Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001339 (acute pancreatitis)
 10,593 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activation of the kallikrein-kinin system is thought to be one of the pathophysiological factors in acute pancreatitis. A radioimmunoassay for porcine, pancreatic tissue kallikrein was developed and used to measure levels in normal plasma and peritoneal fluid and in experimental, bile-induced (group A) and bile trypsin-induced (group B) acute pancreatitis in the pig. Normal porcine plasma and peritoneal fluid contained about 2.17 +/- 0.11 and 1.91 +/- 0.19 microgram/l (SEM) tissue kallikrein, respectively. In experimental, acute pancreatitis there was a rapid rise in the plasma level of tissue kallikrein, followed by a slow increase to a final value of about 150% of the normal plasma level in both groups. In the peritoneal exudate a large increase (200-fold in group A and 2,000-fold in group B) in tissue kallikrein was seen, with a maximum within about 1/3 of the survival time, followed by a slow decrease until death in group B. In group A a smaller second peak was seen at about 2/3 of the survival time. Gelfiltration of peritoneal exudates showed complexes with alpha 1-, alpha 2-macroglobulin (alpha 1 alpha 2-M), and alpha 1-proteinase inhibitor (alpha 1-PI) and a large portion of free tissue kallikrein. The complexes with alpha 1 alpha 2-M and the free tissue kallikrein were found to be enzymatically active when tested on chromogenic tripeptide substrate. The presence of large amounts of free and active tissue kallikrein in the peritoneal exudate leads us to the conclusion that tissue kallikrein may be a major cause of local release of kinins in acute pancreatitis.
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PMID:Studies on the release of tissue kallikrein in experimental pancreatitis in the pig. 800 67

The clinical course of acute pancreatitis is strongly influenced by secondary cardiac, pulmonary and renal damage. The aim of the present study was to gather information about the compartment promoting the systemic damage. Therefore the activity of lipase, phospholipase A and plasma pro-kallikrein and the concentration of tissue kallikrein and kininogen were measured in portal venous blood, pancreatic lymph and peritoneal exudate. Anaesthetized pigs were subjected to fluid resuscitation to keep systemic haemodynamic parameters constant. The pancreas was isolated in situ. The pigs were randomly assigned to a control group (n = 9) or one of the two pancreatitis groups (n = 10 each). Pancreatitis was induced by i.a. infusion of free fatty acid (FFS) or retrograde infusion of 5% sodium taurocholate intraductally (NaT). In both pancreatitis groups the activity of lipase and phospholipase A increased. The most pronounced changes were seen in the peritoneal exudate (phospholipase A activity 40 min after induction: control 10.0 U/l, NaT 72.2 U/l). In both pancreatitis groups there was evidence for activation of the tissue kallikrein kinin system in the form of an increase in the kallikrein concentration and a decrease in the kininogen concentration. Again the changes were most pronounced in the peritoneal exudate (tissue kallikrein 40 min after induction: control 14.7 ng/ml, NaT 452 ng/ml).
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PMID:[Enzyme liberation and activation of the kallikrein-kinin system in experimental pancreatitis. Studies of portal vein blood, pancreatic lymph and peritoneal effusion]. 832 7

The activation of the kallikrein-kinin system is thought to be one of the pathophysiologic mechanisms in acute pancreatitis. A radioimmunoassay for human urinary tissue kallikrein was developed and used to measure tissue kallikrein peritoneal exudate and plasma from 48 patients with severe acute pancreatitis. All patients were treated with intraperitoneal lavage. One group (n = 22) received high doses of the protease inhibitor aprotinin (aprotinin group), and the other group, saline (control group). Levels of kallistatin in peritoneal exudates and plasma were measured with an enzyme immunoassay. A large increase in tissue kallikrein was observed in the peritoneal exudate, which declined in both groups after multiple lavages. Complexing of liberated tissue kallikrein with kallistatin was evidenced by gel filtration in both peritoneal exudates and plasma in both groups. The decrease in kallistatin observed in both peritoneal exudate and plasma is therefore regarded as being due not only to repeated lavage, but also to true consumption of the binding protein. Some of the liberated tissue kallikrein in the peritoneal fluid and plasma was complexed to aprotinin. In the control group, six patients were operated on because of pancreatic necrosis, compared with none in the aprotinin group. The levels of tissue kallikrein in the lavage fluid were lower in the control group, but this was the result of the very low tissue kallikrein values in the six patients operated on for pancreatic necrosis. Levels of kallistatin in plasma and peritoneal exudate in these six patients were lower on the day of admission compared with the other patients, and the plasma levels continued to be lower during the first week. Large amounts of tissue kallikrein were found to be released into the peritoneal exudates in acute pancreatitis. Lavages effectively cleared the released tissue kallikrein. The tissue kallikrein was complexed to kallistatin, whereas in the aprotinin group, also to aprotinin both in plasma and in peritoneal fluid. The partitioning of kallikrein between the two inhibitors was the result of the interaction between enzyme and inhibitors and the turnover of the complexes formed. The low admission levels of kallistatin in the six patients operated on because of pancreatic necrosis suggest that kallistatin may act as an early marker of severity in acute pancreatitis.
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PMID:Tissue kallikrein in severe acute pancreatitis in patients treated with high-dose intraperitoneal aprotinin. 1054 91

It was determined earlier that inhibition of the action of endogenous kinins by the bradykinin B2 antagonist, icatibant (Hoe-140; D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin), prevents pancreatic oedema formation during caerulein-induced acute pancreatitis, and simultaneously improves the egress of activated pancreatic enzymes from the pancreas. We have now investigated whether inhibition of increases in vascular permeability by another approach, i.e., pretreatment with dexamethasone, would have comparable effects. In addition, preliminary data are presented on the effects of the selective low molecular weight inhibitor of tissue kallikrein, H-(4-Cl)-D-Phe-1Nal-(3-aminopropyl)-guanidine (CH-2856). Icatibant abolished plasma extravasation into the pancreatic tissue and prevented the development of hypovolaemia. Caerulein-induced increases of amylase activity in the pancreas were significantly reduced by icatibant, while amylase activity in blood was augmented. Inhibition of kinin generation by CH-2856 had similar effects, as oedema formation was inhibited and enzyme activities were reduced in the pancreas and augmented in the blood serum. Dexamethasone completely abolished oedema formation, but only partially inhibited the development of hypovolaemia and haemoconcentration. Amylase activities in the pancreas and in blood remained completely unaffected by dexamethasone. The results suggest that retention of activated enzymes in the pancreatic tissue during acute pancreatitis involves a B2 receptor-mediated, but glucocorticoid-insensitive mechanism.
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PMID:Inhibition of kinin action and kinin generation compared to dexamethasone pretreatment with respect to vascular effects and pancreatic enzymes in experimental acute pancreatitis. 1059 56

In order to investigate the mechanism of kinin release leading to vascular symptoms in acute interstitial-oedematous pancreatitis, the novel, selective inhibitors of tissue kallikrein, (2S,2'R)-2-(2'-amino-3'-(4'-chlorophenyl)propanoylamino)-N-(3-guanidinopropyl)-3-(1-naphthyl)propanoamide (FE999024, CH-2856), and of plasma kallikrein, (2'S,2"R)-4-(2'-(2"(carboxymethylamino)-3"-cyclohexyl-propanoylamino)-3'-phenyl-propanoylamino)piperidine-1-carboxamidin (FE999026, CH-4215), were used in experimental caerulein-induced pancreatitis in rats. Oedema formation and plasma protein extravasation during the 2 h infusion of caerulein were inhibited in a dose-dependent manner by i.p. pretreatment with FE999024 (7-60 micromol kg(-1)) while FE999026 had no effect at the same doses. Haemoconcentration and hypovolaemia associated with the pancreatic oedema formation during pancreatitis were significantly attenuated by FE999024 at a dose of 20 micro mol kg(-1). The reduction in circulating plasma volume was not affected by FE999026. Accumulation of amylase and lipase in the pancreas was dose-dependently reduced by FE999024 while enzyme activities in the blood serum were increased by FE999024 at 60 micromol kg(-1) indicating improved enzyme removal from the tissue. Enzyme activities in the tissue and in the blood remained unaffected by FE999026. FE999024 (20 micromol kg(-1)) largely inhibited increased tissue kallikrein-like activity in the pancreas during acute pancreatitis and also strongly attenuated influx of plasma kallikrein into the tissue. FE999026 (20 micromol kg(-1)) significantly inhibited plasma kallikrein-like activity in the pancreas but had no effect on tissue kallikrein-like activity. In conclusion, vascular kinin-mediated symptoms observed during oedematous pancreatitis in the rat are caused by the action of tissue kallikrein in the pancreas whereas an involvement of plasma kallikrein seems to be unlikely.
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PMID:Involvement of tissue kallikrein but not plasma kallikrein in the development of symptoms mediated by endogenous kinins in acute pancreatitis in rats. 1238 83

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.
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PMID:Mechanism of kinin release during experimental acute pancreatitis in rats: evidence for pro- as well as anti-inflammatory roles of oedema formation. 1277 Sep 35

Kallikreins are serine proteases, which are divided into plasma kallikrein and tissue kallikrein. Kallikreins cleave kininogen, theirs main substrate to release bradykinin, a potent inflammatory mediator. Kinins act directly by B2 and B1 receptors, or indirectly stimulating synthesis of nitric oxide, prostanoids and cytokinines by epithelial cells, smooth muscle cells, endothelial cells and fibroblasts. Recent experimental studies and clinical data indicate a pathogenic role of the kallikrein-kinin system in gastrointestinal disorders including inflammatory bowel disease, acute pancreatitis, colorectal and gastric cancer and pathogenesis of ascites. New molecular biology techniques and development of specific antibodies permit to evaluate the expression of genes and localization of proteins of the kallikrein-kinin components. Experimental studies indicate a modulatory effect of a specific kallikrein inhibition and kinin receptor antagonist suggesting its therapeutic potential in human gut diseases.
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PMID:[A role of kallikrein-kinin system in gut diseases]. 1623 27