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. 2003 May;162(5):1495-502.
doi: 10.1016/s0002-9440(10)64282-4.

Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis

Marco Chilosi  1 , Venerino Poletti, Alberto Zamò, Maurizio Lestani, Licia Montagna, Paola Piccoli, Serena Pedron, Manuela Bertaso, Aldo Scarpa, Bruno Murer, Alessandra Cancellieri, Roberta Maestro, Gianpietro Semenzato, Claudio Doglioni
Affiliations

Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis

Marco Chilosi et al. Am J Pathol. 2003 May.

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.

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Figures

Figure 1.
Figure 1.
a: Fetal lung (12 weeks): nuclear expression of β-catenin is evident in alveolar buds, but not in airway cells. b: Normal lung: discrete membrane immunoreactivity of β-catenin in basal and ciliated cells in a bronchiole. c: IPF/UIP: aberrant nuclear accumulation of β-catenin in a proliferative bronchiolar lesion. d: IPF/UIP: nuclear expression of β-catenin in basal cells of an abnormal bronchiole. e: IPF/UIP (serial section to d): cyclin-D1-expressing cells. f: IPF/UIP (serial section to d): matrilysin/MMP-7 abnormal expression. g: IPF/UIP: H&E appearance of a small honeycombing bronchiolar lesion. h: IPF/UIP (serial section to g): basal cell hyperplasia as evidenced by ΔN-p63 nuclear expression. i: IPF/UIP (serial section to g): basal cell hyperplasia as evidenced by CK5 expression. j: IPF/UIP (serial section to g): abnormal intracellular expression of β-catenin in both basal and luminal epithelial cells. k: IPF/UIP (serial section to g): increased expression of cyclin-D1. l: IPF/UIP (serial section to g): aberrant expression of matrilysin/MMP-7 in basal cells.
Figure 2.
Figure 2.
a: IPF/UIP: nuclear accumulation of β-catenin in cuboidal type II pneumocytes (arrow) in scarcely affected alveolar structures. b: IPF/UIP: nuclear accumulation of β-catenin in cuboidal type II pneumocytes (arrow) in severely affected alveolar structures. c: IPF/UIP: nuclear accumulation of β-catenin in spindled fibroblasts in subepithelial fibroblast foci. d: IPF/UIP (serial section to c): strong tenascin expression in spindled fibroblasts in subepithelial fibroblast foci. e: IPF/UIP: nuclear accumulation of β-catenin in spindled cells of subepithelial fibroblast foci. Note nuclear expression of β-catenin also in bronchiolar basal cells (arrow). f: OP/BOOP: nuclear β-catenin expression is not observed in spindled cells of an intraluminal Masson’s body and in macrophages (Mc). Note intense nuclear immunostaining in hyperplastic type II pneumocytes (arrow). g: DAD: nuclear β-catenin expression is evident in alveolar pneumocytes. Interstitial fibroblasts (arrow) and macrophages (Mc) lack evident immunoreactivity. h: NSIP: membrane β-catenin expression in bronchiolar cells. i: NSIP: scarce expression of matrilysin/MMP-7 in bronchiolar cells. j: NSIP: nuclear β-catenin expression in many alveolar pneumocytes.
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Comment in

  • Wnt signaling and pulmonary fibrosis.
    Morrisey EE. Morrisey EE. Am J Pathol. 2003 May;162(5):1393-7. doi: 10.1016/S0002-9440(10)64271-X. Am J Pathol. 2003. PMID: 12707021 Free PMC article. Review. No abstract available.

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