Friess H, Duarte R, Kleeff J, Fukuda A, Tang W H, Graber H, Schilling M, Zimmermann A, Korc M, Büchler M W
Department of Visceral and Transplantation Surgery, University of Bern, Inselspital, Switzerland.
Surgery. 1998 Jul;124(1):79-86.
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.
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.
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.
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.
蛋白水解作用和新的细胞外基质成分的形成是组织重塑和修复的重要机制。在本研究中，我们分析了尿激酶型纤溶酶原激活剂（uPA）、其膜受体（尿激酶型纤溶酶原激活剂受体[uPAR]）及其抑制剂（纤溶酶原激活剂抑制剂-1[PAI-1]）在人类急性坏死性胰腺炎中的表达和分布。此外，我们研究了转化生长因子-β1（TGF-β1）的伴随表达，TGF-β1由uPA从前体激活而来，是细胞外基质形成的有力调节因子和刺激因子。
采用免疫组织化学和Northern印迹分析，在12份从器官捐献者获得的正常胰腺组织以及12份因急性坏死性胰腺炎并发症接受手术的患者的胰腺组织中，测定uPA、uPAR、PAI-1和TGF-β1的表达及细胞分布。
Northern印迹分析显示，与正常对照样本相比，12份坏死性胰腺炎样本中分别有8份、7份和9份的uPA、uPAR和PAI-1表达增强。此外，12份坏死性胰腺炎样本中有8份TGF-β1 mRNA表达增加。相反，急性坏死性胰腺炎样本中淀粉酶mRNA表达明显降低。免疫组织化学显示，坏死组织区域附近剩余的腺泡和导管细胞中uPA、uPAR和PAI-1免疫反应性升高。相比之下，距离胰腺坏死较远的腺泡和导管细胞uPA和uPAR免疫反应性较低。在坏死性胰腺炎样本中，TGF-β1呈现相似的染色模式。
激活蛋白水解作用的uPA和uPAR上调，可能营造出一种促进胰腺坏死溶解和清除的环境。TGF-β1的增加可能源于uPA对其前体的催化转化增强，这随后可能刺激细胞外基质形成、肉芽组织形成和纤维化。
