title: Mechanism of kinin release during experimental acute pancreatitis in rats: evidence for pro- as well as anti-inflammatory roles of oedema formation.
abstract: 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.
authors.affiliation: Institute for Experimental and Clinical Pharmacology, University of Graz, A-8010 Graz, Austria. thomas.griesbacher@uni-graz.at
authors.forename: Thomas
authors.initials: T
authors.lastname: Griesbacher
authors.forename: Irmgard
authors.initials: I
authors.lastname: Rainer
authors.forename: Beate
authors.initials: B
authors.lastname: Tiran
authors.forename: Edwin
authors.initials: E
authors.lastname: Fink
authors.forename: Fred
authors.initials: F
authors.lastname: Lembeck
authors.forename: Bernhard A
authors.initials: BA
authors.lastname: Peskar
mesh_terms: D000208:Acute Disease; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002108:Ceruletide; D004487:Edema / Q000378:metabolism / Q000503:physiopathology*; D004789:Enzyme Activation; D005260:Female; D007704:Kininogens / Q000378:metabolism; D007705:Kinins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D020842:Plasma Kallikrein / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors; D015842:Serine Proteinase Inhibitors / Q000378:metabolism; D020840:Tissue Kallikreins / Q000378:metabolism; D014362:Trypsinogen / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007704:Kininogens; D007705:Kinins; D011956:Receptors, Cell Surface; D015842:Serine Proteinase Inhibitors; D000515:alpha 1-Antitrypsin; D000511:alpha-Macroglobulins; C065679:icatibant; D002108:Ceruletide; D014362:Trypsinogen; D020842:Plasma Kallikrein; D020840:Tissue Kallikreins; D001920:Bradykinin