Specific inhibition of plasma kallikrein modulates chronic granulomatous intestinal and systemic inflammation in genetically susceptible rats.
The kallikrein-kinin (K-K) (contact) system is activated during acute and chronic relapsing phases of enterocolitis induced in genetically susceptible Lewis rats by intramural injection of peptidoglycan-polysaccharide (PG-APS). Using the selective plasma kallikrein inhibitor P8720, we investigate whether activation of the K-K system plays a primary role in chronic granulomatous intestinal and systemic inflammation in this model. Group I (negative control) received human serum albumin intramurally. Group II (treatment) received PG-APS intramurally and P8720 orally. Group III (positive control) received PG-APS intramurally and albumin orally. P8720 attenuated the consumption of the contact proteins, high molecular weight kininogen (P<0.03), and factor XI (P<0.04) in group II vs. group III. P8720 decreased chronic intestinal inflammation measured by blinded gross (P<0.01) and histologic (P<0.0005) scores as well as systemic complications (arthritis, splenomegaly, hepatomegaly, leukocytosis, and acute-phase reaction) (P<0.01) in group II as compared with group III. We conclude that relapsing chronic enterocolitis and systemic complications are in part due to plasma K-K system activation, and that inhibition of this pathway is a potential therapeutic approach to human inflammatory bowel disease and associated extraintestinal manifestations.
Stadnicki
A
A
Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Sartor
R B
RB
Janardham
R
R
Majluf-Cruz
A
A
Kettner
C A
CA
Adam
A A
AA
Colman
R W
RW
D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D001896:Boron Compounds / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D005172:Factor XI / Q000378:metabolism; D005260:Female; D006105:Granulomatous Disease, Chronic / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation; D007410:Intestinal Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D007610:Kallikreins / Q000037:antagonists & inhibitors*; D007704:Kininogens / Q000378:metabolism; D009842:Oligopeptides / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D010457:Peptidoglycan / Q000494:pharmacology; D011288:Prekallikrein / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew
D000209:Acute-Phase Proteins; D001896:Boron Compounds; D004791:Enzyme Inhibitors; D007704:Kininogens; D009842:Oligopeptides; D010457:Peptidoglycan; C099457:benzoyl-prolyl-phenylalanyl-boroarginine; D005172:Factor XI; D011288:Prekallikrein; D007610:Kallikreins