Aberrant Wnt/β-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.

Gene Expression Profiling of Familial and Sporadic Interstitial Pneumonia

“…Aberrant activation of the Wnt/␤-catenin signaling pathway has been proposed as a potential molecular event leading to dysregulated repair in the fibrotic lung (41). Our findings indicate that several components of the Wnt signaling pathway are differentially expressed in the lungs of patients with IIP; for example, SFRP2 is almost fourfold upregulated in the diseased tissue.…”

Matrix Metalloproteinase 3 Is a Mediator of Pulmonary Fibrosis

“…Recent evidence has identified ␤-catenin, a powerful regulator of cell proliferation, as a key effector in fibrosis of both pulmonary and extrapulmonary organs. 41 Chilosi et al 18 reported evidence of aberrant Wnt/ ␤-catenin activation in fibroproliferative bronchiolar lesions and also nuclear ␤-catenin accumulation in the fibroblastic foci in lung samples from patients with IPF. More recently, Konigshoff et al 30 reported that WISP1, a target gene of the Wnt/␤-catenin pathway, is a key regulator of pulmonary fibrosis through its ability to induce collagen matrix deposition by fibroblasts and EMT.…”

“…17 Cyclin D1 immunohistochemistry and ␤-catenin immunofluorescence staining (both from Cell Signaling Technology, Danvers, MA) were performed on paraffin-embedded lung tissue. 18,19 Briefly, lung tissue sections were deparaffinized and rehydrated. Antigen retrieval was performed by boiling slides in sodium citrate buffer (pH 6.0) for 10 minutes.…”

“…We focused on the ␤-catenin signaling cascade, which has been recently implicated in the pathogenesis of pulmonary fibrosis 18,30,31 and also in the EMT program. 12,13 For 1738 Yamashita et al AJP October 2011, Vol.…”

Cathepsin-K immunoreactivity distinguishes MiTF/TFE family renal translocation carcinomas from other renal carcinomas

“…The sections from tissue blocks of MiTF/TFE family translocation carcinomas and control cases were immunolabeled with cathepsin-K using two different antibodies (clone CK4, Novocastra, Newcastle, UK and clone 3F9, Abcam, Cambridge, UK) and MiTF (clone D5, Neomarkers/LabVision, Fremont, CA, USA), using previously described methods. 18 Heat-induced antigen retrieval was performed using a microwave oven and 0.01 mol/l of citrate buffer, pH 8.0, for 30 min. All samples were processed using …”