Enhanced urokinase plasminogen activation in chronic pancreatitis suggests a role in its pathogenesis.
OBJECTIVE
Urokinase plasminogen activator (uPA) regulates plasmin generation from plasminogen. The aim of this study was to analyze the role of the plasminogen activator/plasmin system in chronic pancreatitis (CP).


METHODS
Using Northern blot analysis, in situ hybridization, and immunohistochemistry, the expression of uPA, its receptor (uPAR), plasminogen activator inhibitor 1 (PAI-1), and transforming growth factor beta 1 (TGF-beta 1) was studied in 14 patients undergoing pancreatic resection for CP. Normal control pancreatic tissue was obtained through an organ donor program.


RESULTS
Eight of 14 CP samples showed concomitant increased expression (P < 0.001) of uPA (5.2-fold), uPAR (5.9-fold), and TGF-beta 1 (8.8-fold) messenger RNA (mRNA) compared with normal controls. PAI-1 mRNA expression was increased (6.5-fold; P < 0.001) in all CP samples. By in situ hybridization, moderate to strong mRNA staining of all four factors was present in acinar cells, some ductal cells, and areas with ductal metaplasia in CP samples. A similar staining pattern was found by immunohistochemistry. Intense mRNA and immunostaining for all of these factors in CP samples was associated with a higher degree of pancreatic damage.


CONCLUSIONS
uPA and its receptor may contribute to the lytic damage observed in CP by plasmin generation. Similarly, increased amounts of plasmin may activate latent TGF-beta, thereby leading to the accumulation of fibrotic tissue.
Friess
H
H
Department of Visceral and Transplantation Surgery, University of Bern, Inselspital, Switzerland.
Cantero
D
D
Graber
H
H
Tang
W H
WH
Guo
X
X
Kashiwagi
M
M
Zimmermann
A
A
Gold
L
L
Korc
M
M
Büchler
M W
MW
D000293:Adolescent; D000328:Adult; D000368:Aged; D015152:Blotting, Northern; D002908:Chronic Disease; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D010179:Pancreas / Q000601:surgery; D010195:Pancreatitis / Q000209:etiology* / Q000503:physiopathology* / Q000601:surgery; D010960:Plasminogen Activators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015849:Plasminogen Inactivators / Q000502:physiology; D011956:Receptors, Cell Surface / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D013194:Staining and Labeling; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism / Q000502:physiology*
C524898:PLAUR protein, human; D015849:Plasminogen Inactivators; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D016212:Transforming Growth Factor beta; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator