Inhibition of plasma kallikrein prevents peptidoglycan-induced arthritis in the Lewis rat.
We investigate whether the previously shown contact system activation plays a pathogenetic role in a rat model of acute inflammation induced by peptidoglycan-polysaccharide (PG-APS) using a new specific plasma kallikrein inhibitor, Bz-Pro-Phe-boroArg-OH (P8720). Group I (control) received neither PG-APS nor inhibitor. Group II (disease-treated) received PG-APS intraperitoneally (IP) and P8720 orally. Group III (disease-untreated) received PG-APS IP. Anemia was evident at 49 h in group III but was not present (P < 0.01) in groups I and II. Spleen weight was significantly decreased in group II compared to group III. Acute arthritis progressively developed in group III from 27 to 49 h, but P8720 decreased the joint swelling in group II by 61% (P < 0.0005). We observed a significant fall in prekallikrein and factor XI (P < 0.01) in groups II and III but not in group I. The decrease in the functional levels of high molecular weight kininogen (P < 0.05) observed in group III were prevented by P8720 in group II. The changes in T-kininogen and alpha 1-inhibitor 3 acute-phase proteins were partially prevented by P8720. We conclude that the inflammatory reactions leading to arthritis and anemia, as well as the acute-phase reaction, are due in part to contact activation, and that specific kallikrein inhibitors may have therapeutic potential.
Dela Cadena
R A
RA
Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.
Stadnicki
A
A
Uknis
A B
AB
Sartor
R B
RB
Kettner
C A
CA
Adam
A
A
Colman
R W
RW
D000209:Acute-Phase Proteins; D000595:Amino Acid Sequence; D000818:Animals; D001168:Arthritis / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D005260:Female; D007610:Kallikreins / Q000037:antagonists & inhibitors*; D007704:Kininogens / Q000097:blood; D008969:Molecular Sequence Data; D010457:Peptidoglycan; D011480:Protease Inhibitors / Q000097:blood; D051381:Rats; D011917:Rats, Inbred Lew
D000209:Acute-Phase Proteins; D007704:Kininogens; D010457:Peptidoglycan; D011480:Protease Inhibitors; C017894:alpha 1-inhibitor 3; D007610:Kallikreins