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Hallmarks of epithelial to mesenchymal transition are detectable in Crohn's disease associated intestinal fibrosis.

Scharl M, Huber N, Lang S, Fürst A, Jehle E, Rogler G - Clin Transl Med (2015)

Bottom Line: 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.Adjacent to the fibrotic tissue regions, we observed high levels of FAP, a marker of reactive fibroblasts.We demonstrate the presence of EMT-associated molecules in fibrotic lesions of CD patients.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology and Hepatology, University Hospital Zürich, Rämistrasse 100, 8091 Zurich, Switzerland ; Zurich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland.

ABSTRACT

Background: Intestinal 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.

Methods: Human 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.

Results: In 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.

Conclusions: We 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.

No MeSH data available.


Related in: MedlinePlus

FAP expression is strongly detectable in myofibroblasts adjacent to fibrotic areas. Representative images show (A) van-Gieson staining and (B) corresponding FAP staining in fibrotic tissue samples derived from CD patients. (B-D) FAP staining is strongly detectable in myofibroblasts adjacent to the fibrotic areas (black arrows), while FAP staining in myofibroblasts within fibrotic areas is limited (white arrows). Magnification: 10-fold. All analysed patient samples showed comparable staining characteristics when compared to samples from non-affected controls.
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Fig5: FAP expression is strongly detectable in myofibroblasts adjacent to fibrotic areas. Representative images show (A) van-Gieson staining and (B) corresponding FAP staining in fibrotic tissue samples derived from CD patients. (B-D) FAP staining is strongly detectable in myofibroblasts adjacent to the fibrotic areas (black arrows), while FAP staining in myofibroblasts within fibrotic areas is limited (white arrows). Magnification: 10-fold. All analysed patient samples showed comparable staining characteristics when compared to samples from non-affected controls.

Mentions: A number of studies indicated a role for FAP in the pathogenesis of chronic inflammatory and fibrotic conditions, such as liver cirrhosis. Since CD-associated fibrosis also occurs in response to chronic inflammation of the intestinal wall, we investigated whether FAP, a marker of fibroblast activation, would be expressed in or around fibrotic areas in the intestine of CD patients. Figure 5 demonstrates that FAP was only weakly expressed in the fibrotic areas. However, we found a strong, FAP-positive staining in fibroblasts adjacent to the fibrotic areas.Figure 5


Hallmarks of epithelial to mesenchymal transition are detectable in Crohn's disease associated intestinal fibrosis.

Scharl M, Huber N, Lang S, Fürst A, Jehle E, Rogler G - Clin Transl Med (2015)

FAP expression is strongly detectable in myofibroblasts adjacent to fibrotic areas. Representative images show (A) van-Gieson staining and (B) corresponding FAP staining in fibrotic tissue samples derived from CD patients. (B-D) FAP staining is strongly detectable in myofibroblasts adjacent to the fibrotic areas (black arrows), while FAP staining in myofibroblasts within fibrotic areas is limited (white arrows). Magnification: 10-fold. All analysed patient samples showed comparable staining characteristics when compared to samples from non-affected controls.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4384762&req=5

Fig5: FAP expression is strongly detectable in myofibroblasts adjacent to fibrotic areas. Representative images show (A) van-Gieson staining and (B) corresponding FAP staining in fibrotic tissue samples derived from CD patients. (B-D) FAP staining is strongly detectable in myofibroblasts adjacent to the fibrotic areas (black arrows), while FAP staining in myofibroblasts within fibrotic areas is limited (white arrows). Magnification: 10-fold. All analysed patient samples showed comparable staining characteristics when compared to samples from non-affected controls.
Mentions: A number of studies indicated a role for FAP in the pathogenesis of chronic inflammatory and fibrotic conditions, such as liver cirrhosis. Since CD-associated fibrosis also occurs in response to chronic inflammation of the intestinal wall, we investigated whether FAP, a marker of fibroblast activation, would be expressed in or around fibrotic areas in the intestine of CD patients. Figure 5 demonstrates that FAP was only weakly expressed in the fibrotic areas. However, we found a strong, FAP-positive staining in fibroblasts adjacent to the fibrotic areas.Figure 5

Bottom Line: 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.Adjacent to the fibrotic tissue regions, we observed high levels of FAP, a marker of reactive fibroblasts.We demonstrate the presence of EMT-associated molecules in fibrotic lesions of CD patients.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology and Hepatology, University Hospital Zürich, Rämistrasse 100, 8091 Zurich, Switzerland ; Zurich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland.

ABSTRACT

Background: Intestinal 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.

Methods: Human 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.

Results: In 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.

Conclusions: We 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.

No MeSH data available.


Related in: MedlinePlus