Distribution of the matrix metalloproteinases stromelysin, gelatinases A and B, and collagenase in Crohn's disease and normal intestine.

Bailey, Clifford J.; Hembry, Rosalind M.; Alexander, A; Irving, M. H.; Grant, Michael E.; Shuttleworth, C. Adrian

doi:10.1136/jcp.47.2.113

Cited by 131 publications

(104 citation statements)

References 13 publications

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“…However, we were unable to confirm the presence of plasmin in the inflamed tissue. Increased MMP-9 and unchanged MMP-2 expression corroborated the findings of a previous immunohistochemical study, 6 which was unable to distinguish pro-and activated forms. The recent work of Baugh et al 7 clearly shows that MMP-9 is a major factor in human intestinal inflammation, and was assumed to be a product of neutrophilia.…”

Section: Discussionsupporting

confidence: 79%

“…In particular, matrix metalloproteinases (MMPs) -9 and -3 have been associated with mucosal damage and fistulae in Crohn's disease patients, 6,7 MMPs 1, 3, and 13 with intestinal ulcer stroma, and MMPs 10 and 11 with the epithelium. 8,9 Furthermore, CD4 ϩ T cell activation in fetal intestinal explants equated with increased levels of MMP-1 and MMP-3, and exogenous MMP-3 promoted tissue degradation 10 implying a causal role.…”

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confidence: 99%

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The Role of Up-Regulated Serine Proteases and Matrix Metalloproteinases in the Pathogenesis of a Murine Model of Colitis

Tarlton¹,

Whiting²,

Tunmore³

et al. 2000

The American Journal of Pathology

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Proteinases are important at several phases of physiological and pathological inflammation, mediating cellular infiltration, cytokine activation, tissue damage, remodeling, and repair. However, little is known of their role in the pathogenesis of inflammatory bowel disease. The aim of this study was to assess the role of tissue proteases in a mouse model of colitis. Proteolytic activity was analyzed, using gel and in situ zymography, in colonic tissues from severe combined immunodeficient mice with colitis induced by transfer of CD4 ؉ T lymphocytes. Serine proteinase levels increased in colitic tissue, with major species of 23 kd, 30 kd, and 45 kd. Co-migration and inhibition studies indicated that the 23-kd proteinase was pancreatic trypsin and that the 30-kd species was neutrophil elastase. Matrix metalloproteinase (MMP)-9 expression, and MMP-2 and MMP-9 activation, was elevated in colitic tissues. Proteinase levels followed a decreasing concentration gradient from proximal to distal colon. Proteolysis was localized to infiltrating leukocytes in diseased severe combined immunodeficient mice. The inflammatory bowel diseases (IBD), Crohn's disease, and ulcerative colitis, probably share a common etiology, in terms of a dysregulation of mucosal T cell reactivity.

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Section: Discussionsupporting

confidence: 79%

mentioning

confidence: 99%

The Role of Up-Regulated Serine Proteases and Matrix Metalloproteinases in the Pathogenesis of a Murine Model of Colitis

Tarlton¹,

Whiting²,

Tunmore³

et al. 2000

The American Journal of Pathology

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“…The gelatinases A (MMP-2) and B (MMP-9) have been shown to be highly upregulated in small as well as large intestinal inflammation in mice and men [11][12][13][14][15][16]. We have recently reported that selective blockage of gelatinases by the synthetic compound RO28-2653 was effectively ameliorating acute ileitis [17] and colitis [18].…”

Section: Discussionmentioning

confidence: 99%

“…In experimental models of Th1-type inflammation (e.g. rheumatoid arthritis, atherosclerosis and colitis) [7][8][9][10] as well as in humans with inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn's disease [11][12][13][14][15][16], levels of gelatinases A (MMP-2) and B (MMP-9) are increased in inflamed tissue sites.…”

Section: Introductionmentioning

confidence: 99%

The distinct roles of MMP-2 and MMP-9 in acute DSS colitis

Heimesaat¹,

Dunay²,

Fuchs³

et al. 2011

European Journal of Microbiology and Immunology

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Expression of gelatinases A and B, also referred to matrixmetalloproteinases (MMP)-2 and -9, respectively, is increased in inflamed tissues of experimental intestinal inflammation and humans with inflammatory bowel disease (IBDs). Given that we recently reported that treatment with the selective gelatinase inhibitor RO28-2653 ameliorates acute dextrane sulfate sodium (DSS) colitis, we asked whether gelatinase A or B expression is pivotal in mediating large intestinal inflammation. Results from our study reveal that symptoms of acute DSS colitis as well as histopathological colonic changes were ameliorated in MMP-2-, but not MMP-9-deficient mice, and were paralleled by a diminished influx of immune cells. In MMP-2-deficient mice, we observed lower expression of pro-inflammatory cytokines including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and IL-6 in colonic biopsies and less overgrowth of the colonic lumen by potentially pro-inflammatory enterobacteria from the commensal gut microbiota. We conclude that rather MMP-2 than MMP-9 is causative for the establishment of DSS colitis in mice. The discrepancy of these data to prior reports might be due to substantial differences in the intestinal microbiota composition of the mice bred at different animal facilities impacting susceptibility to inflammatory stimuli. Consequently, a detailed survey of the gut microbiota should be implemented in immunological/inflammatory studies in the future in order to allow comparison of data from different facilities.

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“…Furthermore, MMP9 activity is correlated with active inflammation associated with fistula formation (43, 48). In addition, MMP9 tissue and serum levels correlate with disease activity in UC (1,28,35).In this study we utilized MMP9 transgenic mice (Tg-villin-MMP9) generated specifically to express MMP9 in intestinal epithelium to examine the role and underlying mechanism by which MMP9 modulates the pathogenesis of both infectious and chemical-induced colitis. …”

mentioning

confidence: 99%

Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc

Liu

Patel

Walter

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Liu H, Patel NR, Walter L, Ingersoll S, Sitaraman SV, Garg P. Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc. Am J Physiol Gastrointest Liver Physiol 304: G793-G803, 2013. First published March 7, 2013 doi:10.1152/ajpgi.00249.2012.-Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is a chronic inflammatory disease associated with an increased risk for colon cancer. Matrix metalloproteinases (MMPs) are the predominant proteinases expressed in the gut mucosa during active IBD. Our laboratory has previously demonstrated that epithelial-derived MMP9 is absent in normal colonic tissue but is upregulated during IBD. In this study MMP9 transgenic mice (Tg-villin-MMP9) are generated specifically to overexpress MMP9 in intestinal epithelium to examine the role and underlying mechanism by which it modulates the pathogenesis of acute colitis. Dextran sodium sulfate (3% DSS)-and Salmonella typhimurium (S.T.)-induced colitis models were used to study gut inflammation in Tg-villin-MMP9 and wild-type littermates (WT). Colonic tissue was analyzed via Western blot, histology, myeloperoxidase (MPO) assay, and quantitative PCR. Tg-villin-MMP9 mice expressed significantly increased MMP9 mRNA and protein expression at basal level. There was a significant decrease in the goblet cells, but a significant increase in proliferation and apoptosis were observed among Tg-villin-MMP9 mice compared with WT mice. There was also a significant increase in the proinflammatory chemokine Kc among Tg-villin-MMP9 compared with WT mice. Tg-villin-MMP9 exhibited a severe inflammatory response than WT mice in both DSSand S.T.-induced colitis models as evident by greater weight loss and higher clinical score, histological score, and MPO activity, which correlated with relative levels of Kc mRNA. MMP9 expressed by intestinal epithelial cells mediates inflammation in colitis with simultaneous increase in proinflammatory cytokine Kc. inflammation; dextran sodium sulfate; transgenic mice; IL-8 INFLAMMATORY BOWEL DISEASE (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), is a chronic inflammatory disease that affects the entire gastrointestinal (GI) tract and the colonic mucosa and is associated with an increased risk for colon cancer. IBD is characterized by relapses (acute flare) and remissions, which are related to genetic basis and involve immune-mediated tissue injury followed by repair. Recent studies have shown that cytokines play a key role in regulating IBD (9, 40). There is increased incidence of IBD in urban areas of industrialized nations (29,42). Matrix metalloproteinases (MMPs) are a group of zinc-dependent enzymes with proteolytic activity against extracellular matrix (ECM) proteins and are also known to play an important role for normal tissue remodeling (47). MMPs have also been shown to be involved in several pathological conditions such as IBD, tumor invasion, and colorect...

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Distribution of the matrix metalloproteinases stromelysin, gelatinases A and B, and collagenase in Crohn's disease and normal intestine.

Cited by 131 publications

References 13 publications

The Role of Up-Regulated Serine Proteases and Matrix Metalloproteinases in the Pathogenesis of a Murine Model of Colitis

The Role of Up-Regulated Serine Proteases and Matrix Metalloproteinases in the Pathogenesis of a Murine Model of Colitis

The distinct roles of MMP-2 and MMP-9 in acute DSS colitis

Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc

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