The role of up-regulated serine proteases and matrix metalloproteinases in the pathogenesis of a murine model of colitis

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 -