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Murine Colitis Modeling using Dextran Sulfate Sodium (DSS)
Published on: January 19, 2010
Attenuation of dextran sodium sulphate induced colitis in matrix metalloproteinase-9 deficient mice
Alfredo Santana1, Carlos Medina, Maria-Cristina Paz-Cabrera
1Gastroenterology Department and Research Unit, Hospital Universitario de Canarias, Tenerife, Spain.
Aim:
To study whether matrix metalloproteinase-9 (MMP-9) is a key factor in epithelial damage in the dextran sodium sulphate (DSS) model of colitis in mice.
Methods:
MMP-9-deficient and wild-type (wt) mice were given 5% DSS in drinking water for 5 d followed by recovery up to 7 d. On d 5 and 12 after induction of colitis, gelatinases, MMP-2 and MMP-9, were measured in homogenates of colonic tissue by zymography and Western blot, whereas tissue inhibitor of metalloproteinases (TIMPs) were measured by reverse zymography. The gelatinolytic activity was also determined in supernatants of polymorphonuclear leukocytes (PMN) isolated from mice blood. Moreover, intestinal epithelial cells were stimulated with TNF-alpha to study whether these cells were able to produce MMPs. Finally, colonic mucosal lesions were measured by microscopic examination.
Results:
On d 5 of colitis, the activity of MMP-9 was increased in homogenates of colonic tissues (0.24+/-0.1 vs 21.3+/-6.4, P<0.05) and PMN from peripheral blood in wt (0.5+/-0.1 vs 10.4+/-0.7, P<0.05), but not in MMP-9-deficient animals. The MMP-9 activity was also up-regulated by TNF-alpha in epithelial intestinal cells (2.5+/-0.5 vs 14.7+/-3.0, P<0.05). Although colitis also led to increase of TIMP-1 activity, the MMP-9/TIMP-1 balance remained elevated. Finally, in the MMP-9-deficient colitic mice both the extent and severity of intestinal epithelial injury were significantly attenuated when compared with wt mice.
Conclusion:
We conclude that DSS induced colitis is markedly attenuated in animals lacking MMP-9. This suggests that intestinal injury induced by DSS is modulated by MMP-9 and that inhibition of this gelatinase may reduce inflammation.
Insights
Matrix metalloproteinase-9 (MMP-9) plays a key role in dextran sodium sulphate (DSS) induced colitis. MMP-9 deficiency significantly reduces intestinal epithelial damage and inflammation in this colitis model.
Area of Science:
- Gastroenterology
- Immunology
- Molecular Biology
Background:
- Inflammatory bowel disease (IBD) pathogenesis involves complex interactions between the immune system and the intestinal epithelium.
- Matrix metalloproteinases (MMPs) are enzymes implicated in tissue remodeling and inflammation, but their specific role in colitis requires further elucidation.
Purpose of the Study:
- To investigate the role of matrix metalloproteinase-9 (MMP-9) in epithelial damage during dextran sodium sulphate (DSS)-induced colitis in mice.
- To determine if MMP-9 is a critical mediator of intestinal injury in this experimental colitis model.
Main Methods:
- Comparison of MMP-9-deficient and wild-type mice subjected to DSS-induced colitis.
- Assessment of MMP-9 and MMP-2 activity using zymography and Western blot in colonic tissue and peripheral blood polymorphonuclear leukocytes (PMNs).
- Measurement of tissue inhibitor of metalloproteinases (TIMPs) and colonic mucosal lesions via microscopic examination.
Main Results:
- MMP-9 activity was significantly elevated in wild-type mice during DSS colitis but absent in MMP-9-deficient mice.
- Tumor necrosis factor-alpha (TNF-alpha) upregulated MMP-9 production in intestinal epithelial cells.
- Mice lacking MMP-9 exhibited significantly reduced intestinal epithelial injury and attenuated colitis severity compared to wild-type controls.
Conclusions:
- DSS-induced colitis is markedly attenuated in the absence of MMP-9.
- MMP-9 plays a significant role in modulating intestinal injury during DSS colitis.
- Inhibition of MMP-9 may represent a therapeutic strategy for reducing inflammation in colitis.