Mechanism of kinin release during experimental acute pancreatitis in rats: evidence for pro‐ as well as anti‐inflammatory roles of oedema formation

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Abstract
Kinin B2 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. 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 B2 receptor antagonist icatibant abolished kinin formation, while post‐treatment was ineffective. 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. 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. Endogenous protease inhibitors (α1‐antitrypsin, α2‐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. 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. British Journal of Pharmacology (2003) 139, 299–308. doi:10.1038/sj.bjp.0705247