Selective kallikrein inhibitors alter human neutrophil elastase release during extracorporeal circulation.
Cardiopulmonary bypass causes hemorrhagic complications and initiates a biochemical and cellular "whole body inflammatory response." This study investigates whether a variety of selective inhibitors of the contact pathway of intrinsic coagulation modulate complement and neutrophil activation during simulated extracorporeal circulation. After 60 min of recirculation in the presence of the slow tight-binding boronic acid inhibitor, Bz-Pro-Phe-boroArg-OH (10.7 microM), complete inhibition of kallikrein-C1-inhibitor complex formation and marked inhibition of C1-C1-inhibitor complex formation and the release of human neutrophil elastase were observed. Arg15-aprotinin (3.1 microM), Ala357,Arg358 alpha 1-antitrypsin (2.6 microM), and soybean trypsin inhibitor (48.0 microM) either completely or partially inhibited the generation of kallikrein-C1-inhibitor complexes but were less effective inhibitors of human neutrophil elastase release. The second-order rate constants for the inhibition of kallikrein in purified systems are consistent with the order of effectiveness of the inhibitors in blocking human neutrophil elastase release in heparinized blood. Our results suggest that low-molecular-weight selective inhibitors of kallikrein may be effective agents in the attenuation of the contact-mediated inflammatory response in cardiopulmonary bypass.
Wachtfogel
Y T
YT
Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia 19140.
Hack
C E
CE
Nuijens
J H
JH
Kettner
C
C
Reilly
T M
TM
Knabb
R M
RM
Bischoff
R
R
Tschesche
H
H
Wenzel
H
H
Kucich
U
U
D000595:Amino Acid Sequence; D007611:Aprotinin / Q000494:pharmacology; D001777:Blood Coagulation; D001896:Boron Compounds / Q000737:chemistry / Q000494:pharmacology; D002315:Cardiopulmonary Bypass / Q000009:adverse effects; D003171:Complement Pathway, Classical; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007610:Kallikreins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D019272:Leukocyte Elastase / Q000378:metabolism*; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D010196:Pancreatic Elastase / Q000378:metabolism*; D010974:Platelet Aggregation; D014361:Trypsin Inhibitors / Q000494:pharmacology; D000515:alpha 1-Antitrypsin / Q000494:pharmacology
D001896:Boron Compounds; D009842:Oligopeptides; D014361:Trypsin Inhibitors; D000515:alpha 1-Antitrypsin; C043017:trasylol, Arg(15)-; C066062:t-butyloxycarbonyl-phenylalanyl-prolyl-boroarginine-C10H16; D006493:Heparin; D007611:Aprotinin; D007610:Kallikreins; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase