Activation of the kallikrein-kinin system in arthritis and enterocolitis in genetically susceptible rats: modulation by a selective plasma kallikrein inhibitor.
We have developed models of acute and chronic inflammatory arthritis and enterocolitis using peptidoglycan-polysaccharide injected intraperitoneally or subserosally (intramurally) into the distal ileum and cecum. Acute inflammation occurs in both Buffalo and Lewis rats, characterized by inflammation of the injected areas of the intestine. However, only the genetically susceptible Lewis rat develops chronic synovitis and joint erosion or adhesions and granulomatous enterocolitis. In the Lewis rat but not the Buffalo rat, these changes are accompanied by a decrease in plasma prekallikrein and high-molecular-weight kininogen, reflecting activation of the kallikrein-kinin system. Pretreatment with a specific plasma kallikrein inhibitor modulates the acute and chronic arthritis. The same inhibitor partially abrogates the acute changes characteristic of enterocolitis, and preliminary data suggest similar results in the chronic model. The results of these studies indicate that the kallikrein-kinin system plays an important role in arthritis and enterocolitis induced by bacterial products and that kallikrein inhibitors are potential therapeutic agents for inflammatory arthritis and inflammatory bowel disease.
Colman
R W
RW
Sol Sherry Thrombosis Research Center, USA.
Stadnicki
A
A
Kettner
C A
CA
Adam
A A
AA
DeLa Cadena
R A
RA
Sartor
R B
RB
D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D001896:Boron Compounds / Q000494:pharmacology*; D004195:Disease Models, Animal; D004760:Enterocolitis / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007249:Inflammation; D007596:Joints / Q000473:pathology; D007610:Kallikreins / Q000037:antagonists & inhibitors*; D007704:Kininogens / Q000378:metabolism; D007705:Kinins / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D011915:Rats, Inbred BUF; D011917:Rats, Inbred Lew
D000209:Acute-Phase Proteins; D001896:Boron Compounds; D004791:Enzyme Inhibitors; D007704:Kininogens; D007705:Kinins; D009842:Oligopeptides; C099457:benzoyl-prolyl-phenylalanyl-boroarginine; D007610:Kallikreins