title: Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis.
abstract: To investigate the molecular events that may underpin dysfunctional repair processes that characterize idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), we analyzed the expression patterns of beta-catenin on 20 IPF/UIP lung samples, together with two downstream target genes of Wnt signaling, cyclin-D1, and matrilysin. In 18 of 20 cases of IPF/UIP investigated on serial sections, nuclear beta-catenin immunoreactivity and abnormal levels of cyclin-D1 and matrilysin were demonstrated in proliferative bronchiolar lesions (basal-cell hyperplasia, squamous metaplasia, bronchiolization, honeycombing). The nature of these lesions was precisely defined using specific markers (DeltaN-p63, surfactant-protein-A, cytokeratin-5). Interestingly, nuclear beta-catenin accumulation was also demonstrated in fibroblast foci in most (16 of 20) IPF/UIP samples, often associated with bronchiolar lesions. Similar features were not observed in normal lung and other fibrosing pulmonary diseases (diffuse alveolar damage, organizing pneumonia, nonspecific interstitial pneumonia, desquamative interstitial pneumonia). Sequence analysis performed on DNA extracted from three samples of IPF/UIP did not reveal abnormalities affecting the beta-catenin gene. On the basis of these findings new models for IPF/UIP pathogenesis can be hypothesized, centered on the aberrant activation of Wnt/beta-catenin signaling, with eventual triggering of divergent epithelial regeneration at bronchiolo-alveolar junctions and epithelial-mesenchymal-transitions, leading to severe and irreversible remodeling of the pulmonary tissue.
authors.affiliation: Department of Pathology, University of Verona, Verona, Italy. marco.chilosi@univr.it
authors.forename: Marco
authors.initials: M
authors.lastname: Chilosi
authors.forename: Venerino
authors.initials: V
authors.lastname: Poletti
authors.forename: Alberto
authors.initials: A
authors.lastname: Zamò
authors.forename: Maurizio
authors.initials: M
authors.lastname: Lestani
authors.forename: Licia
authors.initials: L
authors.lastname: Montagna
authors.forename: Paola
authors.initials: P
authors.lastname: Piccoli
authors.forename: Serena
authors.initials: S
authors.lastname: Pedron
authors.forename: Manuela
authors.initials: M
authors.lastname: Bertaso
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.forename: Bruno
authors.initials: B
authors.lastname: Murer
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cancellieri
authors.forename: Roberta
authors.initials: R
authors.lastname: Maestro
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Semenzato
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
mesh_terms: D000328:Adult; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005333:Fetus; D005786:Gene Expression Regulation; D006801:Humans; D008168:Lung / Q000196:embryology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000473:pathology*; D015534:Trans-Activators / Q000235:genetics*; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin