Basic Research
Copyright ©2006 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Oct 28, 2006; 12(40): 6464-6472
Published online Oct 28, 2006. doi: 10.3748/wjg.v12.i40.6464
Attenuation of dextran sodium sulphate induced colitis in matrix metalloproteinase-9 deficient mice
Alfredo Santana, Carlos Medina, Maria Cristina Paz-Cabrera, Federico Díaz-Gonzalez, Esther Farré, Antonio Salas, Marek W Radomski, Enrique Quintero
Alfredo Santana, Carlos Medina, Maria Cristina Paz-Cabrera, Enrique Quintero, Gastroenterology Department and Research Unit, Hospital Universitario de Canarias, Tenerife, Spain
Federico Díaz-Gonzalez, Reumathology Department, Hospital Universitario de Canrias, Tenerife, Spain
Esther Farré, Antonio Salas, Pathology Department, Hospital Mutua de Terrassa, Barcelona, Spain
Marek W Radomski, Institute of Molecular Medicine, University of Texas, Houston-Texas, United States
Supported by Instituto de Salud Carlos III (C03/02), FEDER funds, Fundación Canaria de Investigación (PI 21/02), and Spanish Ministry of Education to CM (EX2004-0396)
Correspondence to: Enrique Quintero, MD, PhD, Servicio de Aparato Digestivo, Hospital Universitario de Canarias, Ofra S/N, La Laguna 38320, Tenerife, Spain. gastrohuc@gmail.com
Telephone: +34-922-678554
Received: April 10, 2006
Revised: July 12, 2006
Accepted: September 4, 2006
Published online: October 28, 2006
Abstract

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-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 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.

Keywords: Matrix metalloproteinases, MMP-9-deficient, Dextran sodium sulphate, Inflammatory bowel disease, Experimental colitis