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


CONCLUSIONS
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.
Santana
Alfredo
A
Gastroenterology Department and Research Unit, Hospital Universitario de Canarias, Tenerife, Spain.
Medina
Carlos
C
Paz-Cabrera
Maria-Cristina
MC
Díaz-Gonzalez
Federico
F
Farré
Esther
E
Salas
Antonio
A
Radomski
Marek-W
MW
Quintero
Enrique
E
D000818:Animals; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology* / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate; D020780:Matrix Metalloproteinase 9