Abstract
BackgroundIntestinal fibrosis and subsequent stricture formation represent frequent complications of Crohn’s disease (CD). In many organs, fibrosis develops as a result of epithelial to mesenchymal transition (EMT). Recent studies suggested that EMT could be involved in intestinal fibrosis as a result of chronic inflammation. Here, we investigated whether EMT might be involved in stricture formation in CD patients.MethodsHuman colonic tissue specimens from fibrotic areas of 18 CD and 10 non-IBD control patients were studied. Immunohistochemical staining of CD68 (marker for monocytes/macrophages), transforming growth factor-β1 (TGFβ1), β-catenin, SLUG, E-.cadherin, α-smooth muscle actin and fibroblast activation protein (FAP) were performed using standard techniques.ResultsIn fibrotic areas in the intestine of CD patients, a large number of CD68-positive mononuclear cells was detectable suggesting an inflammatory character of the fibrosis. We found stronger expression of TGFβ1, the most powerful driving force for EMT, in and around the fibrotic lesions of CD patients than in non-IBD control patients. In CD patients membrane staining of β-catenin was generally weaker than in control patients and more cells featured nuclear staining indicating transcriptionally active β-catenin, in fibrotic areas. In these regions we also detected nuclear localisation of the transcription factor, SLUG, which has also been implicated in EMT pathogenesis. Adjacent to the fibrotic tissue regions, we observed high levels of FAP, a marker of reactive fibroblasts.ConclusionsWe demonstrate the presence of EMT-associated molecules in fibrotic lesions of CD patients. These findings support the hypothesis that EMT might play a role for the development of CD-associated intestinal fibrosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s40169-015-0046-5) contains supplementary material, which is available to authorized users.
Highlights
Intestinal fibrosis and subsequent stricture formation represent frequent complications of Crohn’s disease (CD)
To identify fibrotic areas we visualized collagen fibers using van Gieson staining, while we confirmed the presence of inflammatory cells in fibrotic areas by CD68 staining, which is a well-established marker for human monocytes and macrophages [17]
We found a large number of CD68 positive cells in and around fibrotic areas of colonic tissue samples from CD patients (Figure 1), what correlates with the hypothesis that intestinal fibrosis is associated with inflammation
Summary
Intestinal fibrosis and subsequent stricture formation represent frequent complications of Crohn’s disease (CD). Fibrosis develops as a result of epithelial to mesenchymal transition (EMT). Recent studies suggested that EMT could be involved in intestinal fibrosis as a result of chronic inflammation. During EMT, epithelial cells lose their polarized phenotype and convert into mesenchymal-like myofibroblasts which is indicated by co-expression of epithelial markers, such as E-cadherin or cytokeratines 8 and 20, and mesenchymal markers, such as α-smooth muscle actin (α-SMA) or vimentin, in EMT cells [10,12] This way, EMT represents one of the main sources of activated fibroblasts in many organ systems and its most powerful mediator in vitro and in vivo is transforming growth factor beta (TGFβ) [11,12,13,14,15]
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