Matrix metalloproteinases as profibrotic factors in terminal ileum in Crohn's disease.
BACKGROUND
Returning stenosis in Crohn's disease (CD) patients is poorly understood. After resection, newly developed strictures are seen within 10 years in 50% to 70%. Matrix metalloproteinases (MMPs) are involved in matrix-turnover processes. This study analyzes spatial expression of MMP-1, MMP-3, MMP-9, tissue inhibitor of MMP-1, and collagen III to get better insight in tissue remodeling of terminal ileum of CD patients.


METHODS
Expressions were analyzed on mRNA and the protein level (MMP-1, MMP-3) in segments from resected terminal ileum from CD and control patients. In CD, macroscopic distinction was made between proximal resection margin, prestenotic, and stenotic tissue. Immunohistochemistry allowed for expression analyses transmurally.


RESULTS
MMP-1 and MMP-3 gene expression was up-regulated (P < 0.05) in both prestenotic and stenotic tissue. MMP-1 protein was significantly up-regulated in submucosal and muscular tissue of prestenotic parts and in muscular tissue of stenotic Crohn samples. MMP-3 protein was significantly up-regulated in all layers of prestenotic and stenotic Crohn samples. Even in submucosa of proximal resection margin tissue, MMP-3 expression was significantly higher than in controls.


CONCLUSIONS
Surprisingly, in proximal resection margin tissue up-regulated MMP-3 was seen. This suggests that in nonresected terminal ileum, in which anastomosis is made, tissue turnover is present, which may account for the high recurrence of intestinal strictures.
Warnaar
Nienke
N
Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. n.warnaar@chir.umcg.nl
Hofker
H Sijbrand
HS
Maathuis
Mark H J
MH
Niesing
Jan
J
Bruggink
Annette H
AH
Dijkstra
Gerard
G
Ploeg
Rutger J
RJ
Schuurs
Theo A
TA
D000328:Adult; D003251:Constriction, Pathologic / Q000201:enzymology / Q000473:pathology; D003424:Crohn Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007082:Ileum / Q000201:enzymology* / Q000473:pathology* / Q000601:surgery; D019410:Interleukin-16 / Q000096:biosynthesis; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000235:genetics; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012008:Recurrence; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation
D019410:Interleukin-16; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1