Griesbacher Thomas, Rainer Irmgard, Tiran Beate, Fink Edwin, Lembeck Fred, Peskar Bernhard A
Institute for Experimental and Clinical Pharmacology, University of Graz, A-8010 Graz, Austria.
Br J Pharmacol. 2003 May;139(2):299-308. doi: 10.1038/sj.bjp.0705247.
1 Kinin B(2) receptor antagonists or tissue kallikrein (t-KK) inhibitors prevent oedema formation and associated sequelae in caerulein-induced pancreatitis in the rat. We have now further investigated the mechanism of kinin generation in the pancreas. 2 Kinins were elevated in the pancreatic tissue already before oedema formation became manifest. Peak values (421+/-59 pmol g(-1) dry wt) were reached at 45 min and remained elevated for at least 2 h; a second increase was observed at 24 h. Pretreatment with the B(2) receptor antagonist icatibant abolished kinin formation, while post-treatment was ineffective. 3 Total kininogen levels were very low in the pancreas of controls, but increased 75-fold during acute pancreatitis. This increase was absent in rats that were pretreated with icatibant. 4 During pancreatitis, t-KK-like and plasma kallikrein (p-KK)-like activity in the pancreas, as well as trypsinogen activation peptide (TAP) increased significantly. Icatibant pretreatment further augmented t-KK about 100-fold, while p-KK was significantly attenuated; TAP levels remained unaffected. 5 Endogenous protease inhibitors (alpha(1)-antitrypsin, alpha(2)-macroglobulin) were low in normal tissues, but increased 45- and four-fold, respectively, during pancreatitis. This increase was abolished when oedema formation was prevented by icatibant. 6 In summary, oedema formation is initiated by t-KK; the ensuing plasma protein extravasation supplies further kininogen and active p-KK to the tissue. Concomitantly, endogenous protease inhibitors in the oedema fluid inhibit up to 99% of active t-KK. Our data thus suggest a complex interaction between kinin action and kinin generation involving positive and negative feedback actions of the inflammatory oedema.
1 激肽B2受体拮抗剂或组织激肽释放酶（t-KK）抑制剂可预防大鼠蛙皮素诱导的胰腺炎中的水肿形成及相关后遗症。我们现在进一步研究了胰腺中激肽生成的机制。2 在水肿形成明显之前，胰腺组织中的激肽就已升高。在45分钟时达到峰值（421±59 pmol g-1干重），并至少持续升高2小时；在24小时时观察到第二次升高。用B2受体拮抗剂依替巴肽预处理可消除激肽形成，而后处理则无效。3 对照组胰腺中的总激肽原水平非常低，但在急性胰腺炎期间增加了75倍。在用依替巴肽预处理的大鼠中没有这种增加。4 在胰腺炎期间，胰腺中的t-KK样和血浆激肽释放酶（p-KK）样活性以及胰蛋白酶原激活肽（TAP）显著增加。依替巴肽预处理进一步使t-KK增加约100倍，而p-KK则显著减弱；TAP水平不受影响。5 内源性蛋白酶抑制剂（α1-抗胰蛋白酶、α2-巨球蛋白）在正常组织中含量较低，但在胰腺炎期间分别增加了45倍和4倍。当依替巴肽预防水肿形成时，这种增加被消除。6 总之，水肿形成由t-KK启动；随后的血浆蛋白外渗为组织提供了更多的激肽原和活性p-KK。同时，水肿液中的内源性蛋白酶抑制剂可抑制高达99%的活性t-KK。因此，我们的数据表明激肽作用和激肽生成之间存在复杂的相互作用，涉及炎症水肿的正负反馈作用。
