The plasminogen activator/plasmin system is up-regulated after acute necrotizing pancreatitis in human beings.
BACKGROUND
Proteolysis and formation of new extracellular matrix components are important mechanisms in tissue remodeling and repair. In this study we analyzed the expression and distribution of the urokinase plasminogen activator (uPA), its membrane receptor (urokinase plasminogen activator receptor [uPAR]), and its inhibitor (plasminogen activator inhibitor-1 [PAI-1]) in acute necrotizing pancreatitis in human beings. In addition, we studied the concomitant expression of transforming growth factor-beta-1 (TGF-beta 1), which is activated by uPA from its precursor and is a potent regulator and stimulator of formation of extracellular matrix.


METHODS
With immunohistochemistry and Northern blot analysis, the expression and cellular distribution of uPA, uPAR, PAI-1, and TGF-beta 1 were determined in 12 normal pancreata obtained from organ donors and 12 pancreatic tissues obtained from patients undergoing operation because of complications of acute necrotizing pancreatitis.


RESULTS
Northern blot analysis showed enhanced expression of uPA, uPAR, and PAI-1 in eight of 12, seven of 12, and nine of 12 necrotizing pancreatitis samples, respectively, compared with normal control samples. In addition, increased TGF-beta 1 mRNA expression was present in eight of 12 necrotizing pancreatitis samples. In contrast, amylase mRNA expression was markedly decreased in the samples of acute necrotizing pancreatitis. Immunohistochemistry revealed elevated uPA, uPAR, and PAI-1 immunoreactivity in the remaining acinar and ductal cells adjacent to the necrotic tissue areas. In contrast, acinar and ductal cells that were located farther from pancreatic necrosis exhibited less uPA and uPAR immunoreactivity. A similar staining pattern in samples of necrotizing pancreatitis was found for TGF-beta 1.


CONCLUSIONS
Up-regulation of uPA and uPAR, which activate proteolysis, might create a milieu that enhances lysis and removal of pancreatic necrosis. The increase in TGF-beta 1 might result from the enhanced catalytic conversion of its precursors by uPA, which subsequently might stimulate formation of extracellular matrix, formation of granulation tissue, and fibrosis.
Friess
H
H
Department of Visceral and Transplantation Surgery, University of Bern, Inselspital, Switzerland.
Duarte
R
R
Kleeff
J
J
Fukuda
A
A
Tang
W H
WH
Graber
H
H
Schilling
M
M
Zimmermann
A
A
Korc
M
M
Büchler
M W
MW
D000293:Adolescent; D000328:Adult; D015152:Blotting, Northern; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D019283:Pancreatitis, Acute Necrotizing / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D010960:Plasminogen Activators / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
C524898:PLAUR protein, human; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D016212:Transforming Growth Factor beta; D010960:Plasminogen Activators; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator