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Attenuation of dextran sodium sulphate induced colitis in matrix metalloproteinase-9 deficient mice

World Journal of Gastroenterology 2006年第40期12卷 6464-6472页

作者： Alfredo Santana Carlos Medina Maria Cristina Paz-Cabrera Federico Díaz-Gonzalez Esther Farré Antonio Salas Marek W Radomski Enrique Quintero Gastroenterology Department and Research Unit Hospital Universitario de Canarias Tenerife Spain Reumathology Department Hospital Universitario de Canrias Tenerife Spain Pathology Department Hospital Mutua de Terrassa Barcelona Spain Institute of Molecular Medicine University of Texas Houston-Texas United States

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 ***: 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-α 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-α 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 epithelialinjury 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 modu-lated by MMP-9 and that inhibition of this gelatinase may reduce inflammation.

关键词： Matrix metalloproteinases MMP-9-deficient dextran sodium sulphate Inflammatory bowel disease Experimental colitis

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