THE PLASMINOGEN ACTIVATOR PLASMIN SYSTEM IS UP-REGULATED AFTER ACUTE NECROTIZING PANCREATITIS IN HUMAN-BEINGS/

Background. Proteolysis and formation of new extracellular matrix comp onents are important mechanisms in tissue remodeling and repair: In th is study we analyzed the expression and distribution of the urokinase plasminogen activator (uPA), its membrane receptor (urokinase plasmino gen activator receptor [uPAR]), and its inhibitor (plasminogen activat or inhibitor-1 [PAI-1]) in acute necrotizing pancreatitis in human bei ngs. In, addition, we studied the concomitant expression of transformi ng 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 Norther n blot analysis, the expression and cellular distribution of uPA, uPAR , PAI-1, and TGF-beta(1) were determined in 12 normal pancreata obtain ed from organ donors and 12 pancreatic tissues obtained from patients undergoing operation because of complications of acute necrotizing pan creatitis. Results. Northern blot analysis showed enhanced expression of uPA, uPAR, and PAI-1 in eight of 12, seven of 12, and nine of 12 ne crotizing pancreatitis samples, respectively, compared with normal con trol samples. In addition, increased TGF-beta(1) mRNA expression was p resent in eight of 12 necrotizing pancreatitis samples. In contrast, a mylase 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 ce lls adjacent to the necrotic tissue areas. In contrast, acinar and duc tal cells that were located farther from pancreatic necrosis exhibited less uPA and uPAR immunoreactivity. A similar staining pattern in sam ples of necrotizing pancreatitis was found for TGF-beta(1). Conclusion s. Up-regulation of uPA and uPAR, which activate proteolysis, might cr eate a milieu that enhances lysis and removal of pancreatic necrosis. The increase in TGF-beta(1) might result from the enhanced catalytic c onversion of its precursors by uPA, which subsequently might stimulate formation of extracellular matrix, formation of granulation tissue, a nd fibrosis.