TY - JOUR
T1 - The role of up-regulated serine proteases and matrix metalloproteinases in the pathogenesis of a murine model of colitis
AU - Tarlton, J F
AU - Whiting, C V
AU - Tunmore, D
AU - Bregenholt, S
AU - Reimann, J
AU - Claesson, Mogens Helweg
AU - Bland, P W
PY - 2000/12/1
Y1 - 2000/12/1
N2 - 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. Transmural inflammation was associated with serine proteinase and MMP activity in overlying epithelium and with marked subepithelial proteolytic activity. The results demonstrate a clear elevation in the levels and activation of proteases in colitis, potentially contributing to disease progression through loss of epithelial barrier function.
AB - 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. Transmural inflammation was associated with serine proteinase and MMP activity in overlying epithelium and with marked subepithelial proteolytic activity. The results demonstrate a clear elevation in the levels and activation of proteases in colitis, potentially contributing to disease progression through loss of epithelial barrier function.
KW - Animals
KW - CD4-Positive T-Lymphocytes
KW - Cell Movement
KW - Colitis
KW - Colon
KW - Disease Models, Animal
KW - Endopeptidases
KW - Enzyme Activation
KW - Epithelium
KW - Extracellular Matrix
KW - Feces
KW - Intestinal Mucosa
KW - Leukocytes
KW - Matrix Metalloproteinases
KW - Mice
KW - Mice, Inbred Strains
KW - Mice, SCID
KW - Serine Endopeptidases
KW - Severity of Illness Index
KW - Up-Regulation
U2 - 10.1016/S0002-9440(10)64831-6
DO - 10.1016/S0002-9440(10)64831-6
M3 - Journal article
C2 - 11106565
SN - 0002-9440
VL - 157
SP - 1927
EP - 1935
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -