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From the Department of Pathology,* University of Verona, Verona; the Department of Pneumology, Forlì City Hospital, Forlì; the Department of Pathology, Mestre City Hospital, Mestre; the Department of Pathology, Maggiore Hospital, Bologna; the Department of Experimental Oncology,¶ Centro di Riferimento Oncologico Aviano National Cancer Institute, Aviano; the Department of Clinical and Experimental Medicine,|| University of Padua, Padua; and the Department of Pathology,** Belluno City Hospital, Belluno, Italy
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 ß-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 ß-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 (
N-p63, surfactant-protein-A, cytokeratin-5). Interestingly, nuclear ß-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 ß-catenin gene. On the basis of these findings new models for IPF/UIP pathogenesis can be hypothesized, centered on the aberrant activation of Wnt/ß-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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