF-b1) con conseguente attivazione e proliferazione di cellule mesenchimali. Di conseguenza, l’instabilità epiteliale sembra un elemento cruciale nello sviluppo e progressione della malattia, inclusa la trasformazione neoplastica. Pochi markers molecolari sono stati studiati e descritti fino ad ora nella FPI, per meglio chiarire i meccanismi patogenetici della malattia. Lo squamous cell carcinoma antigen (SCCA) è un inibitore delle serin proteasi (serpine) fisiologicamente presente nell’epitelio squamoso normale e specificamente espresso dalle cellule displastiche e neoplastiche epiteliali di varia origine, più spesso nei tumori a cellule squamose. Non sono ancora disponibili informazioni specifiche sulla sua espressione nella FPI.
MATERIALI E METODI
In questo studio abbiamo analizzato l’espressione di SCCA e TGF-b1 in tessuto polmonare ottenuto da biopsie chirurgiche di 22 pazienti affetti da FPI in stadio clinico iniziale (Gruppo A), in polmoni nativi di 48 pazienti con malattia end-stage e sottoposti a trapianto di polmone (Gruppo B) e in 20 polmoni controllo (Gruppo C, 10 polmoni normali ottenuti da donatori cadaveri, 10 polmoni di pazienti affetti da altre malattie interstiziali).
Abbiamo inoltre condotto uno studio in vitro utilizzando pneumociti della linea A549, per investigare il rapporto tra la produzione di SCCA e l’espressione di TGF-b1. L’espressione di SCCA e TGF-b1 nelle cellule epiteliali è stata valutata con tecniche di immunoistochimica e reazione a catena della polimerasi-trascrizione inversa (RT-PCR). La produzione di TGF-b1 nei pneumoniti A549 incubati a diverse concentrazioni di SCCA è stata verificata con real time PCR. La valutazione quantitativa immunoistochimica di SCCA e TGF-b1 è stata eseguita in ciascun campione contando almeno 500 cellule cuboidali. Una valutazione quantitativa dei differenti parametri patologici (fibrosi, foci fibroblastici e honeycombing) è stata eseguita ugualmente in ciascun campione. I dati clinici, inclusi la funzione respiratoria e i parametri cardiovascolari sono stati correlati ai dati patologici. Nel Gruppo A i test di funzionalità polmonare sono stati ripetuti a 8-12 mesi dalla biopsia.
RISULTATI
L’espressione di SCCA nelle cellule epiteliali alveolari era presente nei pazienti con FPI, mentre era assente nei controlli. Nel Gruppo A l’SCCA era correlato positivamente con l’estensione dei foci fibroblastici (r=0.49, p=0.02), l’espressione di TGF-b1 (r=0.78, p<0.0001) e con il declino della DLCO al follow up (r=0.59, p=0.01). L’esperimento in vitro ha dimostrato che l’incubazione di pneumociti con SCCA induceva l’espressione di TGF-b1, con un picco a 24 ore. Nel Gruppo B i valori di SCCA e TGF-b1 erano elevati e correlati positivamente (r=0.45, p<0.001), mentre vi era una correlazione inversa tra SCCA e DLCO (r=-0.43, p=0.005) e TGF-b1 e DLCO (r=-0.42, p=0.04). Tra le cellule epiteliali alveolari metaplastiche, abbiamo riscontrato una diversa espressione di SCCA tra le cellule cuboidali, bronchializzate e squamose, con una crescente espressione per le squamose che inoltre presentavano un maggior grado di displasia.
CONCLUSIONI
La over-espressione di SCCA e TGF-b1 nell’epitelio alveolare corrobora l’ipotesi che una alterata rigenerazione epiteliale alveolare e una secrezione anormale di citochine sono elementi importanti nella patogenesi del rimodellamento e della fibrosi della FPI. L’SCCA potrebbe avere un duplice ruolo influenzando la proliferazione epiteliale (azione autocrina) e promuovendo la fibrosi/proliferazione dei fibroblasti attraverso lo stimolo alla maggior secrezione di TGF-b1. L’SCCA potrebbe essere considerato un marker potenziale di attività della malattia essendo strettamente correlato con la perdita di funzione polmonare.


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Tipo di EPrint:Tesi di dottorato
Relatore:Federico, Rea
Dottorato (corsi e scuole):Ciclo 21 > Scuole per il 21simo ciclo > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > SCIENZE CARDIOVASCOLARI
Data di deposito della tesi:02 Febbraio 2009
Anno di Pubblicazione:02 Febbraio 2009
Parole chiave (italiano / inglese):SERPIN, SQUAMOUS CELL CARCINOMA ANTIGEN, IDIOPATHIC PULMONARY FIBROSIS; TGF-BETA.
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/21 Chirurgia toracica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari
Codice ID:1951
Depositato il:02 Feb 2009
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