BackgroundIdiopathic pulmonary fibrosis (IPF) is a devastating interstitial pneumonia causing a loss of respiratory surface area due to a proliferative fibrotic response involving hyperplastic, hypertrophic, and metaplastic epithelium, cystic honeycomb change, septal expansion, and variable inflammation. Wnt (wingless) signaling glycoproteins are known to be involved in lung development and tissue repair, and are up-regulated in patients with IPF. Based on previous qRT-PCR data showing increased Wnt7B in lungs of IPF patients, a systematic, quantitative examination of its tissue site distribution was undertaken.MethodsTissue samples from the Lung Tissue Research Consortium (LTRC) of 39 patients diagnosed with mild to severe IPF/usual interstitial pneumonia (UIP) and 19 normal patients were examined for the immunolocalization of Wnt7B.ResultsIn normal lung, moderate Wnt7B reactivity was confined to airway epithelium, smooth muscle of airways and vasculature, and macrophages. IPF lung showed strong Wnt7B reactivity in fibroblastic foci, dysplastic airway and alveolar epithelium, and in highly discrete subepithelial, basement membrane-associated regions. All reactive sites were sized and counted relative to specific microscopic regions. Those in the subepithelial sites were found in significantly greater numbers and larger relative area compared with the others. No reactive sites were present in normal patient controls.ConclusionsThe results demonstrate Wnt7B to be expressed at high concentrations in regions of active hyperplasia, metaplasia, and fibrotic change in IPF patients. In this context and its previously established biologic activities, Wnt7B would be expected to be of potential importance in the pathogenesis of IPF.
Rationale:Previous studies have shown that specific Wnt (wingless) signaling ligands, including Wnt7b, are involved in lung development and homeostasis and shown to be quantitatively dysregulated in patients with idiopathic pulmonary fibrosis (IPF). However, how these specific changes are reflected in the tissue/cellular distribution of Wnt7b expression has not been explored. Methods: Tissue samples obtained from the Lung Tissue Research Consortium (LTRC) of 40 patients diagnosed with mild to severe IPF or usual interstitial pneumonia (UIP) were sectioned and stained for the immunolocalization of Wnt7B ligand. Reactive sites were measured and counted relative to designated regions, quantitatively analyzed, and found to be significantly different from 19 patient controls provided by LTRC. Results: Wnt7B was localized in discrete anatomic sites, including fibroblastic foci, dysplastic airway and alveolar epithelium, a subpopulation of fibroblasts, and of particular note, a large number of subepithelial, basement membrane-associated regions. Conclusions:The results demonstrate the presence of Wnt7B in significantly increased concentrations in regions of active cellular hyperplasia, metaplasia, and fibrosing change, while it was not abundantly expressed in normal lung. The site distribution suggests that Wnt7b could be a compelling candidate for contributing to the initiation and/or progression of IPF. This abstract is funded by: PHS grants HL44497, HL95411, and the State of North Carolina Am J Respir Crit Care Med 185;2012:A5533 Internet address: www.atsjournals.org Online Abstracts Issue
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